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Progress in Neurobiology 74 (2004) 127–166
The supramammillary area: its organization, functions
and relationship to the hippocampus
Wei-Xing Pana, Neil McNaughtonb,*
Department of Physiology and Center for Neuroscience, University of Otago, POB56, Dunedin, New Zealand
Department of Psychology and Center for Neuroscience, University of Otago, POB56, Dunedin, New Zealand
Received 20 March 2004; accepted 15 September 2004
The supramammillary area of the hypothalamus, although small in size, can have profound modulatory effects on the hippocampal
formation and related temporal cortex. It can control hippocampal plasticity and also has recently been shown to contain cells that determine
the frequency of hippocampal rhythmical slow activity (theta rhythm). We review here its organization and anatomical connections providing
an atlas and a new nomenclature. We then review its functions particularly in relation to its links with the hippocampus. Much of its control of
behaviour and its differential activation by specific classes of stimuli is consistent with a tight relationship with the hippocampus. However, its
ascending connections involve not only caudal areas of the cortex with close links to the hippocampus but also reciprocal connections with
more rostral areas such as the infralimbic and anterior cingulate cortices. These latter areas appear to be the most rostral part of a network that,
via the medial septum, hippocampus and lateral septum, is topographically mapped into the hypothalamus. The supramammillary area is thus
diffusely connected with areas that control emotion and cognition and receives more topographically specific return information from areas
that control cognition while also receiving ascending information from brain stem areas involved in emotion. We suggest that it is a key part of
a network that recursively transforms information to achieve integration of cognitive and emotional aspects of goal-directed behaviour.
# 2004 Elsevier Ltd. All rights reserved.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Anatomy of the supramammillary area . . . . . . . . . . . . . . . . . . . . .
2.1. The boundaries of the supramammillary area and its parts . .
2.1.1. Where is it best to place the boundary of SuM?. . . .
2.1.2. What are the parts of SuM?. . . . . . . . . . . . . . . . . .
2.1.3. Construction of an atlas of SuM. . . . . . . . . . . . . . .
2.2. The connections of SuM . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.1. Afferents to SuM . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.2. Efferents from SuM . . . . . . . . . . . . . . . . . . . . . . .
2.2.3. Neuronal types in relation to projections from SuM .
2.2.4. Neuronal types in relation to projections to SuM . . .
Neurophysiology of SuM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1. SuM and hippocampal theta activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.1. What is theta activity? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
* Corresponding author. Tel.: +64 3 479 7634; fax: +64 3 479 8335.
E-mail address: [email protected] (N. McNaughton).
0301-0082/$ – see front matter # 2004 Elsevier Ltd. All rights reserved.
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
Behaviour and c-fos activation of SuM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SuM, behavioural change and theta frequency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.1. Theta frequency change and behaviour: relative change or absolute value? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2. Changes in behaviour with no absolute change in theta frequency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SuM—an interface between cognition and emotion? . . . . . . .
7.1. SuM, behaviour and hippocampal function . . . . . . . . .
7.2. SuM, the amygdala and thalamus . . . . . . . . . . . . . . . .
7.3. SuM and forebrain control of emotion . . . . . . . . . . . .
7.4. SuM—a controller of cognitive–emotional interaction? .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.2. The septum as a pacemaker for hippocampal theta activity .
3.1.3. Integration of theta frequency by SuM under urethane . . . .
3.1.4. Descending influences controlling SuM theta activity . . . . .
3.1.5. Multiple frequency integrators in freely moving animals . . .
SuM and hippocampal modulation . . . . . . . . . . . . . . . . . . . . . . . .
Multiple influences of SuM on the hippocampus . . . . . . . . . . . . . .
dysfunction and behaviour. . . . . . . . . . . . . . . .
Methods of inducing SuM dysfunction . . . . . .
Spatial cognition . . . . . . . . . . . . . . . . . . . . .
Exploratory and defensive behaviour . . . . . . .
Behavioural inhibition. . . . . . . . . . . . . . . . . .
SuM lesions compared to hippocampal lesions.
1. Introduction
The supramammillary area (SuM) is a relatively thin,
chemically distinct, layer of cells overlying the mammillary
bodies in the hypothalamus. While relatively few in number,
the cells of this area have recently become of interest as they
appear to exert significant modulatory control over the
hippocampus and, directly and via the hippocampus,
substantial portions of the telencephalon. Thus, like the
raphe serotonergic system and the coerulear noradrenergic
system, SuM may have functional importance out of all
proportion to its size. Its connection with the hippocampus is
made early in primate development and it has been suggested
that ‘‘the early ingrowth of the excitatory SuM–hippocampal
system in human and non-human primates may contribute to
the prenatal activity-dependent development of the hippocampal formation’’, perhaps as a result of its control of
hippocampal theta activity (Berger et al., 2001).
It contrasts with the mammillary bodies in being much more
a source of input to archicortex (particularly hippocampus)
than a receptor of output from it. It also contrasts, as far as can
be told, with many other hypothalamic areas in being a specific
controller of hippocampal theta activity. It is, then, located in an
area of the brain usually associated with emotion and
motivation and not only connects with areas of the brain
thought to be involved in predominantly cognitive functions
but controls a pattern of brain activity (theta) that has been
postulated to be important for control of cognition and
particularly memory. We argue, on several different grounds,
therefore, that its modulation of telencephalic activity is
fundamental to cognitive–emotional interactions.
This claim is subject to two caveats. First, we are
claiming only a modulatory role for SuM. It is likely to pace
information around circuits but not to encode and transform
that information itself. It is likely to determine whether other
inputs produce plasticity in target structures but not to
induce plasticity solely through its own inputs. Second, as
will become clear, it is likely to be only the first discovered
of a number of (perhaps topographically organized)
structures that function in this specific way.
To both make our claim, and flesh out our caveats, we
analyse the anatomy, physiology and contributions to
behavioural function of SuM. We focus, in particular, on
the extent to which SuM may discharge behaviourally
important functions through its afferent and efferent
connections with the hippocampal formation. Our conclusions may seem to present SuM as fundamentally
controlling hippocampal function—but not only must
SuM be only one of several structures that control the
hippocampus (each, we argue under different behavioural or
cognitive circumstances) but also the hippocampus must be
only one of many widely separated structures modulated by
SuM. Some of the parallels we identify between SuM and
hippocampal function are likely, therefore, to be functions
that depend on the joint activity of many ‘‘limbic’’
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
Our specific link with the hippocampus is made by the
fact that SuM has recently been shown to contain cells
that can control plasticity in the hippocampus via
monosynaptic input. It also contains other cells that
control the frequency of the rhythmic phasic firing of
hippocampal cells (theta activity) via a relay in the medial
septum (MS). These two types of interaction with the
hippocampus are functionally separate and anatomically
distinct. But they are of such a kind (controlling general
tone and controlling the timing of firing of large
populations of cells) that it is likely that SuM neurones
play a much more important modulatory role in hippocampal function than their paucity and distance from the
hippocampus might suggest. SuM also has similar
extensive connections with many other structures and
may, then, similarly modulate many areas of the forebrain.
The hippocampus has been postulated to contribute to
cognitive functions such as spatial mapping (O’Keefe and
Nadel, 1978) and relational memory (Cohen and Eichenbaum, 1993) and emotional functions (Papez, 1937),
particularly behavioural inhibition (Gray, 1982; Gray and
McNaughton, 2000). All components of the hippocampal
formation, including the entorhinal and posterior cingulate
cortex as well as hippocampus proper (Gray and McNaughton, 2000; Leung and Borst, 1987), show theta activity. This
can be viewed as regular phasic firing controlled by
pacemaker impulses relayed to the hippocampal formation
from the MS (Brucke et al., 1959; Gogolák et al., 1968;
Petsche et al., 1962; Tömböl and Petsche, 1969). Thus, the
time at which the population of cells in the hippocampus
fires is strongly influenced by afferent theta activity that
produces regular changes in membrane potential (Bland,
1986). This control could be viewed as septal input actively
eliciting theta activity in the hippocampus. However, it is
probably better viewed as a temporal gating of activity by
phasic inhibitory input (Leung, 1998). Thus when cells are
permitted to fire is determined largely by phasic release from
inhibition (Smythe et al., 1992), but it is also influenced by
other factors (O’Keefe and Recce, 1993; Bose and Recce,
2001). By contrast, which cells fire during the appointed
time is determined by other specifically patterned inputs.
Theta activity is likely to play a significant specific role in
the cognitive and/or emotional functions of the hippocampal
formation (O’Keefe and Nadel, 1978; Gray, 1982; Miller,
1991; Gray and McNaughton, 2000) as well, perhaps, as a
more general role in the control of sensori-motor integration
(Bland and Oddie, 2002; Oddie and Bland, 1998) or sensory
inhibition (Sainsbury, 1998). The postulated power of the
control of hippocampus (and other areas like entorhinal,
posterior cingulate and possibly perirhinal cortex) by SuM
rests in the possibility that a failure of appropriate timing of
computations carried out between these structures could
result in serious degradation or even total loss of the critical
information (Miller, 1991).
The frequency of hippocampal theta activity is controlled
in part by medially placed SuM neurons (Kirk, 1993, 1997,
1998; Kirk and McNaughton, 1991, 1993). However, lateral
rather than medial areas of SuM project preferentially to the
MS (Vertes, 1992; Vertes and Kocsis, 1997; Vertes and
McKenna, 2000). There is also monosynaptic input from
more laterally placed SuM neurons (but not more medially
placed ones) to the hippocampus. The ascending pathways
that control theta and other hippocampal activity appear,
then, to be topographically organized and to be both direct
and relayed (as with the MS). The hippocampus, in turn, has
topographically organised, relayed, projections back to the
hypothalamus including SuM (Risold and Swanson, 1996).
The details of the system, then, need to be understood if its
function (and by implication that of much of the forebrain) is
to be fully understood.
SuM, at least on occasion, controls the frequency of theta
activity. Theta activity, in turn, is most associated with the
hippocampus. SuM is, therefore, likely to be important for
the behavioural functions of the hippocampus. As noted,
different parts of SuM may also contribute differentially to
hippocampal function. However, as detailed below, SuM
also has extensive connections with many other areas. We
would expect it (through similar computational mechanisms) to contribute to a variety of different functions. This
paper, therefore, reviews the neuroanatomy, neurophysiology and molecular biology of SuM, and provides a
preliminary assessment of the functions of SuM, the relation
of these functions to its known parts, and the extent to which
those functions are discharged by interaction with the
hippocampus and particularly by the control of theta activity
by SuM.
Abbreviations used in the remainder of the text are
defined in Table 1 to allow ready reference.
2. Anatomy of the supramammillary area
2.1. The boundaries of the supramammillary area and its
There are small but important differences in the definition
and dissection into parts of SuM by different researchers
(Fig. 1). We will focus below on a concordance between the
full-scale atlases of Paxinos and Watson (1998) and
Swanson (1998).
According to the rat brain atlas of Paxinos and Watson
(1998) (see Fig. 1), SuM is a small nucleus or set of nuclei,
which is about 2000 mm 500 mm 500 mm, lying above
the mammillary bodies and below the posterior hypothalamic area. The lateral area of the hypothalamus borders it
dorsolaterally. The caudal lateral part of the area is named,
by them, the lateral SuM (abbreviated by them, SuML), and
the caudal medial part is named medial SuM (SuMM), but
the rostral part is simply called SuM and is not explicitly
divided into medial and lateral parts. It is unclear from this
precisely how Paxinos and Watson separate the subnuclei
within SuM.
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
Table 1
Abbreviations used within the text (excluding figures)
(RS)-a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
Central grey/periaqueductal grey
Diagonal band of Broca
Dorsal raphe
Differential reinforcement of low rates of response: a schedule in which a reward can be obtained if the animal makes a
response that is delayed by at least the DRL interval (often 15 s) since the last response, i.e. a reward would always be
obtained if the animal responded every 15.1 s and would never be obtained if it responded every 14.9 s
Fixed interval schedule: a schedule in which a reward can be obtained if the animal makes one response at any time after a
fixed interval (often 60 s) has expired since the last reward was obtained
Gamma amino butyric acid
Lateral septum
Lateral hypothalamus (no specific boundaries)
Medial septum
Mammillary bodies
Median raphe
Principal mammillary tract/mammillothalamic tract
Nucleus reticularis pontis oralis
Supramammillary area, largely as defined by Swanson (1998) including parts of the LH of Paxinos and Watson (1998)—essentially
all those nuclei immediately superior to MB
Supramammillary core—most central and compact portion of SuM, including SuMp and SuMg. see section at AP2.2, Fig. 4
Grandicellular supramammillary nucleus—contains but is not limited to distinctive large cells and is placed between SuMp and
SuMs, see section at AP2.2, Fig. 4
Lateral supramammillary nucleus as defined by Swanson (1998)
Lateral supramammillary nucleus as defined by Paxinos and Watson (1998)
Medial supramammillary nucleus as defined by Swanson (1998)
Medial supramammillary nucleus as defined by Paxinos and Watson (1998)
Parvicellular supramammillary nucleus—most medial portion of SuM, see section at AP2.2, Fig. 4
Supramammillary shell—most lateral and diffuse portion of SuM, see section at AP2.2, Fig. 4
Nucleus of the supramammillary decussation—location as in Paxinos and Watson’s (1998) supramammillary decussation,
boundaries of the nucleus poorly defined, see Section 2.2
Swanson (1998) divided SuM into a medial part
(abbreviated by him, SuMm)1 and a lateral part (SuMl).
The medial part contains smaller cells and the lateral part
larger ones (Swanson, 1982; Risold and Swanson, 1997).
This division was on the basis that (a) SuMm includes
dopaminergic cells, which provide a major input to the
lateral septal nucleus (LS), but not to the hippocampus
(Swanson, 1982); while (b) SuMl contains large cells that
project directly to the hippocampus (Haglund et al., 1984;
Maglóczky et al., 1994) and the entorhinal area (Swanson,
As we can see in Fig. 1, the differences between the two
atlases are not only how they divide SuM into two parts, but
also the shape of the nucleus and, in particular, the location
of the lateral border of the SuM area. The SuM area in
Swanson’s atlas is larger. Swanson’s SuMl includes parts of
the lateral hypothalamus (LH) of Paxinos and Watson and, at
its most rostral, includes their submammillothalamic
nucleus. We must, therefore, answer two questions before
proceeding to any analysis of the SuM area: (1) what is its
boundary; (2) what is its division into subnuclei.
Conveniently, the two atlases use different abbreviations. So while
‘‘medial supramammillary nucleus’’ is ambiguous, SuMM is the medial
part as defined by Paxinos and Watson while SuMm is the, different, medial
part defined by Swanson.
2.1.1. Where is it best to place the boundary of SuM?
Since we will later be subdividing SuM into distinct
nuclei, the initial inclusion or exclusion of any particular
homogenous area in our definition of SuM is to some extent
arbitrary. We will concern ourselves first, therefore, with the
boundaries between distinct nuclei above the mammillary
bodies and only later consider whether they should be
counted as parts of the more general supramammillary area
The location of the ventral boundary of SuM is largely
uncontroversial. It can be taken, by exclusion, to be the most
dorsal limits of the mammillary bodies and almost all the
different authorities agree on the boundary of the latter.
There are minor differences in the precise depth within the
area between the principal mammillary tracts (pm) at which
this boundary is placed. We have found that, with the
neurotoxin AMPA, there is a very distinct boundary between
totally lesioned supramammillary cells and virtually totally
spared mammillary cells (see Fig. 2B and C) that is not seen
with ibotenic acid lesions. This places the boundary almost
exactly half way between the most dorsal and most ventral
extent of the pm in sections taken at 4.5 mm posterior to
bregma. This placement also corresponds to an area that can
appear relatively clear of cells in normal histology (see Fig.
2A). This placement of the boundary is slightly higher than
the position shown by Maglóczky et al. (1994), lower than
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
Fig. 1. Comparison of the boundaries of SuM as given in different sources.
(A) Modified from Hayakawa et al. (1993). Superimposed on the drawings
of SuM are dots representing terminals arriving from the preoptic area.
These extend beyond the lateral boundary of SuM, as defined by the authors,
in the most rostral section. (B) Modified from Maglóczky et al. (1994).
Superimposed on the drawings of SuM are cells retrogradely labelled from
the hippocampus. Note that these cells cluster around pm in the two more
rostral sections and maintain an equivalent position more caudally. Note
also the wider boundaries assigned to SuM laterally by these authors than in
A. (C) From Vertes and McKenna (2000). (D) From the electronic copy of
the atlas of Paxinos and Watson (1998). Note the limited lateral extent of
SuM, extending only a small way beyond pm. (E) From the electronic copy
of the atlas of Swanson (1998) with line thicknesses modified.
Swanson (1982) and essentially the same as Borhegyi and
Leranth (1997) and as Paxinos and Watson (1998). We will
therefore take it as the ventral limit of SuM for the purposes
of the present review.
The dorsomedial boundary of SuM is also fairly well
agreed on, running in an essentially flat line 300–500 mm
above pm. Disagreement starts lateral to pm, at which point
SuM is either represented as continuing in a straight line or
in a descending curve, depending on the lateral limits that
are accepted for SuM (see below).
We turn now to a consideration of the lateral limits of
SuM. These are quite different depending on whether one
takes Paxinos and Watson or Swanson as a guide. Superficial
inspection of thionin stained sections can support both types
of division. As can be seen in Fig. 4 (section 4.5), the area
immediately dorsal to the mammillary bodies includes a
densely packed medial core and a more loosely packed
lateral shell. The atlas of Paxinos and Watson allocates the
rostral core to SuM but incorporates the shell into LH.
Caudally they divide SuM into SuMM and SuML and this
would be consistent with a similar subdivision of rostral
SuM. Swanson’s atlas defines part of the core, which
Fig. 2. Gross histological observations of SuM (Pan and McNaughton,
2002) and the effects of AMPA lesions on medial SuM (mSuM) and the
mammillary bodies (MB). (A) A section taken from an unlesioned rat. Note
that in this section there appears to be a thin cell free zone corresponding to
the division between mSuM and MB. A similar separation was observed
between lesioned and intact cells at this level. (B) A section taken from a
more caudal level than (A) from an AMPA lesioned rat. The line marks the
division between mSum and MB with cells above the line having been
replaced by glia and cells below the line remaining intact. (C) Section from a
second rat with a substantial AMPA lesion of mSuM demonstrating the lack
of damage to MB as a whole.
contains dopamine cells, as SuMm. He adds the remainder of
the core to the shell to generate his SuMl.
The question, then, is whether it is necessary to include
the shell (Paxinos and Watson’s LH) with Paxinos and
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
Watson’s SuML, treating it as a single area, Swanson’s
SuMl. One reason for inclusion would be some structural or
functional consistency between the shell and the core. The
distributions of CCK-immunopositive cells (Lantos et al.,
1995) and calretinin cells (Borhegyi and Leranth, 1997)
clearly delineate the more medial portions of SuM and
extends homogeneously into, and in parts delineates, the LH
area of Paxinos and Watson. ‘‘The supramammillary nucleus
[is] far more rich in CCK-ir perikarya than any other
premammillary-posterior hypothalamic nuclei’’ (Lantos et
al., 1995). There is a similar distribution of expression of
5HT1A receptor mRNA (Gundlah et al., 1999). These data
suggest considerable chemical similarity between the core
and the shell areas. Swanson (1982) also found that his SuMl
(core and shell) as a whole projects directly to the entorhinal
area and receives input from the caudal dorsal part of lateral
septum whereas the core as a whole receives input from the
caudal ventral part of lateral septum (Risold and Swanson,
1997). This projection distinguishes the shell (Swanson’s
SuMl) from other parts of LH. Taken together, these criteria
allow a convenient description of SuM itself as the entire
area immediately superior to the mammillary bodies. As
such it is an area that stains distinctly for CCK and calretinin,
and that has its dorsolateral boundary defined by projections
to the entorhinal area. So, in agreement with Swanson
(1998) we will include a large medial portion of the LH of
Paxinos and Watson within SuM for the purposes of this
review. As will be seen, not only does this place ‘‘SuM’’
immediately above the mammillary bodies, the parts we can
distinguish of SuM (so defined) appear to mirror the
conventional mediolateral division of the mammillary
2.1.2. What are the parts of SuM?
As we have seen there is good reason to follow Swanson
and include more lateral areas in SuM. However, there are
also good reasons for the division chosen by Paxinos and
Watson. In particular, there is reason to distinguish the core
from the shell, a division that separates Swanson’s SuMl into
distinct parts. There is a high level of trkC mRNA expression
in the core but not the shell (Numan and Seroogy, 1999). The
cells projecting into the hippocampus, especially into dorsal
hippocampus, are mainly located in the core, particularly
around pm (Maglóczky et al., 1994; Haglund et al., 1984);
although there are scattered cells in the shell. There are
neurons clustered in the core, around the principal
mammillary tract, which project to both MS/DBB and the
hippocampus (Borhegyi et al., 1998). For all these reasons, it
seems proper to treat the shell area as separate from the
lateral part of the core.
On similar grounds it is necessary to divide the core area
into two parts. The core in the region that surrounds pm is
distinct in containing large cells, having strong projections
to the hippocampus and having cells that do not stain for
substance P (Borhegyi and Leranth, 1997). Indeed, Paxinos
and Watson classify the rostral part of Swanson’s SuMl as a
quite distinct area, SMT. The more medial core region has
small cells, has only weak connections to hippocampus and
has cells that stain for substance P, including ones that are
double labelled for substance P and calretinin. The substance
P cells appear to be the source of the weak projection from
the most medial portions of SuM to the hippocampus and
they terminate on interneurones in the dentate gyrus and
cells in CA2 and CA3 in the monkey (Leranth and Nitsch,
1994; Nitsch and Leranth, 1993) appearing early in prenatal
development (Berger et al., 2001). The same projections are
present in the rat, guinea pig and cat but mostly contain
calretinin with substance P only present in the projection to
area CA2 (Nitsch and Leranth, 1993; Borhegyi and Leranth,
1997; Gall and Selawski, 1984; Ino et al., 1988). The medial
core region is also distinctive in containing a large number of
dopaminergic neurones (Swanson, 1982; Gonzalo-Ruiz et
al., 1992a,b).
It seems best, therefore, to include in SuM all the area
above the mammillary bodies that stains for CCK and
calretinin. The dorsal and lateral boundaries of SuM we then
take, given this inclusion, essentially as the consensus
boundaries of the atlases. We then divide this overall area,
where it is immediately above the mammillary bodies, into
three major parts (Fig. 3). We leave open the possibility (see
below) that there is a fourth part, above these three, located
in the supramammillary decussation.
Given previous nomenclature that uses the terms
supramammillary, medial and lateral in differing and,
often, ambiguous ways we are also proposing a new, nonoverlapping, nomenclature (with non-overlapping abbreviations) derived from the superficial appearance of the
cells in the different areas. The most central area, we have
termed the parvicellular SuM (SuMp). This is characterised
most easily by having small cells (10–15 mm, Borhegyi and
Leranth, 1997) and being centrally located without making
contact with pm. As noted above, it is also histochemically
distinct in containing cells that label for substance P and in
having a substantial number of dopamine cells (Fig. 3). It
corresponds to the most medial part of medial SuM in most
other classifications. It is largely the same as Swanson’s
SuMm except that its border remains clear of pm. The next
area, moving laterally, we have termed the grandicellular
SuM (SuMg). This is characterised most easily by the fact
that it contains large cells (30 mm, Borhegyi and Leranth,
1997) that are clustered around, or located above and to
either side of, pm. But these large cells are scattered among
smaller cells and so the boundary of the nucleus does not
correspond to the location of the large cells themselves. The
nucleus corresponds, caudally, in its lateral boundary to
Paxinos and Watson’s SuML and rostrally to their SMT. It is
a medial portion of Swanson’s SuMl. It is histochemically
distinct in containing cells that stain for caltretinin but not
substance P. The next, and most lateral, area we have termed
the supramammillary shell (SuMs). This corresponds to the
lateral part of the SuMl of Swanson and to the ventromedial
part of the LH of Paxinos and Watson. It is characterised by
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Fig. 3. Lower part of figure: the parts of SuM in relation to its cell types and
their connections to entorhinal cortex, septum and hippocampus. Cells are
indicated by symbols indicating specific characteristic histochemical markers but with no indication of co-localisation of multiple markers. SuM as a
whole contains calretinin-containing cells. The most medial portion of SuM
contains small cells (and is therefore termed by us the parvicellular portion)
and is distinguished by having substance P containing cells and a high
density of dopamine containing cells. Around the pm fibre tract (solid black)
is an area most clearly distinguished by containing large cells (and is
therefore termed by us the grandicellular portion) that has projections to the
medial septum as well as to the hippocampus. More laterally is an area with
much more loosely packed cells (and so termed by us the shell portion) that
is most clearly delineated by containing cells that project to entorhinal
cortex. The parts of SuM as described by us occupy approximately the same
medio-lateral positions as the parts of the mammillary bodies. Lateral to
both SuM and the mammillary bodies, and occupying an intermediate
dorso-ventral position are clusters of histaminergic cells that we see as
bordering both the mammillary and supramammillary areas. Upper part of
figure: interconnections of parts of SuM with the septum and hippocampus.
Excitatory connections are indicated with solid lines and arrows and
inhibitory ones with dashed lines and rectangles. The medial septum is
divided into three distinct zones with an intermediate zone characterised by
presumed cholinergic cells and an outer zone characterised by calretinin
containing cells that receive projections from the entorhinal cortex (see text)
(Borhegyi and Freund, 1998; Vertes and McKenna, 2000; Borhegyi et al.,
1998; Kiss et al., 2002; Borhegyi and Leranth, 1997; Leranth et al., 1999;
Leranth and Kiss, 1996; Maglóczky et al., 1994; Vertes, 1992; GonzaloRuiz et al., 1992).
smaller cells that are less tightly packed than those of SuMp.
It does not stain for trkB mRNA (Numan and Seroogy,
1999) but is otherwise like SuMg in projecting to the
entorhinal area and staining for CCK (Lantos et al., 1995)
and calretinin (Borhegyi and Leranth, 1997). Functional
divisions appear consistent with these morphological ones.
The most marked increases in c-fos activity are in the core of
SuM with little change in the shell with challenges such as
changes in temperature (see Section 4). As to the boundary
of the lateral side of the shell area, we follow Swanson’s
atlas. This leaves a small amount of tissue lateral to it (but
not above the mamillary bodies) as lateral hypothalamic
area. This is populated with histaminergic cells. These latter
were included in SuM as defined by Maglóczky et al. (1994)
(see Fig. 1B). However, not only are these cells chemically
distinct from SuM, their location at some levels is somewhat
more ventral than is typical of the parts of SuM and
nonetheless lateral to what is generally accepted as the
mammillary bodies.
The above description accounts for the area immediately
above the mammillary bodies. However, there is a loose
aggregation of cells located in the supramammillary
decussation, immediately above SuMp, which also stain
for CCK. This nucleus (if such a diffuse cluster can be
treated as such) is not supramammillary in the same sense as
SuMp, SuMg and SuMs since it is separated from the
mammillary bodies by SuMp. However, given our use of
CCK as a basis for including nuclei within SuM, it should
probably be included for the sake of completeness within our
nomenclature. It also appears functionally similar to SuMp
in that both show high c-fos expression (relative to the
number of cells in the area) in rats placed in an open field (Ito
et al., 2003). The area (as opposed to the cells themselves) is
also labelled, elsewhere, as the supramammillary decussation (usually abbreviated sumx). We think it reasonable,
therefore, to refer to it as the nucleus of the supramammillary decussation (SuMx) both to avoid confusion from the
earlier terminology and because the area shares with all the
other supramammillary nuclei the staining for CCK that we
have used to delineate them. However, since its conformation at the more rostral and caudal levels of the
supramammillary area is not known, we have not included
it in the consensus atlas described in the next section. Nor
does it figure largely in the data reviewed later.
2.1.3. Construction of an atlas of SuM
Our novel separation and delineation of the parts of SuM
led us to construct an atlas of SuM as a means of providing
concordance between and with other atlases and publications. In addition, the small size of SuM coupled with its
detailed division suggested that a finer grain separation of
successive sections would be advantageous.
Our first step was to produce drawings that integrated the
atlas of Paxinos and Watson with that of Swanson. To do this
we traced over the drawings from Swanson’s atlas and
overlaid these drawings on the corresponding nearest match
in Paxinos and Watson to produce an approximation to a
fixed number of tens of millimeters A-P from bregma. In
some cases the same (intermediate) Swanson drawing was
overlaid on two (anterior and posterior respectively)
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
Fig. 4. An atlas of SuM. This shows consensus drawings derived from the atlases of Paxinos and Watson (1998) and Swanson (1998) as described in the text.
Matching sections from one rat selected from our own histology are also shown. The division of SuM into its individual parts is described in detail in the text but
can be thought of as accepting the two part divisions of both atlases to achieve a resulting three-part consensus. Where AP location is indicated in normal roman
numerals the drawing is an average of the equivalent drawings of the two atlases. Where it is in italics the drawing is an average interpolated between two other
drawings, except at 5.0 where it was derived from the matching histological section since the conformational change between the adjacent sections was too great
for interpolation to be accurate. Note that the boundaries of the grandicellular portion of SuM (dashed lines) do not coincide with the, unclear, limits of the main
occurrence of the large cells from which we have derived the name. The approximate location of the main concentration of large cells within SuMg is indicated
by a change of texture.
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
Fig. 4. (Continued ).
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
Fig. 4. (Continued ).
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
Fig. 4. (Continued ).
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
drawings from Paxinos and Watson to generate successive
cases. We then traced lines intermediate between those of
the two atlases.
Our second step was to fill the gaps at 4.3, 4.6, 4.8, and
5.0 mm by interpolation (Fig. 4). There was a remaining gap
at 5.1 mm, which could not be bridged by interpolation since
the change in form between 5.0 and 5.2 mm is too great. This
gap was filled using our own histology after the next step
described below.
Our third step was to match the drawings with our own
histological material (Fig. 4). From over 100 cases of
histology, we selected a continuous series of 100 mm thick
serial sections that corresponded in plane of section and
general conformation to that of our atlas drawings. We first
anchored these sections in relative AP location with respect
to the drawings by the transition from the presence of the
ventral tongue of the third ventricle at 4.4 mm to its absence
at 4.5 mm. We then matched sections with drawings in
simple 100 mm steps from this point rostrally and caudally.
The correspondence between the remaining drawings and
sections was assessed as a check on the accuracy of the
interpolation of the drawings between the atlases and of the
positional matching of the resultant drawing to our sections.
No A-P adjustment was required and, once this was
confirmed, the histological section at 5.1 mm was used as a
basis for the drawing provided at this level. A few minor
inconsistencies were detected at this point between
particular drawings and our sections. These turned out to
be due to anomalies in the equivalent drawing in one or
another of the atlases both when that drawing was compared
with the other atlas and when it was compared with the
preceding and following drawing from the same atlas. These
drawings were then brought into line with the preceding and
following drawings, which also achieved correspondence
with our histology.
Our fourth step was to take SuMg, defined from the
atlases as described above, and divide it roughly into two
parts, one containing only smaller cells and the other
containing both small and large cells. This is marked in the
drawings by a change in pattern within the line bounding the
nucleus but, since there is no strict boundary between the
two parts, they are not separated by a solid or dotted line,
unlike the major divisions of SuM.
As noted above, we have not included SuMx in the atlas
as its conformation, or indeed existence, in more rostral and
caudal sections is not well defined in the literature.
2.2. The connections of SuM
SuM is one of a range of brainstem areas that project to
the hippocampus (Wyss et al., 1979; Segal and Landis, 1974;
Pasquier and Reinoso-Suarez, 1978a,b; Amaral and Cowan,
1980; Stanfield and Cowan, 1984; Stanfield et al., 1980)—
The others include the raphe nuclei and locus coeruleus.
Like the monoamine nuclei, despite its small size, SuM
produces direct diverse innervation of many forebrain areas.
This suggests that SuM, like the monoamine systems, may
execute some general modulatory, possibly emotional,
function. We have suggested elsewhere that theta activity
(which is controlled by SuM) may produce an improvement
in the signal–noise ratio of neuronal processing in relation to
temporal summation that is equivalent to the improvement in
signal–noise ratio produced by the monoamine systems in
relation to spatial summation (Gray and McNaughton,
Consistent with a role in emotion, SuM connects with
widespread regions of the limbic system, such as anterior
limbic cortex, amygdala, entorhinal cortex, dentate gyrus,
septum, preoptic area, anterior hypothalamus, LH, thalamus,
locus coeruleus, DR and MR (Swanson, 1976, 1982;
Shibata, 1987; Vertes, 1992; Hayakawa et al., 1993;
Thinschmidt, 1993; Risold and Swanson, 1997; Vertes et
al., 1999; Swanson and Cowan, 1975, 1979; Conrad and
Pfaff, 1976; Saper et al., 1976; Krayniak et al., 1980;
Ottersen, 1980; Sakanaka et al., 1980; Contestabile and
Flumerfelt, 1981; Price and Amaral, 1981; Deacon et al.,
1983; Kiyama et al., 1984a,b; Haglund et al., 1984; Chiba
and Murata, 1985; Shibata et al., 1986; Grove, 1988). That
its role involves higher (more rostral/cortical) levels of the
nervous system is suggested by the fact that its connections
avoid the striatum and the nucleus accumbens (Swanson,
1982; Vertes, 1992). Fig. 5 illustrates the main connections
of SuM taken as a whole.
There is some semblance of a pattern in these
connections. SuM is reciprocally connected with more
rostral, essentially, limbic cortical and subcortical areas. It
has predominantly efferent connections to somewhat more
caudal, again essentially limbic (and thalamic), areas.
Where its connections are predominantly afferent, they are
subcortical and, except for the habenula, from relatively low
subcortical levels. In Fig. 5, there are a few structures that on
current data appear to depart from the expectation of
reciprocal connections. These are the dorsal hypothalamus,
the ventromedial hypothalamus and the premammillary
2.2.1. Afferents to SuM
The main ascending afferents are of two types. There are
inputs that are likely to be modulatory from the cholinergic
laterodosal tegmental nucleus, and the serotonergic raphe
(Gonzalo-Ruiz et al., 1999). There are also inputs that are
likely to convey specific information or be involved in
specific functional output from the median raphe, and the
CG (Gonzalo-Ruiz et al., 1999; Shibata, 1987; Vertes et al.,
1999; Hayakawa et al., 1993).
There is no solid evidence that the magnocellular RPO
and the pedunculopontine tegmental nucleus in the brain
stem project directly into SuM (Hayakawa et al., 1993;
Thinschmidt, 1993). One report of a connection between
RPO and SuM (Vertes and Martin, 1988) appears to be due
to the absorption of the tracer by fibres of passage
(Hayakawa et al., 1993). This lack is surprising since, in
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
Fig. 5. General connections of SuM ignoring its division into parts. The figure is an exploded diagram approximating a 3D representation and has been derived
from the 2D representation in Paxinos and Watson (1983; Fig. 78–80) with the addition of known monosynaptic connections (Vertes, 1988, 1992; Hayakawa et
al., 1993; Shibata, 1987; Risold and Swanson, 1997; Swanson, 1982; Thinschmidt, 1993; Kiss et al., 2002). Dashed lines with arrows indicate connections
currently thought to be unidirectional, solid lines with balls indicate those known to be bidirectional. There appears to be a topographic division of ascending
connections with bidirectional connections going to more ventral and rostral areas and unidirectional ones going to more dorsal and caudal areas (DH, VMH and
PM appear to be exceptions). The representation of LHb has been displaced caudally to achieve clarity and to locate it closer to the superior colliculus (the area
above CG), CG and DR with all of which it has connections. Abbreviations: AH, anterior hypothalamic area; AM, anteromedial thalamic nucleus; Amyg,
amygdala; AV, anteroventral thalamic nucleus; Ce, cerebellar nuclei; CG, central gray; CgCx, cingulate cortex; CM, central medial thalamic nucleus; DBB,
diagonal band of Broca; DH, dorsal hypothalamic area; DP, dorsal peduncular cortex; DR, dorsal raphe nucleus; EC, entorhinal cortex; Hip, hippocampus
proper; IL, infralimbic cortex; IP, interpeduncular nucleus; L6, spinal cord, lamina 6; LC, locus coeruleus; LDTg, laterodorsal tegmental nucleus; LH, lateral
hypothalamus; LHb, lateral habenula; LS, lateral septal nucleus; MB, mammillary bodies MD, mediodorsal thalamic nucleus; mfb, medial forebrain bundle;
MR, median raphe nucleus; MS, medial septal nucleus; PH, posterior hypothalamic area; PM, premammillary nucleus; PO, preoptic nuclei; Re, nucleus
reuniens; SI, substantia innominata; SuM, supramammillary area; VMH, ventromedial hypothalamus; VTg, ventral tegmental nucleus.
urethane-anaethsetised animals, electrical stimulation of
these areas elicits theta very effectively (Vertes, 1982) and,
under these conditions, SuM appears to act as the sole relay
to the hippocampus (Kirk and McNaughton, 1993).
The main descending afferents to SuM are from the
infralimbic cortex, the dorsal peduncular cortex, DBB, the
medial and lateral septal nuclei, the lateral habenula and the
medial and lateral preoptic area (Vertes, 1988, 1992;
Hayakawa et al., 1993; Shibata, 1987; Risold and Swanson,
1997; Swanson, 1982; Thinschmidt, 1993; Chiba and
Murata, 1985; Kiss et al., 2002). In this respect the
connections of SuM appear similar to those of the
mammillary bodies and in many cases are likely to be
collaterals of the same neurones (Hayakawa and Zyo, 1994).
It should be noted, however, that hippocampal output is
topographically mapped in such a way that information
destined for SuM arises in area CA3 and is first relayed in the
lateral septum, while information destined for MB arises in
the subiculum and is transferred direct to SuM (Risold and
Swanson, 1996). The inputs to the dopaminergic cells of
SuMp have been suggested to be excitatory (Hayakawa and
Zyo, 1994).
GABAergic neurons located at the border between the LS
and MS project to SuM (Borhegyi and Freund, 1998;
Leranth et al., 1999). These cells contain calretinin and/or
calbindin. They form a skin that surrounds choline acetylase
containing cells. These in turn surround ‘‘like the skins of an
onion’’ (Borhegyi and Freund, 1998) GABAergic parvalbumin-containing neurones (Kiss et al., 1997a,b; Henderson et
al., 2001). These centrally located GABAergic cells also
have projections to SuM—but these are very weak compared
to the cells on the MS/LS border and the cells in LS (Fig. 3).
The calretinin containing cells do not project to the
hippocampus or the amygdala (Kiss et al., 1997a,b). The
various types of medial septal cell appear to be highly
interconnected via recurrent axon collaterals (Henderson et
al., 2001; Kiss et al., 1997a,b). It was previously thought that
LS cells might also control MS cells (Leranth and Frotscher,
1989). However, more modern methods suggest that LS–MS
connections are sparse with the main hippocampal feedback
being direct to MS and strong inhibitory connections from
MS to LS (Leranth et al., 1992).
The LS/MS/DBB projections to SuM are likely to be the
basis for complex interrelations with the hippocampal
formation and related structures. The GABAergic cells on
the border of MS/LS relay information from the entorhinal
cortex to SuM (Leranth et al., 1999), but their precise
topographic organisation is not known. However, the
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
hippocampal formation as a whole is topographically
mapped into the lateral septum and this in turn is
topographically mapped into the hypothalamus (Risold
and Swanson, 1996) including SuM (Borhegyi and Freund,
1998). This suggests that for some functions, SuM is a
relatively small part of a much larger parallel system.
2.2.2. Efferents from SuM
SuM sends ascending projections to the diencephalon and
telencephalon (Swanson, 1976, 1982; Shibata, 1987; Vertes,
1992; Hayakawa et al., 1993; Thinschmidt, 1993; Risold and
Swanson, 1997; Vertes et al., 1999; Swanson and Cowan,
1975, 1979; Conrad and Pfaff, 1976; Saper et al., 1976;
Krayniak et al., 1980; Ottersen, 1980; Sakanaka et al., 1980;
Contestabile and Flumerfelt, 1981; Price and Amaral, 1981;
Deacon et al., 1983; Kiyama et al., 1984a,b; Haglund et al.,
1984; Chiba and Murata, 1985; Shibata et al., 1986; Grove,
1988). SuMg and SuMs project to the MS, the DBB,
hippocampus, entorhinal cortex, cingulate cortex, frontal
cortex, and amygdala. SuM as a whole, projects to LS, the
preoptic area, most of the medial nuclei of the thalamus, the
subthalamus and other parts of the hypothalamus (for
references see Fig. 5). The descending projections from SuM
(principally from SuMg and SuMs) are mainly to the CG,
MR, DR and locus coeruleus (for references see Fig. 5), and
even the cerebellar nuclei in monkeys (Haines et al., 1990)
and spinal cord in rabbits (Gong, 1984).
On a large scale, the projections from SuM tend to show a
simple topographic organisation. The medial SuM mainly
projects to more medial structures and the lateral SuM
mainly projects to more lateral structures. For instance, the
dopamine cells of SuMp project to the LS, the large cells of
SuMg project to the hippocampus and the small cells of
SuMg and SuMs project to the entorhinal cortex. Similarly,
SuMp projects mainly to the medial preoptic area and SuMs
project mainly to the lateral preoptic area.
2.2.3. Neuronal types in relation to projections from SuM
SuM neurons include dopaminergic cells (Swanson,
1982; Gonzalo-Ruiz et al., 1992a,b), calretinin neurons,
aspartergic/glutamatergic cells (Carnes et al., 1990; Leranth
and Kiss, 1996; Kocsis et al., 2003), substance P neurons as
shown in Fig. 3 (Ino et al., 1988; Gall and Selawski, 1984;
Borhegyi and Leranth, 1997), and CCK immunoreactive
neurons (Kiyama et al., 1984a,b; Lantos et al., 1995) and
VIP immunoreactive neurons (Haglund et al., 1984; Seroogy
et al., 1988).
The dopaminergic cells are located mainly in SuMp (Fig.
3), and project to the LS (Swanson, 1982; Shepard et al.,
1988) and mamillary bodies (Gonzalo-Ruiz et al., 1992a,b).
Swanson (1982) thought that the dopaminergic cells in SuM
could be a dense extension of the A10 (ventral tegmental
area) cell group. Shepard et al. (1988) argued that those cells
do not appear to be a rostral extension of the A10 neurons
since the cytological characteristics of the dopaminergic
cells in SuM differ from the cells in A10. The former are
significantly smaller than the latter (Phillipson, 1979;
Shepard et al., 1988). It is well known that both the
dopaminergic pathway from A9 to the striatum and the one
from A10 to the nucleus accumbens play a role in reward
learning. There are no direct data implicating the SuM–LS
or SuM–MB dopaminergic pathway in reward. But, singleunit recording has shown that the firing of the dopaminergic
cells of SuM shows essentially the same response pattern to
conditioned stimuli as the dopaminergic cells of A9 and A10
(Pan and Hyland, 2001). Likewise (Ikemoto et al., 2003), the
cholinergic agonist carbachol, when self-administered into
VTA, produces c-fos expression in SuM neurons, which
suggests that SuM may be linked to the reward system.
Calretinin containing neurons are distributed throughout
SuM (Borhegyi and Leranth, 1997). Some of the calretinin
neurons are aspartergic/glutamatergic neurons. These are
mainly in SuMg and SuMs, and project to MS cholinergic
cells and LS calbindin cells (Leranth and Kiss, 1996) and
hippocampus (Kiss et al., 2000). In contrast, the glutamatergic neurons located in SuMp project to the medial
preoptic area (Kocsis et al., 2003).
Some calretinin neurons (Borhegyi and Leranth, 1997),
substance P neurons (Borhegyi and Leranth, 1997; Gall and
Selawski, 1984; Ino et al., 1988), and VIP immunoreactive
neurons (Haglund et al., 1984) project to the hippocampus.
In rats, substance P fibres from SuMp terminate only in the
CA2 region and, in contrast to more lateral areas of SuM, not
in the dentate gyrus (Borhegyi and Leranth, 1997). In
monkeys, however, they contact dentate granule cells, hilar
cells and CA3 cells (Leranth and Nitsch, 1994) and are
formed prenatally (Berger et al., 2001). These latter
projections are present in the rat but contain calretinin
and not substance P. In rats, CCK immunoreactive neurons
project to the nucleus anterior ventralis thalami (Kiyama et
al., 1984a,b), ventral tegemental nucleus (Kiyama et al.,
1984a,b), and the hippocampaus (Greenwood et al., 1981).
Cells in SuMg that project to the hippocampus also
contain estrogen receptors. These receptors appear to be
responsible for plastic changes in the density of spine
synapses in area CA1 that result from changes in systemic
estrogen level (Leranth and Shanabrough, 2001).
The postsynaptic targets of SuM projections in the
hippocampus are both principal cells (Maglóczky et al.,
1994) and GABAergic interneurons (Nitsch and Leranth,
1996). These neural circuits could all play a role in the
control of hippocampal theta rhythm.
2.2.4. Neuronal types in relation to projections to SuM
Combining retrograde labelling with immunohistochemistry techniques, Gonzalo-Ruiz et al. (1999) mapped the
localization of neurotransmitter-related molecules in the main
projection neurons to the SuM. They found that there are
1. Cholinergic neurons projecting from the MS/DBB and
the laterodorsal tegmental nucleus to the SuM, and they
suggested these connections were likely to be excitatory.
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2. GABA-containing neurons projecting from the compact
subnucleus of the central superior nucleus and from DBB
to the SuM, which they suggested are likely to be
3. Serotonergic neurons projecting to the SuM from DR.
4. A few neurons projecting to the SuM from the
rostroventral part of the subiculum, the DBB and the
DR containing glutamate-like immunoreactivity, which
they suggested are likely to be excitatory.
5. Neurons containing neuropeptides projecting to the SuM
which are from several sources—somatostatin-positive
neurons from the medial preoptic nucleus, enkephalinpositive neurons from the compact subnucleus of the
central superior nucleus, neurotensin-positive neurons
from the medial preoptic nucleus, DR and compact
subnucleus of the central superior nucleus, and substance
P neurons from the laterodorsal tegmental nucleus.
In addition, Leranth et al. (1999) showed that the GABAergic neurons located in the border between the LS and
MS (but not within the main body of these nuclei) project to
calretinin containing (non-GABAergic) cells in SuM. These
data show that the ascending and descending projections to
the SuM are chemically very diverse. They are likely, therefore, to be the basis of complex interactions in SuM.
3. Neurophysiology of SuM
3.1. SuM and hippocampal theta activity
3.1.1. What is theta activity?
Hippocampal ‘‘theta rhythm’’ (Jung and Kornmüller,
1938; Green and Arduini, 1954) is one aspect of
hippocampal EEG, which in some species is within the
human EEG theta range (4–8 Hz) but in the rat and some
other species can span frequencies between 4 and 14 Hz.
Hippocampal theta rhythm recorded extracellularly with
gross electrodes results from sources and sinks associated
with the synchronised oscillations of IPSPs or EPSPs, or
perhaps both (Fujita and Sato, 1964; Nunez et al., 1987,
1990; Leung, 1998). These also determine the phasic firing
of hippocampal neurons (Bland, 1986). We will term the
phasic firing of individual neurons ‘‘theta activity’’. When
this theta activity (synchronized phasic firing of individual
cells) is present in individual neurons it tends to involve the
entire hippocampal formation. But in some areas, such as
CA3, large-scale synchronous firing of individual neurons is
not accompanied by a gross recordable rhythm. The
frequency and amplitude of theta rhythm have been the
main measures of the frequency and population distribution,
respectively, of single cell theta activity in the majority of
The synchronous firing of hippocampal cells, and the
frequency of the resultant theta activity is critically
dependent upon the constant inflow of impulses from
outside the hippocampus. The MS and DBB are known to be
the last relay in the ascending synchronising inputs to the
hippocampal formation. MS/DBB cells act as the ‘‘pacemaker’’ for hippocampal theta. Each burst of septal cell
firing produces synchronous changes in the excitability of
the hippocampal formation as a whole (Gogolák et al., 1968;
Petsche and Stumpf, 1960; Petsche et al., 1962; Sailer and
Stumpf, 1957; Stumpf, 1965; Stumpf et al., 1962; Chrobak
et al., 1987, 2000; Lee et al., 1994).
The pathways controlling theta frequency appear to
originate in the brain stem reticular formation in the region
of the pons (Vertes, 1981, 1982, 1986; Vertes and Kocsis,
1997). These sites of origin are well caudal to the areas
known to project directly to SuM (Fig. 5) and SuM is well
caudal to MS. Probably one of the most important facts
about the electrophysiology of the core of SuM is that it
contributes to the control of the frequency of hippocampal
theta activity and that, at least on some occasions, the MS
appears to be simply a relay for supramammillary activity.
3.1.2. The septum as a pacemaker for hippocampal theta
The immediate source of the high degree of concurrent
synchrony not only across the entire hippocampal formation
but also the entorhinal and posterior cingulate cortices, is the
MS/DBB complex. The MS/DBB is best thought of, in this
context, as a pure ‘pacemaker’. The term ‘pacemaker’ is to
some extent ambiguous. Its simplest meaning (and the one
we will use here) is that it is a structure that controls phasic
activity, ‘‘pacing’’ the firing of its target cells. When training
a runner, it is often convenient to have someone who runs
ahead for some period to ‘‘set the pace’’. In this sense the
frequency of hippocampal theta is controlled by the septal
pacemaker since phasic firing of the hippocampus simply
follows that of the septum and so has the same pace.
However, ‘‘pacemaker’’ could also be taken to mean the
site at which the phasic frequency of both structures is itself
calculated by the integration of non-phasic inputs. As we
will see there is at present no evidence that the MS/DBB is a
pacemaker in this sense and considerable evidence against it.
To use our running analogy, the pacemaker controls the
speed at which the followers run—but it is the coach who
will have determined what pace that should be (and who may
alter it from time to time by instructions). In the brain, the
structure in which non-phasic inputs are integrated and
converted into frequency of phasic output will also be a
‘‘pacemaker’’ for the structures it controls. But we will
reserve for it the term ‘‘frequency integrator’’ to distinguish
it from the more passive pacemakers that relay alreadyphasic activity. Let us first consider the evidence for the
septum as a simple pacemaker for hippocampal theta.
As we noted above, there are cells in the MS/DBB which
fire in bursts that are locked to a specific phase (for any
individual cell) of the waves of the theta rhythm
This section is based on Appendix 5 of Gray and McNaughton (2000).
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
simultaneously recorded in the hippocampus (Brucke et al.,
1959; Petsche and Stumpf, 1960; Petsche et al., 1962;
Gogolák et al., 1967, 1968; Tömböl and Petsche, 1969;
Stumpf, 1965; Apostol and Creutzfeldt, 1974). GABAergic
interneurons within the septum appear to keep the whole
septum synchronized (Brazhnik and Fox, 1997). To simplify
somewhat, phasic GABAergic input from the septum
appears to combine with effectively tonic cholinergic input
from the septum to control hippocampal phasic activity (Lee
et al., 1994; Gray and McNaughton, 2000).
Phasic activity in the septum could be the result of
hippocampal input rather than vice-versa. However,
destruction of the MS/DBB produces permanent disruption
of hippocampal theta activity (Green and Arduini, 1954;
Petsche and Stumpf, 1960; Stumpf, 1965; Gray, 1971;
Rawlins et al., 1979; Bland et al., 1996). Medial septal
procaine also eliminates both theta rhythm and theta activity
in the entorhinal cortex (Dickson et al., 1995; Jeffery et al.,
1995). Critically, injection of GABA agonists also reduces
theta amplitude, without changing its frequency (Lamour et
al., 1984; Dutar et al., 1989; Bland et al., 1996; Jiang and
Khanna, 2004). This shows that GABA receptors in the
septum are located on cells that transmit phasic activity to
the hippocampus and that the effects of lesions and procaine
are not due to an action simply on fibres of passage.
By contrast, disruption of input from the hippocampus to
the septum increases the regularity and persistence of theta
activity in the septum (Vinogradova, 1995); disruption of
hippocampal theta by medial septal lesions increases cingulate
theta (Borst et al., 1987); and partial section of the descending
columns of the fornix increases the frequency of theta, an
effect which can be reversed with the noradrenergic agonist
clonidine (Ammassari-Teule et al., 1991). These observations
make sense if there is negative feedback control of the
frequency integrator that controls (or is) the septal pacemaker
for hippocampal rhythmicity. (The effects of medial septal
lesions on cingulate theta can be understood if the MS/DBB
pacemaker has a similar topographic organization to the MS/
DBB cholinergic system, with output to the cingulate cortex
being from more ventral locations.). The effects of lesioning
the descending columns of the fornix would tend to suggest
that the site on which the negative feedback operates is the
hypothalamus or some structure at a similar level of the brain.
If the MS/DBB is a pacemaker is it also a frequency
integrator? Here, temporary disruption of theta by injections
of local anaesthetic into MS/DBB and surrounding regions is
of particular interest. Injections of local anaesthetic reduce
theta amplitude progressively even to the point of total
elimination with no reduction in frequency (Dickson et al.,
1995; Jeffery et al., 1995; Jiang and Khanna, 2004; Oddie et
al., 1996). At intermediate doses, some of this local
anaesthetic would be expected to affect input fibres as well
as cell bodies and output fibres. We will discuss frequency
integration in more detail later—but we would expect a
reduction in input to the integrator to produce a reduction in
theta frequency. The lack of such a frequency reduction with
local anaesthetics argues against the septum normally acting
as an integrator (but see also below). Similarly, injections of
procaine into the medial forebrain bundle, which contains
the input to the MS/DBB pacemaker, reduce the amplitude
of theta to zero without affecting frequency (Kirk and
McNaughton, 1993). This is in contrast to the effects of
similar injections into SuM (Kirk and McNaughton,
1993)—which we will discuss further below.
What kind of injection into a frequency integrator would
be expected to reduce theta frequency? The frequency of
theta varies linearly with the level of high-frequency
(usually 100 Hz) input from reticular regions whether this
level is altered by changing stimulation voltage/current,
altering stimulating pulse width or altering the frequency of
stimulation. This frequency is reduced by drugs that act on
the GABA–benzodiazepine–chloride–ionophore complex to
potentiate the effects of GABA, such as benzodiazepines and
barbiturates (McNaughton and Sedgwick, 1978). The
simplest explanation of these data is that the incoming
level of tonic input is integrated as summed EPSPs in cells
that then fire and are shortly shut down by recurrent
GABAergic inhibition. Higher levels of input would
overcome this recurrent inhibition sooner giving rise to a
higher frequency (shorter interburst interval) of phasic
output. Drugs that potentiate endogenously released GABA
would decrease theta frequency. Drugs that act simply as
tonic GABA agonists would tend to shut the system down
altogether. We noted earlier that medial septal GABA has
little effect on theta frequency. Unfortunately benzodiazepine injections have not been tested there. However,
injections of barbiturate into the medial septum also do
not reduce theta frequency even at concentrations that totally
eliminate it (McNaughton, 1977)—and this elimination
appeared to be due simply to the pH of the solution as it
could be reproduced by simple sodium salts. These data all
suggest that the MS/DBB contains a pacemaker for
hippocampal theta activity but not, at least usually, a
frequency integrator.
Evidence for the septum as a pacemaker can also be
drawn from the effects of electrical stimulation. Stimulation
of the MS/DBB at theta frequencies drives hippocampal
theta rhythm with each septal pulse producing a phaselocked theta wave (Ball and Gray, 1971; Gray and Ball,
1970; James et al., 1977; Wetzel et al., 1977a,b). However,
spontaneous theta is replaced by small irregular activity if
the MS/DBB is stimulated continuously at high frequencies,
above about 70 Hz (Stumpf, 1965; Ball and Gray, 1971).
This is what we could expect from blockade of the normal
phasic pattern of MS/DBB firing. It would be difficult to
understand if theta was the result only of tonic cholinergic
afferent drive onto intrinsically oscillatory hippocampal
neurons, or if the MS/DBB complex were the site of
frequency integration. But it can be explained by there being
both excitatory and inhibitory inputs from the MS/DBB to
the hippocampal formation (Bland and Colom, 1993) and by
the driving of the septum by phasic input from elsewhere.
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
The blocking of theta by high-frequency stimulation
of MS/DBB is in strong contrast to the effects of stimulation
of more caudal areas of the brain. Particularly in the
pons, continuous high-frequency stimulation elicits
theta, the frequency of theta then generally increasing with
the strength of stimulation (Sailer and Stumpf, 1957;
Stumpf, 1965; McNaughton and Sedgwick, 1978; Vinogradova, 1995). The transition between theta elicitation
and theta blocking by high-frequency stimulation can,
then, be used to indicate the location of the frequency
In general, sites at which high-frequency stimulation
elicits theta are well caudal to the MS/DBB and, critically,
do not include sites in the medial forebrain bundle
afferents to MS/DBB. Although found in many parts of
the brain, including the lateral hypothalamus, the posterior
hypothalamus and the midbrain reticular formation (Stumpf,
1965; Anchel and Lindsley, 1972; Whishaw et al., 1972;
Robinson and Vanderwolf, 1978; Smythe et al., 1991)
effective sites have not generally been reported rostral to
SuM. Consistent with this, Vertes’s mapping of the
ascending synchronizing pathway originating in nucleus
reticularis pontis oralis leads to and stops at SuM (Vertes,
1980, 1981, 1982).
There are a few apparent exceptions to this rule
(Destrade, 1982; Destrade and Ott, 1982) with highfrequency stimulation of the medial forebrain bundle.
However, these authors used trains with phasic gaps. This
type of stimulation of the septum is known to be capable of
driving theta in the same way as phasic single pulses (James
et al., 1977), and inspection of their data (e.g. Fig. 1A and
especially 1B in Destrade and Ott (1982)) suggests that their
stimulation was driving theta at various harmonics of the gap
frequency. According to the authors, the frequency of theta
increased with increasing strength of stimulation, as would
be expected with more posterior stimulation sites. However,
inspection of the figures suggests that this was the result of
increasing phase locking of activity with the gaps in the
phasic delivery of the high-frequency pulses. Unlike
conventional ‘theta driving’, the phasic frequency was
below the theta range. However, septal input or sensory
stimuli (Givens, 1996) can reset ongoing theta as well as
drive it. Since the hippocampus has a tendency to intrinsic
oscillation in the theta frequency range, Destrade’s results
appear to be due to driving of various harmonics of the
imposed phasic frequency, with the resultant theta frequency
determined by the natural period of oscillation of the septohippocampal system. Thus, the driving in Fig. 1B of
Destrade and Ott (1982) is at the third harmonic of the
stimulation gap frequency.
It is clear from the above that MS/DBB controls
hippocampal theta activity in the sense of being a
pacemaker. However it is also seems clear, contrary to
earlier views, that it cannot normally be the site at which the
intensity of ascending reticular activity is integrated into the
frequency of theta activity (but see below).
3.1.3. Integration of theta frequency by SuM under
Given the data on MS/DBB, a search had to be made for
an extra-septal frequency controller for hippocampal theta.3
This search led to the core of SuM. Vertes (1986) proposed,
from mainly anatomical data, that SuM might act as a relay
of brainstem input to the MS. Kirk and McNaughton (1991,
1993) refined this idea further and proposed that SuM rather
than the MS/DB integrates the frequency of theta, at least in
urethane-anaesthetised rats. They found that SuMp and
SuMg cells discharge rhythmically and that they do so in
phase with any concurrent hippocampal theta activity (Kirk
and McNaughton, 1991). As far as can be told, all SuMp
cells show theta activity as do cells in the most medial
portions of SuMg (Kirk and McNaughton, 1991; Kirk et al.,
1996; Kocsis and Vertes, 1994; Bland et al., 1995; Bland and
Oddie, 1998; Kirk, 1998) and, under urethane, SuM
generates a local theta rhythm with its phase varying
relative to the hippocampus as frequency changes but with a
fixed time delay of about 70 ms (Kocsis and Vertes, 1997;
Kirk, 1997).
Sampling of SuMg has been sparse but suggests that this
may contain both rhythmic and non-rhythmic cells with,
perhaps, the former located more medially (Kirk and
McNaughton, 1991; Kocsis and Vertes, 1994). Alternatively,
the lateral boundary between primarily rhythmic and
primarily arhythmic populations of cells may be at the
border between SuMg and SuMs (Kocsis and Vertes, 1994).
The vertical boundary appears to be between SuMp and
SuMx with cells in SuMx firing tonically rather than
phasically (Bland et al., 1995).
Kirk and McNaughton (1991) found that procaine
injections into MS blocked hippocampal theta but not the
rhythmic bursting of SuM cells (Fig. 6), suggesting that SuM
cells controlled hippocampal cells rather than the other way
round. Consistent with this, Kocsis and Vertes (1994) found
that SuM firing rates were relatively homogenous in contrast
‘‘with the discharge of theta-related cells in other structures
of the brainstem or forebrain’’.
Kirk and McNaughton (1993) found (Fig. 7) that procaine
injections into SuMp or SuMg decreased both the frequency
and amplitude of reticular-elicited theta in urethaneanaesthetised rats, while procaine injected into the medial
forebrain bundle decreased the amplitude only, and procaine
injected into the reticular formation decreased the frequency
only (Kirk and McNaughton, 1993; Kirk, 1993; Bland and
Oddie, 1998). This shows that non-phasic reticular input
enters SuM and is there integrated into phasic theta activity
that leaves SuM. So Kirk and McNaughton (1993) proposed
that, at least under urethane, the core of SuM integrates level
of tonic reticular input to the frequency of theta output. As
discussed above this integration is simply explained if the
Kirk and McNaughton (1993) used procaine mapping to locate SuM
but then had to demonstrate SuM rythmicity (Kirk and McNaughton, 1991)
before their results were accepted for publication.
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
Fig. 6. Examples of unit activity in SuM and its relation to hippocampal theta. (A) One 240 ms sweep showing a burst of unit activity. (B–F) Sweeps of 2 s
showing (top trace) hippocampal EEG activity and (bottom trace) unit activity from medial SuM. (B) Rhythmicity of SuM locked to hippocampal theta—this
was shown by all cells. (C) Lack of rhythmicity of SuM during large irregular activity in the hippocampus (same electrode placement as (B)). (D) Rhythmicity of
SuM retained after blockade of hippocampal theta by medial septal procaine injection (same placement as (B) and (C)). (E) A different site showing an example
of relatively poor rhythmicity. (F) The same site as (E) showing improved rhythmicity after blockade of hippocampal theta with septal procaine. From Kirk and
McNaughton (1991).
frequency of theta output is determined by relatively fixed
amounts of recurrent inhibition and higher levels of
excitatory input overcome this, temporally decaying,
inhibition at earlier timepoints. That is, output from
principal SuM cells instantly activates recurrent inhibitory
interneurones and so terminates the firing of both sets of
neurons. As the resultant IPSPs decay over time, the level of
inhibition is eventually overcome by the current level of
afferent excitation, the cells pass threshold and fire a new
burst of action potentials that, in turn, shut the system down
It should be emphasised here that the ascending theta
system is polysynaptic. Its source, in these experiments, is
RPO (Vertes, 1980, 1981; Vertes and Kocsis, 1997). Yet, as
noted earlier, this has no direct projection to SuM
(Hayakawa et al., 1993; Thinschmidt, 1993). Likewise,
we as well as others (Vertes and Kocsis, 1997; Bland and
Oddie, 1998) have reason to see SuM as the source of phasic
impulses that control the MS/DBB. Yet SuMp (the principle
area targeted by Kirk and McNaughton) projects primarily
to the LS not MS, while SuMg and SuMs project to the
medial septum (Fig. 3). This suggests that any phasic control
of theta activity by SuMp (which shows the clearest theta
activity) is likely to be relayed, and SuMg is one likely
candidate. However, anatomical evidence of a projection
between SuMp and SuMg is lacking. The scattered cells in
SuMp that do project to MS (Vertes, 1988) could perhaps
provide all the necessary control. Alternatively they may be
an extension into SuMp of a class of cells mostly located in
SuMg. If so control of phasically firing MS cells would be
distributed throughout the core of SuM.
Recently, Jiang and Khanna (2004) replicated the effects
of local anaesthetic found by Kirk and McNaughton (1993)
using smaller injection volumes (0.1–0.2 mL). They
obtained effects within SuMp but also in sites in SuMg
and in the medial forebrain bundle dorsal to SuMg. Of
particular interest, they also injected the inhibitory
transmitter GABA. Previous injections of synaptically
active agents into SuM have involved benzodiazepines.
These would act on the benzodiazepine–GABA–chloride–
ionophore complex to potentiate the effects of endogenously
released GABA (Haefely, 1990a,b, 1991, 1992). A critical
aspect of benzodiazepine function is that the benzodiazepine
has no intrinsic inhibitory effect. It solely potentiates the
effect of endogenous GABA. In the theta frequency
integrator (assuming this depends on recurrent GABAergic
inhibition), the benzodiazepines would increase the inhibitory power of the pulsed release of GABA from
interneurones. However, as the GABA was eliminated from
the synaptic cleft, the benzodiazepines would become
ineffective and cell firing could recommence, The benzodiazepine would thus increase the duration of effect of
endogenous phasically released GABA but without any
permanent effect on excitability and so it would increase the
interburst interval and so decrease the theta frequency of
burst firing of cells but without any general reduction in cell
firing (McNaughton et al., 1995).
However, tonically applied GABA would remain in the
synaptic cleft over tens of minutes rather than, like the
benzodiazepine, potentiating the effects of endogenous
GABA that would remain in the synaptic cleft only for tens
of milliseconds. It would be expected therefore to depress
firing generally and have little effect on the duration of
action of endogenously released GABA. Consistent with this
prediction, Jiang and Khanna found that GABA injected into
SuMp reduced the amplitude of theta, ultimately eliminating
it without reducing frequency. Their most significant finding
was that GABA injections also had this effect when injected
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
Fig. 7. Effects on hippocampal theta of injection of 0.5 mL procaine at different sites before and at indicated times after injection. (A) Effect of injection into the
medial septum. Note the almost immediate reduction in the amplitude of theta with, as shown by fast Fourier transform (FFT) no decrease in frequency. (B)
Mapping of effective and ineffective sites. The boxed areas were mapped and symbols indicate sites at which there was an effect. Rostral to SuM injections
reduced amplitude but not frequency (~) as illustrated in (A). Caudal to SuM injections reduced frequency but not amplitude (&) as illustrated in (C). In the
region of SuM both effects were obtained together (*). (C) Effect of injection into the midbrain, caudal to SuM. Note the substantial change in frequency with
minimal changes in amplitude. Adapted from Kirk and McNaughton (1993).
into SuMg. There are also indications that effects in SuMg as
well as SuMp can be produced in freely moving animals by
injections of muscimol (Saji et al., 2000).
The probability is, then, that the frequency of theta
depends in part on integration (summation) of the inputs to
SuMp cells (Kirk and McNaughton, 1991, 1993; Kirk, 1993;
McNaughton et al., 1995; Kocsis and Vertes, 1997; Vertes
and Kocsis, 1997; Bland et al., 1994; Kirk et al., 1996). But
both the anatomy and the effects of GABA suggest that
phasic activity could then be relayed laterally to SuMg,
which then sends its output rostrally into the medial
forebrain bundle and thence to the MS. Alternatively,
injections of procaine or benzodiazepine, nominally into
SuMp, might affect both it and SuMg with the SuMg cells
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
that project to the septum being the key location of
frequency integration. However, an exclusive involvement
of SuMg seems impossible given the tight localisation of
effects that can be demonstrated within SuMp (McNaughton
et al., 1995).
The most obvious frequency reductions produced by the
benzodiazepines (either by direct injection or implied by
injection of the antagonist after i.p. injection of the
benzodiazepine) are in SuMp. However procaine injections
directly into SuMg alter frequency as well as amplitude. If
SuMp were the sole site of frequency integration, one might
expect that SuMg procaine would reduce amplitude but not
frequency—as is observed with injections into more rostral
sites such as the medial forebrain bundle.
A frequency reducing effect of procaine in SuMg could
be due to an action on fibres of passage from more caudal
areas passing through SuMg on their way to SuMp. But there
are a wide variety of cell types intermingled in SuM. So it is
possible that, while SuMp and SuMg can be distinguished by
their containing distinct groups of cells unrelated to theta
rhythm, that they have in common a single type of thetacontrolling cells (possibly calretinin positive but not
substance P positive). These theta cells could then be
evenly distributed across what we have classified as SuMp
and SuMg. This suggestion is reinforced by data (Ito et al.,
2003), reviewed in Section 4, that suggests that fos reactivity
under conditions which activate hippocampus, is very strong
in SuMp but also present in SuMg and comes from calretinin
cells rather than, e.g. substance P cells. There may, then, be
distinct non-theta-related populations of cells (substance P
in SuMp and large cells in SuMg) embedded in a
homogenous group of theta-related cells (calretinin positive
spread through SuMp and SuMg). If this is true, however, it
is difficult to see why the projection from SuMp to MS
should be so weak relative to that from SuMg and why no
non-rhythmic cells have been found in SuMp (Kirk and
McNaughton, 1991). Further work, in particular extensive
mapping of SuMg with benzodiazepines, is required to
answer these questions.
SuM cells innervate both cholinergic and GABAergic
cells in MS/DBB (Borhegyi et al., 1998). These GABAergic
and cholinergic cells then innervate hippocampal cells and
are very likely to play a crucial role in theta rhythm
(Frotscher and Leranth, 1985; Lee et al., 1994; Freund and
Antal, 1988; Tóth et al., 1997; Smythe et al., 1992). The cells
in SuM are, despite their consistent firing rates, of different
types (as would be expected from its histochemical
complexity, see Sections 2.2.3 and 2.2.4). Four distinct
groups of cells fire at different phases of theta (Kocsis and
Vertes, 1997). Those firing in phase and 1808 out of phase
are likely to represent excitatory and inhibitory neurons and
to act as a lower level of the parallel cholinergic and
GABAergic systems (Kocsis and Vertes, 1997). This is not to
say that there is a cholinergic projection from SuM to the
medial septum. But there is reason to think that there are
cholinoceptive cells in SuM (whatever transmitter they
release in the septum) that contribute to the generation of
theta rhythm (Oddie et al., 1994). These cholinoceptive cells
are likely to receive their input from the cholinergic neurons
projecting from the MS/DBB and the laterodosal tegmental
nucleus to SuM.
Under urethane, then, theta rhythm appears to arise when
tonic activation of the reticular formation (particularly RPO)
is relayed through unknown nuclei to SuMp (and perhaps
SuMg) where it is integrated into phasic activity that is
relayed via SuMg to MS/DBB and thence to the
hippocampal formation. Consistent with this, under
urethane, phasic firing is not observed in RPO whereas
tonic theta-on cells are (Hanada et al., 1999). The generation
of phasic activity is likely to depend on both excitatory cells
and recurrent inhibitory interneurones, firing with different
phase relations to each other (Kocsis and Vertes, 1997;
Vertes and Kocsis, 1997).
However, there are two ways in which we must
complicate this already fairly complex picture. First, there
are descending influences that may be involved in
controlling the phase of theta or its amplitude (without
necessarily affecting frequency). Second, in freely moving
animals, other nuclei than the supramammillary nucleus can
help to control theta frequency.
3.1.4. Descending influences controlling SuM theta activity
That there are descending influences, even in urethaneanaesthetised animals, is shown by the fact that procaine
injection into the medial septum, that abolishes hippocampal
theta, reduces the number of spikes per burst of some SuMp
cells. However, this change in firing pattern was obtained
without any change in interburst interval and so without any
change in the frequency of theta (Kirk and McNaughton,
1991). This finding suggests the loss of an excitatory or
disinhibitory influence. Consistent with this, cells in SuMx
that fire tonically rather than phasically (Bland et al., 1995)
and become silent when hippocampus is showing theta may
act to ‘‘inhibit discharge of theta-on cells in the posterior
hypothalamus and SuM during non-theta hippocampal
states’’ (Bland et al., 1995).
However, procaine injection into MS that blocks theta but
not the rhythmic bursting of SuM cells has also been
reported to increase the number of spikes per burst (Kirk and
McNaughton, 1991) or to increase the theta burst frequency
of SuM cells (Kirk et al., 1996) (increased burst frequency
being a decrease in the interburst interval). This suggests that
hippocampal or septal output can inhibit SuM cells (Kirk et
al., 1996).
It seems likely that these different reported results may
stem from sampling of different cell types. Kirk and
McNaughton (1991) injected urethane i.p. and elicited theta
with a tail pinch (or allowed it to occur spontaneously) in
Sprague-Dawley rats. They reported that their SuM cells
fired on a single phase of hippocampal theta matching just
one of the four phase groups described by Kocsis and Vertes
(1997) mentioned in the previous section. By contrast, Kirk
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
et al. (1996) injected urethane through a jugular cannula and
elicited theta with RPO stimulation in Long-Evans rats.
These plus other possible consistent differences (such as
level of anaesthesia) could have resulted in them sampling
different cells, or the same cells in a different state, than Kirk
and McNaughton.
The four distinct groups of SuM cells that fire at different
phases of theta (Kocsis and Vertes, 1997) could then reflect
both excitatory and inhibitory cells that send output to the
medial septum (as already suggested above) and also
excitatory and inhibitory cells receiving input from the
hippocampus and related theta-generating structures.
For example, entorhinal aspartate/glutamatergic cells
innervate GABAergic neurons located at the border between
the LS and MS that, in turn, project to calretinin positive
SuMg cells (Leranth et al., 1999). These SuMg cells are
known to project to MS (Vertes, 1992), hippocampus (Nitsch
and Leranth, 1996) and so, closing the loop, entorhinal
cortex (Swanson, 1982). This descending GABAergic
pathway is likely to exercise an inhibitory influence on
SuM. There may also be a descending excitatory pathway.
High doses of carbachol injected into RPO replaced theta
with sharp waves in the hippocampus and SuM and
transection rostral to SuM returned it to theta activity (Kirk,
1997). Matching the ascending parallel excitatory and
inhibitory pathways controlling theta, there may then be
parallel descending excitatory and inhibitory pathways.
Under conditions where these do not influence frequency of
theta as such (Kirk and McNaughton, 1991) it is likely that
they are nonetheless either involved in the control of
amplitude or are part of the phase reset system (Givens,
3.1.5. Multiple frequency integrators in freely moving
That SuMp is not the only area controlling theta in freely
moving animals is shown by the fact that large lesions of
SuM in freely moving rats did not affect the theta rhythm
accompanying spontaneous movement (Thinschmidt et al.,
1995). Nor do such lesions have large effects on reticularelicited theta (McNaughton et al., 1995). However, even
specific SuM dysfunction produced with either benzodiazepine infusion or chemical lesion can produce modest
decreases in theta frequency (by about 0.4 Hz) in some
behavioural schedules such as FI and DRL (see Table 1). In
these, the critical factor seems to be that the amount of
movement is either not increased extensively by the
treatment or is limited (e.g. by stereotypical execution) at
the points in time when theta is assessed (Pan and
McNaughton, 1997, 2002). With an FI schedule, injection
of chlordiazepoxide into SuM can affect theta and behaviour
as extensively as when it is injected i.p. (Woodnorth and
McNaughton, 2002a,b) and injection of the benzodiazepine
antagonist, flumazenil, can completely block the i.p. effects
of the drug (Woodnorth and McNaughton, 2002a,b).
These data suggest that SuM may determine the
frequency of even reticular-elicited theta (i) completely in
urethane-anaesthetised rats, but (ii) only partly in freemoving rats. Similarly, SuM may control the frequency of
theta under some behavioural conditions but not others and
cooperate with other structures in controlling theta in yet
further conditions. A complicating factor here is that
movement elicits theta and that SuM lesions can increase
movement. Where the absolute contribution of SuM to theta
frequency appears modest in behaving rats it may then have
a greater contribution relative to the specific level of the
animal’s movement. Stimulation of the SuM area can
produce limb stepping in anaesthetised rats (Sinnamon,
1984) but changes in theta were not assessed in this paper.
Movement–theta relations need, therefore, to be very
carefully controlled in future experiments. Despite this
quantitative caveat, SuM clearly cannot be the only nucleus
controlling theta frequency since theta activity can be
essentially unaffected and never totally disappears in freely
moving rats after even large SuM lesions that would be
expected to destroy the bulk of input fibres even when they
do not destroy all SuM cells (Thinschmidt et al., 1995;
McNaughton et al., 1995). Capsaicin, a neurotoxin that
selectively damages unmyelinated primary sensory neurons,
also hits the SuM core (Ritter and Dinh, 1988), which
suggests that the core of SuM might mediate sensory input.
This would be consistent with an involvement of SuM in the
controlling of theta that is elicited by tail pinch or reticular
stimulation rather than by movement.
There are reports of subcortical areas different from SuM
that contain cells showing theta activity (Kocsis et al., 2001;
Kocsis and Vertes, 1992, 1996) or even theta rhythm
(Routtenberg and Taub, 1973). But, unfortunately, none of
these have been challenged with septal blockade of
hippocampal theta and could easily be driven by hippocampal output rather than acting as hippocampal input. It
should also be noted that, given our hypothesis of theta
frequency integration through recurrent inhibition, both the
MS/DBB and the hippocampus itself (which contain the
appropriate circuits) have the capacity for intrinsic oscillation and could on occasion act as frequency integrators.
However, at present, there is no evidence that they ever do so
under normal conditions (as opposed to when, e.g.,
superfused with carbachol).
3.2. SuM and hippocampal modulation
SuM stimulation has been reported to have a potent
inhibitory effect on cells in the dentate gyrus with the
remarkably short latency of 3–5 ms (Segal, 1979) but also
has been reported to potentiate population spikes in the
dentate gyrus elicited by perforant path stimulation
(Mizumori et al., 1989; Nakanishi et al., 2001; Carre and
Harley, 1991). This apparent contradiction was resolved in
part by evidence that SuM stimulation that increased
population spikes was inhibiting inhibitory interneurones
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
(Mizumori et al., 1989). However, it should also be noted
that stimulation of noradrenergic or serotonergic fibres that
inhibit ongoing spontaneous single-unit activity also
potentiate population spikes, essentially because they
increase signal to noise ratio (Segal, 1977; Segal and
Bloom, 1974, 1976; Assaf, 1978; Assaf et al., 1979; Assaf
and Miller, 1978). It is possible, therefore, that SuM exerts a
similar influence, suppressing low levels of activity but
enhancing higher levels.
An important point to note, given the involvement of
SuMp in the control of theta frequency is that effective
stimulation sites for hippocampal potentiation were in
SuMg. Sites in SuMp are ineffective. Potentiation from SuM
or MS can be blocked by lesion of the dorsal fornix and
potentiation from SuM can be blocked by lesions of the
ascending columns of the fornix. However, critically, MS
lesions do not block potentiation from SuMg (Mizumori et
al., 1989). This suggests that potentiation arising in SuMg is
transferred directly to the hippocampus and is unrelated to
the pathways controlling theta frequency. Although SuMp
does not appear to be involved in population spike
modulation, a more general disinhibitory role for it has
also been suggested by the fact that its inactivation can
interrupt hippocampal epileptic discharge (Saji et al., 2000).
While SuMg stimulation can potentiate hippocampal
responses, stimulation in the region of RPO, at sites that can
also elicit hippocampal theta, suppresses hippocampal
population responses recorded in area CA1. Injections of
procaine into SuMp or SuMg or MS attenuate this
suppression (Jiang and Khanna, 2004). While it could be
that RPO stimulation was activating cells in SuMg that both
suppress CA1 responses and potentiate dentate responses
this seems unlikely since, as noted above, medial septal
blockade did not affect the latter whereas it does affect the
The effects of RPO stimulation on theta can also be
separated from its effects on CA1 suppression (Jiang and
Khanna, 2004). First, suppression is produced at stimulation
intensities that do not elicit theta and effects on theta
increase steadily with changes in intensity that produce
constant, maximal, suppression. Secondly, the time course
of the effects of neuronal inactivation with procaine on the
two responses is different. Thirdly, injections of GABA
affect theta when they are made in both SuMp and SuMg but
they only affect suppression of CA1 responses in SuMp.
3.3. Multiple influences of SuM on the hippocampus
We have evidence, then, for multiple direct and indirect
projections between SuM and the hippocampus. First, there
are the neurones that control dentate gyrus potentiation.
These are most likely to be one of the several cell types
located in SuMg but could perhaps also involve the direct
inputs from SuMp to the hippocampus that terminate on
CA2, CA3 and interneurones of the dentate gyrus. Next,
there are the neurones that control CA1 depression. These
appear to have their cell bodies located in SuMp but then
send their fibres laterally to pass through SuMg before
joining the medial forebrain bundle. Finally, there are the
neurones that control theta rhythm. These appear to be of
several types. First, there are cells in SuMp (and possible
SuMg) that determine the frequency of theta rhythm. These
are likely to be the start of an ascending GABAergic
inhibitory system that controls the timing of theta
activity. However, they do not project directly to the
GABAergic cells of the MS and it appears likely that cells in
SuMg relay their output. Certainly (Jiang and Khanna, 2004)
there are cells in SuMg that can control the amplitude of
hippocampal theta activity and it seems likely, therefore, that
two systems ascend from SuMg to control theta, one
relaying with the GABAergic cells and one relaying with the
cholinergic cells that together can control theta activity (Lee
et al., 1994).
4. Behaviour and c-fos activation of SuM
Activation, as shown by c-fos immunoreactive cell
mapping, is found in SuM neurons in response to either
electrical stimulation or microinfusion of the excitatory
amino acid kainate or of the GABA antagonist SR-95531,
applied to the medial hypothalamus—a defensive area
(Silveira et al., 1995). Electrical stimulation of the dorsal
CG, another defensive area, resulted in striking c-fos
immunoreactivity in SuM (Sandner et al., 1992). SuM is also
one area (others, Fig. 8, include the piriform and entorhinal
cortices, amygdala, CG and DR) in which fos immunoreactivity was induced by 15 min exposure of rats to the
elevated plus-maze, an ethologically based animal model of
anxiety that involves no explicitly noxious stimulation
(Silveira et al., 1993). Placing rats in a novel open field,
which is also a task used to assess animal anxiety, showed
that fos-like immunoreactivity was significantly more
common in SuM cells projecting to the hippocampus than
in those projecting to the midbrain (Wirtshafter et al., 1998).
Recent data further show that the strongest reactivity
induced by exposure to a novel open field is in SuMp (Ito et
al., 2003). SuM is also activated in animals trained to run a
radial arm maze when the maze is placed in a novel room
(Vann et al., 2000).
Interestingly, in the open field experiment (Ito et al.,
2003) there was a high level of fos reactivity in the dentate
and CA3 (as well as CA1) which, in the rat, receive input
from calretinin positive cells of SuMp but not in area CA2,
which is, in the rat, the only area receiving input from
substance P containing SuMp neurons. Consistent with this,
the fos reactivity, while much the strongest in SuMp was also
present in SuMg which also contains calretinin cells. There
may, then, be distinct functional populations of cells
(substance P in SuMp and large cells in SuMg) embedded
in a homogenous group of cells (calretinin positive in SuMp
and SuMg).
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
Fig. 8. Areas showing c-fos reactivity in response to exposure to an elevated plus maze. There is clear selective activation of the supramammillary area in
contrast to more lateral hypothalamic areas and to the mammillary bodies. More anterior portions of the hypothalamus also show reactivity as do parts of the
superior colliculus, thalamus, central gray, amygdala, and ventrolateral portions of the cortex (adapted from Silveira et al. (1993)).
SuM also is one of the only two structures in the brain (the
other is retrosplenial cortex) which show a decrease in fearinduced c-fos expression with low dose diazepam (Beck and
Fibiger, 1995). It is important to note, here, that the
procedure they used was contextual rather than simple CS
fear conditioning and that the diazepam produced a doserelated decrease in freezing to the context. This is consistent
with the involvement of SuM in contextual fear conditioning
described below. These data suggest that the core of SuM
plays a role in defensive function and in the actions of
anxiolytic drugs. In the open field, at least, the shell does not
appear to be involved (Ito et al., 2003).
SuM also expresses fos protein after cold or warm
ambient exposure (Kiyohara et al., 1995; Miyata et al., 1995)
or swim stress (Cullinan et al., 1996). More recently, a fos
study (Lin et al., 1998) showed clearly that SuM is also one
of the areas in which a significant number of fos-positive
neurons in parturient and lactating rats was observed as
compared to virgin or pregnant female rats. This activity
may be in the cells that contain estrogen receptors and
control spine synapse density in the hippocampus (Leranth
and Shanabrough, 2001). The number of c-fos labelled
neurons also increased in the core of SuM, especially in
SuMp, after intravenous injection of naloxone (an opioid
antagonist)—and the endogenous opioid system is thought
to be involved in cardiorespiratory function and emotional
and learning processes (Gestreau et al., 2000). All these data
suggest that SuM may play a role in physiological stress and/
or emotional stress.
Consistent with this, the areas of increased fos activity are
almost all structures of the limbic system. However, despite
its being conventionally seen as a critical node of the limbic
system, the hippocampus appears silent. This is all the more
surprising, given the demonstrated functional involvement
of the hippocampus in behavioural tests that demonstrate
SuM c-fos activation, such as the open field (Harley and
Martin, 1999; Hausheer-Zarmakupi et al., 1996; Herman et
al., 1998; Rossi-Arnaud and Ammassari-Teule, 1992), and
given the involvement of the hippocampus in the control of
stress hormones (Bhatnagar et al., 1997; Born and Fehm,
1998; Brake et al., 1999; Ferrini et al., 1999; Herman et al.,
1998; Uno et al., 1989).
There is also activation of SuM in the water maze during
reference and working memory forms of the task (Santin et
al., 2003). There will, of course, be effects of swim stress in
these rats (Cullinan et al., 1996), but the increases in trained
rats were relative to controls that received equivalent
swimming time in the water maze. Interestingly, there was
somewhat greater activation in the working memory than in
the reference memory form of the task. There is also
activation of SuM by exposure to an eight-arm (as opposed
to one arm) radial maze condition (Vann et al., 2000).
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
Surprisingly, given the above results, ventral tegmental
injections of carbachol that induce c-fos expression
throughout the brain, presumably related to the rewarding
effects of the injections, seem to have a special effect in
relation to SuM. Significant correlations between locomotion and c-fos-positive nuclei were found in the retrosplenial
area and the posterior hypothalamus including the supramammillary nucleus. The authors focus on the retrosplenial
area and supramammillary nucleus as areas that may,
therefore, be parts of the circuitry for the reward triggered by
ventral tegmental cholinergic stimulation (Ikemoto et al.,
2003). This would not seem unreasonable given the presence
of dopaminergic cells in SuM—but there is no other
behavioural evidence for a link between SuM and reward.
5. SuM dysfunction and behaviour
The electrophysiological data (both from theta and from
analysis of hippocampal evoked potentials) suggest links
between both SuMp and SuMg and the modulation of
hippocampal processing. SuMs projects to the entorhinal
cortex which is one of the major inputs to the hippocampus
proper. These data all suggest that lesions of SuM should
affect some behaviours in the same way as hippocampal
Similarly, the c-fos data suggest that SuM is involved in
emotional behaviour, particularly defensive behaviour, and
that it is involved in at least some aspects of anxiolytic drug
action. While the hippocampus is most often seen as being
involved in memory rather than emotion, it should be noted
that there are many apparently emotional tests (e.g.
contextual fear conditioning) where hippocampal lesions
have significant effects. The hippocampal formation has also
been suggested to be the core of a ‘‘behavioural inhibition
system’’ that mediates anxiolytic drug action (Gray, 1970,
1976, 1982; Gray and McNaughton, 2000).
Both for some cognitive and some emotional tasks there are
reasons (direct or indirect) to expect some similarity between
the effects of SuM lesions and hippocampal lesions. However,
SuM also has major descending connections with lower levels
of the defense system and ascending connections with a
multitude of limbic and extralimbic structures—although not
being included in what some might see as the systems most
fundamentally controlling defense (Risold and Swanson,
1997). A question for the current section, therefore, is: ‘‘to
what extent do SuM lesions have effects specifically related to
the non-hippocampal connections of SuM’’? These nonhippocampal connections, although they have not been
electrophysiologically characterised, appear anatomically to
be at least as important as the hippocampal ones.
5.1. Methods of inducing SuM dysfunction
Given the location of SuM, close to the medial forebrain
bundle and mammillary peduncles, specific conclusions can
only be drawn with fibre sparing lesions. Likewise, given its
depth in the brain, damage to more dorsal structures needs to
be minimised. Pan and McNaughton (2002) developed an
appropriate ‘‘minimal lesion’’ technique, using silica
capillary tubing (140 mm external diameter) as an injection
needle to minimize damage to the SuM, adjacent structures
and all structures in the path of the needle. They compared
the effects of the two popular neurotoxins—ibotenic acid
and AMPA. They found that both ibotenic acid and AMPA
injected into SuM destroyed both SuM and adjacent
neurons. However, importantly, AMPA had no effect on
the cells in the mammillary bodies (Fig. 2). With this latter
technique, and small injections, it was possible to directly
investigate, for the first time, the effect of fairly large
selective lesions of SuM on behaviour.
An alternative technique that has proved successful is to
inject a benzodiazepine or GABA into SuM. Benzodiazepines reduce the frequency of hippocampal theta when
injected systemically (McNaughton and Sedgwick, 1978;
McNaughton and Coop, 1991) or directly into SuM
(McNaughton et al., 1995). At least in urethane-anaesthetised rats, GABA injected into SuM can reduce the
amplitude of theta and block it but without reducing
frequency (Jiang and Khanna, 2004).
It should be clear from the complex anatomy of SuM and
from these simple electrophysiological results that it is
important to record concurrent hippocampal theta activity
when using these treatments. The treatment may reduce
theta frequency or amplitude selectively and could also,
clearly, have major effects on some parts of SuM without
altering theta at all. The situation, as will be seen, is further
complicated by the fact that whether SuM is involved in the
control of theta depends on the behavioural state of the
5.2. Spatial cognition
The Morris water maze (Morris, 1984) is perhaps the
quintessential test of hippocampal function (Morris et al.,
1982). A key point is that it is a test of active rather than
passive avoidance—a class of learning that is not normally
affected by hippocampal lesions (Gray and McNaughton,
1983). It can be viewed, then, as a test of cognitive aspects of
hippocampal function rather than of defensive systems.
Spatial working memory can be tested in a single-day of
continuous training in the water maze task (or assessed by
within day changes with small numbers of trials). Spatial
reference memory can be tested with multiple days of
With four trials per day for 4 days, systemic benzodiazepine treatment (5 mg/kg, i.p. chlordiazepoxide prior to
each day’s testing), which might be expected to reduce theta
frequency, impairs learning (McNaughton and Morris,
1987). By contrast, with the same behavioural testing quite
large (albeit incomplete) lesions of the core of SuM (made
well prior to training) decrease theta frequency only
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
modestly (by about 0.4 Hz) and produce little effect on
spatial reference memory or swimming speed. Lesions of
SuMs4 did not impair learning or theta (Pan and
McNaughton, 2002). With multiple trials (and so complete
learning) within 1 day, systemic benzodiazepine produces a
large impairment in spatial learning and concurrent with
this relatively large impairment it produces a reduction in
theta frequency of about 1 Hz (Pan and McNaughton,
1997). By contrast, benzodiazepine infusion into SuM,
decreased theta frequency by only 0.35 Hz in the first two
trials and, at this time, produced no obvious learning
impairment. A learning impairment did appear about the
seventh trial.
There could be, here, a partial confound. The rats were
exposed to water for over 10 min and all rats in the
experiment showed a logarithmic decrease in theta
frequency over the course of training. Pre-exposure to
water both decreases theta frequency (Whishaw and
Vanderwolf, 1971; Pan and McNaughton, 1997) and impairs
water maze learning (Pan and McNaughton, 1997). While
the injection of benzodiazepine into SuM produced a modest
behavioural effect in the late trials of this experiment, it also
produced more of a reduction in theta frequency at this time
when the effect of the drug might be expected to be wearing
off. Primary treatment-induced deficits may then be
potentiated by decreases in body temperature. SuM does
not appear, therefore, to play a major role in either spatial
working memory or reference memory or, indeed the theta
that accompanies these tasks. However, the data are
consistent with the idea that the small effect on theta
frequency in early trials may have impacted on immediate
consolidation (rather than working or reference memory as
such) and so have affected later trials. If so, this would be
consistent with effects on passive avoidance discussed
This conclusion is consistent with the bulk of results from
electrical lesion of SuM and the mammillary bodies in the
radial arm maze (Jarrard et al., 1984). Large lesions of the
mammillary bodies, SuM and surrounding tissue (including
the ventral tegmental area and premammillary nuclei) do not
affect visual–spatial conditional associative learning (Sziklas et al., 1995) although such lesions do impair radial arm
maze learning. Smaller lesions, still including the medial
mammillary bodies and SuM, do not affect radial arm maze
learning (Sziklas and Petrides, 1993, 1998; Sziklas et al.,
1996). An important point, when we consider later tests, is
that the data show only that SuM is minimally involved in
both the control of behaviour and theta in the water maze.
Theta activity itself (controlled by some other area) is
involved in spatial learning, since systemic benzodiazepine
or cooling by water exposure both decreased theta frequency
by about 1 Hz (to lower then 6.5 Hz) and clearly impaired
spatial learning.
SuMs is designated LH by Pan and McNaughton (2002) following
Paxinos and Watson.
5.3. Exploratory and defensive behaviour
Defensive behaviour has been categorised into three
levels (Blanchard and Blanchard, 1988). Exploratory
behaviour (when danger is uncertain or weak) is the first
level of defense and so we have included it in the current
section. The second level is that of freezing or avoidance
when danger has been identified but is not immediate. The
third level involves fight/flight or rage/panic when danger is
The open field is a common test for exploration (the first
level of defense). Neurotoxic lesions of the core of SuM
increase exploratory ambulation but do not reduce the
average frequency of theta (Pan and McNaughton, 2002).
Electrolytic lesions of SuMp and SuMg also appear not to
affect theta frequency during ambulation (Thinschmidt et
al., 1995). Interestingly, injection of a benzodiazepine into
SuM had no effect on theta frequency in the open field, but
did reduce theta frequency when this was elicited by
reticular stimulation (Pan and McNaughton, 1996). This
confirms that a particular treatment can affect theta elicited
by one stimulus while not affecting theta elicited by a second
stimulus. Lesions of SuMs did not impair behaviour and
theta in this task.
Probably the simplest test for the next level of defense is
fear conditioning (LeDoux, 1995). An interesting point
about fear conditioning in relation to the hippocampus is that
hippocampal lesions impair conditioning of fear to the
context in which conditioning is carried out but do not
impair conditioning to the discrete fear stimulus itself
(Phillips and LeDoux, 1992, 1994). Neurotoxic lesions of
the core of SuM also decrease contextual fear conditioning
(i.e. decrease freezing and so increase movement) without
affecting conditioning to the discrete stimulus (Pan and
McNaughton, 2002). Lesions of the mammillary bodies,
including SuM, also do not affect taste aversion conditioning
(Sziklas and Petrides, 1993).
A related test is passive avoidance (Gray and McNaughton, 1983). This has been tested with reversible inactivation
of SuM by lidocaine (Shahidi et al., 2004). This has the
disadvantage relative to neurotoxic lesions that effects can
be due to either cells or fibres of passage but has the
advantage that the time of inactivation can be varied. They
found that retention (but not immediate acquisition) of
passive avoidance was impaired by SuM inactivation either
before or 5 min after acquisition. However, SuM inactivation at 90 or 360 min after acquisition or inactivation during
the retention test did not have this effect. Importantly, this
study (particularly with the effects obtained with injections
5 min after training) suggests that SuM is involved in the
consolidation of the acquired information rather than initial
learning or later retention. Consistent with this (but
potentially a result of state dependency or spread to the
mammillary bodies) injections of benzodiazepines into SuM
appear to release punished (but not unpunished) responding
in a conflict schedule (Kataoka et al., 1982) and lesion of the
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
mammillary area including SuM increased approach
and aggression towards an intruder in rats (Olivier et al.,
5.4. Behavioural inhibition
Passive avoidance is a test not only of defense but also of
behavioural inhibition—a postulated fundamental function
of the hippocampus (Gray, 1982; Gray and McNaughton,
2000). Behavioural inhibition can be tested without the use
of shock in non-reward schedules such as FI and DRL (see
Table 1).
With FI, injections of benzodiazepine into SuMp
produce increased responding and a concomitant decrease
in theta frequency—and these effects are as large as the
effects of i.p. injection of benzodiazepine (Woodnorth and
McNaughton, 2002a,b). The benzodiazepine antagonist,
flumazenil, injected into SuM also totally blocks the effect
of the systemic drug on theta frequency (Woodnorth
and McNaughton, 2002a,b). This suggests a particularly
strong involvement of SuM with behavioural inhibition,
in contrast to its weak involvement in spatial learning.
Interestingly, neurotoxic lesions of either the core
(SuMp + SuMg) or the shell (SuMs) increase responding
and so impair inhibition. In contrast to defensive behaviour,
however, and consistent with the effects of benzodiazepine
injections in the same task, the change in behaviour
produced by lesions of the SuM core is accompanied by a
clear decrease in theta frequency of about 0.4 Hz (Pan and
McNaughton, 2002). Lesions of SuMs by contrast did not
reduce theta frequency. There was also a different response
pattern between lesions of the core and the shell. The
rats with core lesions showed more responding at the end
rather than the beginning of the fixed interval, while the
rats with shell lesions showed a high response rate over
the whole interval.
Neurotoxic lesions of the SuM core also produced
increased responding in DRL. The results here are
particularly interesting as theta could be recorded in relation
to both rewarded and non-rewarded trials (in FI the vast
majority of responses are non-rewarded). SuM lesions
decreased theta frequency (by about 0.4 Hz) immediately
prior to non-rewarded responses but not immediately prior to
rewarded responses. This shows, within a single task, a
dissociation of involvement and lack of involvement of SuM
in the control of theta and, most importantly, it does so under
conditions where the nature of the motor response is
essentially the same. This suggests that SuM is involved in
the control of theta under some psychological circumstances
but not others.
5.5. SuM lesions compared to hippocampal lesions
This review has focussed to an extent on the relation
between SuM and the hippocampus. SuM is involved in the
control of hippocampal theta activity and also, apparently
via separate neurones, in hippocampal excitability and
plasticity. However, both in terms of the different types of
neurones in SuM and in terms of its diverse connections with
structures other than the hippocampus we should expect
only partial, and indeed quite small, overlap between
supramammillary and hippocampal function.
The observed overlap between the behavioural effects of
supramammillary lesions and hippocampal lesions, however, is at present almost total (Table 2). This might not be
surprising since the tasks have largely been chosen to test a
supramammillary–hippocampal relation. They would not,
therefore, be likely to demonstrate effects of supramammillary lesions that did not mimic hippocampal lesions.
However, there are two important points to note here. First,
with the exception of the radial arm maze, in all the cases so
far tested if hippocampal lesions have an effect then
supramammillary lesions or injections of chlordiazepoxide
also have an effect. Supramammillary effects are of course
smaller. The supramammillary lesions (or drug injections)
produce subtotal dysfunction. Further, even a total loss
of theta rhythm (and perhaps hippocampal non-theta
modulation) should not produce the equivalent of total
removal of the hippocampus. Nonetheless the qualitative
pattern of positive results is surprisingly complete. The
case where hippocampal lesions are without effect (simple
fear conditioning) also shows complete concordance—a
Table 2
The effects of SuM or hippocampal dysfunction on behaviour
Open field
Fear conditioning (CS)
Fear conditioning (context)
Passive avoidance
FI (rate of response)
DRL (rate of response)
Water maze
,a, +j
Measure increased (*) or decreased (+) or unchanged (,). More arrows
indicate larger effects. Question marks indicate marginal and/or inconsistent
effects. All SuM effects (except passive avoidance) confirmed with fibresparing techniques (neurotoxic lesion or synaptically active agent injected
into SuM). For a detailed review of the effects of hippocampal and septal
lesions see Gray and McNaughton (1983).
Pan and McNaughton (2002). Note: SuMs is designated LH by Pan and
McNaughton (2002) following Paxinos and Watson.
Rossi-Arnaud and Ammassari-Teule (1992), Earley et al. (1992),
Stefanski et al. (1993) and Cannon et al. (1992).
Phillips and LeDoux (1994, 1995).
Shahidi et al. (2004).
Best and Orr (1973), Brunner and Rossi (1969), Kveim et al. (1964) and
Miller et al. (1975).
Woodnorth and McNaughton (2002).
Manning and McDonough (1974) and Rabe and Haddad (1968).
Jarrard and Becker (1977), Acsádi et al. (1986), Woodruff et al. (1987)
and Tonkiss et al. (1988).
Sziklas and Petrides (1998).
Pan and McNaughton (1997).
Morris et al. (1982) and Moser et al. (1995).
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
dissociation of simple fear conditioning from contextual fear
conditioning by supramammillary lesions.
Taken together, the studies summarised in Table 2 show
that dysfunction of the core of SuM (the shell has not been
specifically tested) in rats produces a pattern of changes in
both simple motivated and emotional behaviours that is
qualitatively similar to the pattern produced by hippocampal
lesions. This said, it should be noted that effects on spatial
learning in the water maze were barely detectable with
benzodiazepine injection and essentially absent in rats with
small neurotoxic lesions that were adequate to produce
effects in other tasks. The Morris water maze is highly
sensitive to hippocampal lesions (Morris et al., 1982;
McDonald and Hong, 2000) and this suggests that SuM may
be more involved in changes in emotional behaviour (as
exemplified by behavioural inhibition according to Gray and
McNaughton (2000)) that can be produced by hippocampal
lesions than by changes in cognition. The apparent lack of
effect of SuM (and mammillary) damage in the radial arm
maze is consistent with this suggestion. On the other hand, it
should be born in mind that, to produce relatively specific
medial SuM dysfunction, the lesions used were far from
complete in the anterior, posterior and lateral directions as
will have been true also of the spread of injected drugs.
Estimation of the extent of involvement of SuM in these
behaviours would require total lesion of SuM with
appropriate control lesions damaging the same areas outside
SuM while sparing SuM itself as far as possible. It also
seems likely that damage to both SuMg and SuMp would be
required to maximize elimination of hippocampal modulation by SuM.
6. SuM, behavioural change and theta frequency
The neurophysiological data make it clear that SuM is not
the only nucleus involved in the control of theta. With
reticular stimulation even large lesions of SuM produce only
a modest reduction in theta frequency (McNaughton et al.,
1995). The behavioural data reinforce this picture with,
in the DRL task, a lack of change in theta frequency
immediately before rewarded responses and a reduction
in theta frequency immediately before non-rewarded
responses. Given that lever pressing is likely to be
stereotyped and given that theta frequency anticipates
upcoming movement (Morris and Hagan, 1983) this strongly
suggests that the control of theta frequency shifts between
SuM and other areas depending on immediate task
While the DRL task suggests highly labile control it
does not allow us to dissect out the possible functional
relationships between the control of theta by SuM and
its involvement in behaviour. Here the results in the
Morris water maze are of particular interest. SuM
dysfunction had either a very small or no effect on theta
frequency and other treatments (including reduction of
temperature with which SuM dysfunction appeared to
interact) that reduced theta frequency also reduced spatial
learning in proportion to the frequency reduction. (See
below considerations of relative frequency reduction
versus absolute frequency achieved.) Likewise, in FI,
benzodiazepine injection into SuM produced an equivalent
reduction in theta frequency to that of systemic injection
and concurrently produced an equivalent change in
behaviour. In all these cases, then, a sufficient reduction
in theta frequency appeared to produce a change in
behaviour. Conversely the minimal effects of SuM
dysfunction on behaviour could, potentially, be attributed
to its minimal effects on theta frequency.
6.1. Theta frequency change and behaviour: relative
change or absolute value?
Where there are relatively large changes in theta
frequency we cannot tell whether it is the size of reduction
in frequency that is important or a transfer of treated
animals from above to below a critical functional threshold
for frequency. Where changes are small, as with SuM
dysfunction, it becomes possible that the same relative
change might affect behaviour or not depending on the
absolute frequency achieved in the control and treated
group. Poor performance might be observed only in treated
(or control) rats whose frequency was below a particular
threshold value.
Certainly, changing theta frequency seems to be the
common link between the behavioural effects of quite
different treatments. Decrease of body temperature or
systemic benzodiazepine both change theta frequency and to
similar extents. They also impair spatial working memory to
similar extents. Givens and Olton (1990, 1994, 1995) and
Givens (1995) also suggested spatial working memory is
theta-dependent. They tested working memory in a
continuous conditional discrimination task and reference
memory in a sensory discrimination task after infutions of
tetracaine, scopolamine, or muscimol into the medial
septum or the nucleus basalis magnocellularis (NBM).
MS infusion suppressed theta activity (amplitude) and
impaired working memory but not reference memory. NBM
infusion impaired reference memory but did not change
theta. In a T-maze task, tetracaine, scopolamine, or
muscimol into the medial septum decreased spatial working
memory and theta, and so did low doses of ethanol.
The pattern is more complex when we look at the smaller
effects produced by SuM lesions. In the water maze, Pan
and McNaughton (2002) found no effect on spatial
reference memory and only slight signs of an effect on
spatial working memory with lesions that reduced theta
frequency from 7.5 to 7.1 Hz (0.4 Hz). By contrast, a
significant (albeit small) effect on spatial working memory
was obtained by Pan and McNaughton (1997) with
benzodiazepine injections but: (a) this effect only appeared
later in training when theta frequency was reduced (relative
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
to control) from 6.0 to 5.5 Hz (0.5 Hz) and (b) was not
seen earlier when theta frequency was reduced from 7.5 to
7.15 Hz (0.35 Hz).
Pan (2000) reanalyzed the raw data of Pan and
McNaughton (1997) to investigate the detailed relationship
between frequency and spatial learning. He analyzed the
relationship between theta frequency and performance
efficiency over trial blocks 3–4, 5–6 and 7–8 in both the
control (SuM saline injected) and treated (SuM benzodiazepine injected) rats. As can be seen in Fig. 9, the water maze
performance tended to be poor when the theta frequency
dropped below about 6.5 Hz in both control and treated rats.
Water maze performance appeared good when theta
frequency was above about 7 Hz.
These water maze data suggest that there may be a
threshold in the region of 6.5 Hz below which frequency
must drop to produce substantial impairments. Consistent
with this, systemic benzodiazepine and ‘‘long cooling’’
exposure decrease the frequency to 6.5 Hz at the beginning
of training and impair learning clearly, but ‘‘short cooling’’
exposure decreases theta frequency to 6.8 Hz and has no
significant effect on the learning (Pan and McNaughton,
1997). With increasing dose of ethanol, frequency decreased
and at 1.0 g/kg, when a clear impairment of spatial working
memory was obtained, theta frequency dropped to about
6.38 Hz (Givens, 1995).
With operant schedules the same kind of pattern emerges.
Pan and McNaughton (2002) obtained reductions from 7.3
to about 6.75 Hz (0.55 Hz) with clear but relatively modest
changes in behaviour. Woodnorth and McNaughton
(2002a,b) obtained reductions from 7.0 to 6.3 Hz
(0.7 Hz) and obtained a substantial change in behaviour
(indeed one identical in size to systemic injection of the
There is a tendency for larger reductions in frequency to
have been produced against the background of a lower
control frequency and so these data cannot easily separate
the effect of the size of reduction from the absolute value of
theta frequency obtained. However, the individual data
shown in Fig. 9 suggest that it is the reduction of frequency
of theta below a critical threshold value that is functionally
important rather than the relative difference between the
theta frequencies of treated and control rats. That said, in
both cases, it is clear that some form of threshold is
operating. Behaviour is not changed until a sufficiently
substantial effect is obtained on theta. The same may be true
of increases in frequency above the norm. This suggests that
future experiments may need both to monitor theta
frequency and to attempt to produce dysfunction that is
both large and specific.
Fig. 9. Relationship between theta frequency and performance in the water
maze. (A) In general over the course of training (trials 3–4, 5–6, 7–8, data
across the pair of trials were averaged for each individual rat) there is an
inverse relationship between theta frequency and distance traveled to reach
the hidden platform. Thus a higher frequency is related to better performance. This relationship is essentially similar for both rats receiving
injections of the benzodiazepine chlordiazepoxide (CDP) in SuM and saline
(SAL) injected controls (compare fitted curves). There is some suggestion
that this effect is due to a deterioration in performance when the frequency
drops below a threshold value of about 6.5 Hz (dashed vertical line). This
suggestion is supported by the data in B. (B) Manipulations of SuM
produced a change in theta frequency relative to their controls that was
as large as that of cooling water relative to its control. Yet the latter had a
much greater effect on performance. Systemic administration of CDP
produced a greater change in frequency relative to its control than did
cooling water, but these two manipulations reduced frequency to about the
same absolute value (below 6.5 Hz) while both their controls were above
6.5 Hz, and they produced similar changes in performance relative to their
controls. Data re-analyzed from Pan and McNaughton (1997, 2002).
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
6.2. Changes in behaviour with no absolute change in
theta frequency
In the water maze and operant schedules theta and
behaviour both changed. However, SuM lesion did not
change theta frequency during either of the defensive tasks
in which it was measured, despite its ability to change
behaviour. One possible explanation of this is that the
increase in movement produced by the lesions produced an
increase in theta. This increase in movement then counteracted a concurrent lesion-induced decrease in theta
frequency. Certainly the normal relation between movement
and frequency must have been disturbed or an increase in
theta frequency would otherwise have been observed.
However, it is difficult to see this providing a total
explanation of a lack of frequency reduction. The data
suggest, then, that changes in defensive behaviour produced
by SuM dysfunction are not totally mediated by changes in
There are two ways in which an uncoupling of defensive
behaviour and theta is consistent with other data in this
paper. First, there is modulation by SuMg of the
hippocampus that is independent of theta. We would expect,
therefore, at least some SuM-induced changes in behaviour
mediated by the hippocampus to be independent of theta.
Secondly, SuM has extensive non-hippocampal connections,
including direct connections with the defense system.
Indeed, in this context, its connections with the hippocampus could be viewed as just another part of its widespread
connection with the limbic system in general. Here any
parallels with the behavioural effects of hippocampal lesions
could be the result of output from both SuM and
hippocampus affecting common targets.
In relation to defense, indeed, even the functional links
between SuM and the hippocampus are likely to involve not
only ascending pathways but also descending. There are
connections from the septo-hippocampal system, via LS to
SuM and thence to CG. This would allow SuM to mediate
the effects of hippocampal output on defensive behaviour
without interacting with the outputs that alter spatial
learning. This suggestion is consistent with the fact that
water maze learning involves quite different systems from
defensive behaviour (Roozendaal and McGaugh, 1997;
Roozendaal et al., 1996, 1998). SuM also connects to the
amygdala and the amygdala–CG path is regarded as a central
part of an emotional system (LeDoux, 1995; Fendt and
Fanselow, 1999). We would, therefore, expect SuM to alter
defensive behaviours in addition to those affected by
hippocampal lesions.
Here, the results with fear conditioning are somewhat
surprising. Lesions of the septal (dorsal) portion of the
hippocampus affect contextual fear conditioning only
(Phillips and LeDoux, 1994, 1995). This dorsal hippocampal
control appears to be mediated by interaction with the
amygdala (LeDoux, 1995). The amygdala, by contrast,
controls both contextual and CS conditioning of fear
(LeDoux, 1993a,b). Yet, despite its direct connections to the
amygdala, SuM lesions act more like dorsal hippocampal
than amygdala lesions. There are indications that the
temporal (ventral) portion of the hippocampus is involved in
both simple and contextual fear conditioning, like the
amygdala, and is relatively uninvolved in spatial learning
(Richmond et al., 1999). We will argue shortly that SuM
receives information more from the septal portion than the
temporal portion of the hippocampus. This would account
for its involvement in contextual as opposed to simple fear
conditioning. But it leaves unclear why it should be so little
involved in spatial learning. These data suggest that future
work may need to explore different defensive behaviours to
a greater extent and/or investigate the effects of more
complete SuM lesions. Equally, given the heterogeneity of
the amygdala, which is so great that it cannot be viewed as a
distinct structural entity (Swanson and Petrovich, 1998), the
targets of SuM and hippocampal connections in this region
could prove to be common and to be distinct from the
portions of the amygdala that mediate simple fear
7. SuM—an interface between cognition and emotion?
All the above suggests that SuM may be an important
cross-road linking higher cognitive and lower emotional
structures—so mediating cognitive–emotional interactions.
Here, rostral forebrain–SuM–CG pathways may be of
particular importance. SuM connects bidirectionally with a
range of structures including LS, ventromedial prefrontal
areas and the cingulate (Fig. 5). The LS plays a clear role in
defensive behaviour (Risold and Swanson, 1997). Lesions of
the ventromedial prefrontal cortex (prelimbic/infralimbic
cortex) impair anxiety-related behaviours, passive avoidance, and delayed response tasks often producing perseveration but, like lesions of SuM, they do not affect behaviour in
the Morris water maze (Heidbreder and Groenewegen,
2003). Anterior cingulate lesions can increase conditioned
fear responses, but also can ‘‘reduce the aversiveness or
perceived unpleasantness of nociceptive stimuli’’ and impair
some avoidance tasks as well as ‘‘produce dysfunctions in
the motor planning resulting from nociceptor stimulation’’
(Heidbreder and Groenewegen, 2003). Like ventral prefrontal cortex and SuM, anterior cingulate does not appear to
be involved in spatial learning (Heidbreder and Groenewegen, 2003).
SuM bidirectionally connects with the CG. CG is a
critical output structure for emotional behaviours. It
mediates the behavioural output of fear conditioning
(LeDoux et al., 1988; Wilson and Kapp, 1994; Fendt and
Fanselow, 1999), or fear to a natural predator (Canteras and
Goto, 1999), as well as anxiety-related behaviour in the open
field (McCarthy et al., 1995) and elevated plus-maze
(Schmitt et al., 1990, 2001; Silveira et al., 1993; Souza et al.,
1998). Similarly, SuM has bidirectional connections with the
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
raphe nuclei and a variety of hypothalamic structures
all of which are involved in the control of motivation and
Notwithstanding these bidirectional connections of SuM,
this review has presented a picture of SuM as tightly linked
to the hippocampus and related caudal limbic structures. In
part this is driven by the importance (and even now the
enigmatic nature) of the hippocampus coupled with the role
of SuM in hippocampal modulation and the control of
hippocampal theta activity. In greater part it is driven by the
fact that much of the research on SuM has taken a
hippocampal focus. However, one could also justify this
focus if we take the view that the bidirectional connections
of SuM reflect its involvement in a distributed system that
assesses the emotional and motivational value of stimuli
while its unidirectional connections represent outputs that
control cognitive processing. (There are of course,
descending feedback loops from caudal limbic structures
to SuM but these appear both less direct and less powerful
than the ascending inputs to them from SuM.) In this final
section, therefore, we will discuss the functions of SuM in
relation to the hippocampus before taking a more general
point of view.
7.1. SuM, behaviour and hippocampal function
For the purposes of this section we will treat the
entorhinal cortex and hippocampus proper as parts of an
extended hippocampal formation (Gray and McNaughton,
2000). Both show theta activity controlled by MS and both
receive direct input from more lateral portions of SuM and
send feedback to SuM that is relayed in the septum (Fig. 3).
SuM dysfunction produces hyperactivity in defensive
tasks, including passive avoidance, and non-reward schedules (increased bar pressing). This is similar to, but much
weaker than, the effect of hippocampal dysfunction in those
tasks. A critical point is that the hippocampal parallel
extends to a specific effect on contextual fear conditioning
with no effect on simple fear conditioning. In this respect,
SuM dysfunction is unlike amygdalar dysfunction.
However, SuM dysfunction has relatively little effect on
spatial learning in the water maze task. This dissociation is
made most clear by comparing injection of benzodiazepines
into SuM with systemic injections. In the water maze,
systemic benzodiazepine has substantial effects on both
theta frequency and behaviour; SuM injection has little
effect on either (Pan and McNaughton, 1997). By contrast,
in FI both types of injection have the same substantial effects
on both theta frequency and behaviour (Woodnorth and
McNaughton, 2002a,b). These data suggest that SuM plays a
more important role in relation to the involvement of the
hippocampus in behavioural inhibition (emotion) than
spatial learning (cognition). This is consistent with the
c-fos studies discussed earlier that implicated SuM in
emotional behaviours.
This raises a question: how does SuM dysfunction
impair emotional behaviours in ways that are similar to
those produced by hippocampal lesion if the same level of
SuM dysfunction does not have the same magnitude of
effect on the paradigm test of hippocampal function—
the water maze. This question can be answered in two
First, the relative lack of effect of SuM dysfunction in the
water maze is paralleled by a lack of effect on theta
frequency. The control of theta in the water maze (and its
benzodiazepine sensitivity) has partially transferred to
another structure. From this we can deduce (a) that larger
SuM dysfunction would show somewhat larger effects, but
(b) given the data with chlordiazepoxide, SuM involvement
in the water maze will never be as complete as in, for
example, FI. Conversely, in defensive situations and in
schedules requiring behavioural inhibition, SuM is more
substantially in control of theta and so can demonstrate a
greater functional contribution to behaviour.
Second, we need to consider the outputs of the
hippocampus. There is no evidence that its control of
spatial learning or spatial working memory is mediated by
defensive areas such as the amygdala. By contrast, its
control of defense would be expected to be mediated by
outputs to the amygdala and CG. SuM output is sent to the
same targets and so could produce the same effects as
hippocampal lesions (on defense)—but without requiring
any mediation by the hippocampus. This explanation
appears particularly likely for defensive tasks—as these
demonstrate substantially greater effects of SuM function on
behaviour than on theta relative to systemic benzodiazepine
injections. Mediation of the effects of SuM dysfunction by
the amygdala appears unlikely for FI—as this task is not
affected by lesions of the amygdala (Gray and McNaughton,
2000). Further, FI demonstrates essentially the same effects
of SuM dysfunction on behaviour as theta relative to
systemic benzodiazepine injection.
Thus SuM is likely to have two parallel effects on tasks
involving behavioural inhibition—an indirect effect on the
amygdala, CG and other structures mediated by changes in
hippocampal theta (which would themselves be larger than
the changes in theta seen in the water maze) and direct
effects on the amygdala and CG mediated by its outputs to
these structures (which would be irrelevant for spatial
learning). Thus SuM would be involved in both ascending
and descending control of these behaviours.
We would also expect future research to demonstrate
additional parallels between SuM and hippocampal function. The treatments we have considered have usually
targeted the core of SuM and, in addition, have often used
benzodiazepine injections in attempts to restrict effects to
the aspects of SuM that control theta. Further studies should
selectively target SuMp, SuMg and SuMs and aim to use
specific neurotoxic or pharmacological treatments aimed at
the cells that can modulate hippocampal responses
independently of theta. So far we have no specific evidence
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
that these SuMg cells have been affected significantly in any
behavioural task.
7.2. SuM, the amygdala and thalamus
Like the hippocampus and entorhinal cortex, the
amygdala and thalamus primarily receive direct input from
SuM with any feedback to SuM being relayed in other
structures. To some extent all these targets of SuM afferents
can be seen as dealing with more cognitively than
emotionally loaded information. For example, as noted
already, the connection of SuM with the amygdala (as the
connection of the hippocampus with the amygdala) may
modulate contextual fear conditioning but does not
modulate simple fear conditioning. This said, we should
remind ourselves (Section 7.1) that SuM appears not to be
greatly involved in more cognitively loaded tasks. SuM,
then, can be seen as dealing with classes of information that
are to some extent common to the hippocampus and
amygdala—the more emotionally loaded aspects of hippocampal function and the more cognitively loaded aspects of
amygdalar function.
The role of the thalamus is unclear in this context.
However, it too can be seen as involving cognitive–
emotional compounds if we can presume that SuM is
making connections in the thalamus with components of the
Papez circuit and so modulating information being passed
from the mammillary bodies to the thalamus and so affecting
interactions of the latter with neocortex (Parmeggiani et al.,
1971, 1974). The direct output from SuM to the mammillary
bodies (Gonzalo-Ruiz et al., 1992a,b) may be involved in
similar control. We have argued previously that a critical
function of theta activity may be to pace the passage of
information round the Papez circuit and related hippocampal–neocortical loops (Gray and McNaughton, 2000) that
are likely to circulate information at frequencies in the theta
range (Miller, 1989, 1991).
One particularly interesting suggestion relates to the
mediodorsal thalamus. ‘‘We also found multi-unit activity
coherent with hippocampal theta EEG in the medial dorsal
nucleus of the thalamus. The medial dorsal nucleus does not
receive input from the mammillary bodies so is unlikely to
be part of the same re-entrant circuit as the anteroventral,
anterodorsal and anteromedial nuclei. However, the medial
dorsal thalamus is in receipt of afferent input from the
SuM. . . . Medial dorsal thalamus–perirhinal and hippocampal–anterior thalamic systems may well be capable of
independent theta generation and . . . independently coordinate task-related activity between nodes in their own
network [dealing with] item recognition and episodic
processes. . . . Appropriate coherent theta activity across
particular nodes would facilitate transfer of information
between systems’’ (Kirk and Mackay, 2003). It could be
added that although Kirk and McKay locate the anteromedial thalamic nucleus within the cluster of thalamic
nuclei supposedly receiving theta rhythmic information
from the hippocampus, via the mammillary bodies, it also
(Fig. 5) receives direct input from SuM and so could be
particularly involved in interactions between the two
postulated memory systems. Also remaining to be
fully categorised, but receiving direct unidirectional input
from SuM are the central medial nucleus and nucleus
reuniens. Under urethane, at least, the central medial
nucleus (which like SuM and nucleus reuniens receives
tonic, theta-related, input from the posterior hypothalamus)
shows only tonic theta-related activity and so would
appear to precede SuM in the generation of theta—likewise
high-frequency stimulation of nucleus reuniens elicits
rather than blocks theta (Bland et al., 1995; Kirk, 1998).
7.3. SuM and forebrain control of emotion
The forebrain structures we have considered so far
(Sections 7.1 and 7.2) return information to SuM only via
relays and can either be thought of as primarily cognitively
oriented (entorhinal cortex, hippocampus, thalamus) or
interacting with SuM only to execute limited emotional
functions (amygdala). Nonetheless, we argued that their
involvement with SuM was linked to some degree of
emotional content. We now turn to structures that are
reciprocally connected to SuM, that are more fundamentally
involved in emotion and that, interestingly, often
receive output from the structures we have already
considered. They are not only reciprocally connected with
SuM, therefore, but are also often components of feedback
loops to SuM.
Potentially the most revealing of these structures is the
LS. This is thought to be an important structure mediating
defensive behaviour and receives topographically organised
input from the hippocampal formation that it then relays,
topographically, to the hypothalamus (Risold and Swanson,
1996). From this perspective, the various LS–SuM connections can be seen as parts of a parallel system that
topographically maps specific parts of the hippocampal
formation into specific parts of the hypothalamus. This
system is likely to be involved in the hippocampal control of
emotion, and perhaps more specifically goal-directed
behaviour, more than cognition (Risold and Swanson,
1996). Similarly, the amygdala (like the hippocampus)
receives input from SuM and projects to the medial
hypothalamus and CG.
The main cortical areas reciprocally connected to SuM
are the infralimbic cortex, the dorsal peduncular cortex and
the cingulate cortex. As we noted above these all have some
claim to involvement in defensive behaviour (as well as
other motivated behaviours) and all also have reciprocal
connections to the amygdala.
‘‘Although the medial prefrontal cortex is clearly involved in
a variety of cognitive and emotional processes, its dorsal and
ventral subregions seem to be involved in different aspects of
the information processes. Thus, the dorsal part of the medial
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
prefrontal cortex (dorsal anterior cingulate and dorsal
prelimbic areas) is mainly involved in the temporal patterning
of behavioural sequences. In contrast, the ventral part of the
medial prefrontal cortex (ventral prelimbic area, as well as
infralimbic and medial orbital cortices) appears to be critical
for the flexible shifting to new strategies or rules in spatial and
visual-cued discrimination tasks and, perhaps even more
importantly, for the integration of internal physiological states
with salient environmental cues to guide behaviour in
situations of perceived threat or exposure to aversive stimuli.
. . . Prelimbic cortex [may be] responsible for voluntary
responses (goal-directed initial responding), whereas the
infralimbic cortex would mediate the progressive and
incremental ability of overtraining to lead to behavioural
autonomy and develop habits that are no longer voluntary or
goal-directed’’ (Heidbreder and Groenewegen, 2003).
The medial prefrontal cortex is topographically mapped
into the MS/DBB (Fig. 10). ‘‘More ventral regions,
including the infralimbic and ventral prelimbic areas,
project more densely to the septum and medial areas of
the basal forebrain, while the dorsal parts of the prelimbic
area and the anterior cingulate area project more laterally to
reach the horizontal limb of the diagonal band of Broca’’
(op. cit., p. 563). The medial septum and diagonal band, then
project topographically to ventral (temporal) and dorsal
(septal) portions of the hippocampus, respectively. The
ventral and dorsal aspects of the hippocampus then project
topographically via the LS (as noted above) to rostral and
caudal hypothalamus, respectively. The mapping achieved
by this putative polysynaptic pathway appears to be the same
(infralimbic cortex to rostral hypothalamus, anterior
cingulate to caudal hypothalamus) as the principle direct
projections from these areas. Further, ‘‘the different regions
of the medial prefrontal cortex . . . [also] project in a
topographical way to functionally distinct parts of the [CG
and so may] engage in parallel, functionally distinct
‘emotional motor’ circuits. These ‘emotional motor’ circuits
[would] underlie different aspects of integrated behavioural
and autonomic/endocrine responses, such as active and
passive coping with stress’’ [op. cit., p. 569].
Thus the rostral limbic cortex and lateral septum not only
share reciprocal connections with SuM but also appear to be
part of an extensive topographically homogenous system
(Fig. 10). They also all receive direct input from but do not
project directly to the hippocampal formation. Taking all of
the above areas together with the raphe nuclei and CG, we
can conclude that SuM has direct reciprocal connections
Fig. 10. Some selected structures and connections focussing on the role of SuM. SuM connects bidirectionally with rostral limbic cortex including the
infralimbic (IL) and anterior cingulate (AC) cortex. As described in the text this cortex is topographically mapped into the septum and topographic mapping
continues via the hippocampus, lateral septum and hypothalamus, as shown. (Note that dorsomedial septum is shown below the ventrolateral septum to simplify
the topographic mapping.) The mapping is illustrated for only one dimension in each structure but is, in fact, two-dimensional (with respect to flat sheet
representations of each level of the system). We postulate that the most extreme strands of this topographically organised system are specialised for more
cognitive (AC, septal pole of hippocampus) and more emotional (IL, temporal pole of the hippocampus) processing—but with each representing goals and thus
encoding conjunctions of cognitive and emotional features. This would be consistent with previous independent suggestions about the partitioning of function in
the cortical structures (Heidbreder and Groenewegen, 2003) and the hippocampus (Richmond et al., 1999). It would also be consistent with, for example, the
greater input from the amygdala to temporal portions of the hippocampus. In this descending scheme, SuM is just one of an array of hypothalamic structures
receiving topographically mapped input, presumed to be involved in the control of goal-related behaviour (Risold and Swanson, 1996). The direct connections
of the cortex to the hypothalamus appear to show the same mapping as the relayed connections. It is likely that the topographic mapping of the various parts of
the system extends to their connections with the central gray (CG). In contrast to the descending connections the ascending connections of SuM are quite diffuse
and passage of information around these recurrent circuits could, we postulate, control cognitive–emotional interactions.
W.-X. Pan, N. McNaughton / Progress in Neurobiology 74 (2004) 127–166
with structures, including rostral components of the limbic
system, that uniformly have a close involvement in the
control of emotion. SuM also has unidirectional projections
that connect it directly to more caudal aspects of the limbic
system but these can then provide feedback relayed through
the structures with which SuM has reciprocal connections.
7.4. SuM—a controller of cognitive–emotional interaction?
Given the tentative functional circuitry proposed in Fig.
10, we can now approach a suggestion as to the role of SuM.
The entorhinal cortex, hippocampus, thalamus (and possibly
the SuM-related aspects of the amygdala) are likely to be
involved in the processing of more cognitive components of
emotional reactions. They all receive input from SuM and,
directly or indirectly, can send output to alter the functioning
of structures more intimately involved in the generation of
emotional outputs. It seems likely, then, that a primary
function of SuM is to modulate cognitive processing
involved in emotional reactions. In this context, the control
of theta activity by SuM is likely to be just one of a range of
ascending influences it can exert on caudal limbic structures.
An involvement of these circuits in stress is suggested both
by the c-fos data in SuM and the fact that the hippocampus is
a major site at which there are corticosterone receptors and it
is involved in the control of the pituitary–adrenal axis
(McEwen, 1994, 1999; McEwen et al., 1969).
In turn, these primary targets of SuM output can send
relayed feedback to SuM. If theta activity is a guide here, this
relayed feedback is likely to be, in and of itself, fairly minor.
We have evidence for hippocampal control of the number of
action potentials per theta burst in SuM but this is related to
only minor alteration in theta frequency itself (Kirk and
McNaughton, 1991) and such alteration as can be demonstrated is an increase not a decrease in theta (Kirk et al.,
1996)—suggesting simple negative feedback. Further, while
the input of SuM to limbic cortical areas appears quite diffuse,
their output to SuM appears to be just one part of a tightly
topographically organized output to the hypothalamus as a
whole. Thus, only parts of these structures project to SuM and
the areas that do not project to SuM project, topographically,
to other areas of the hypothalamus. If other parts of the
hypothalamus contain additional controllers of theta (and
additional systems that modulate plasticity) then we can
imagine a system where rostral limbic areas, caudal limbic
areas and the hypothalamus are all similarly interconnected
with ascending connections being diffuse (one to all) and
descending ones being tightly topographic (one to one).
While there are some structures that appear to provide
unidirectional input to SuM, it seems likely that the bulk of its
significant input allows it to monitor activity in structures that
control emotion (as with CG) or that evaluate significant
emotional stimuli (infralimbic cortex, cingulate cortex).
Again, we can perhaps use theta activity as a guide. The
control of theta by SuM (as opposed to the control of theta by
some other structure or structures) is evident only with more
emotionally loaded tasks (and even then is obvious only when
movement is not increased). This would be simply achieved if
the inputs to SuM (but less so inputs to other theta-controlling
structures) are primarily from areas that control emotion. The
higher is the intensity of such inputs, the higher is the
frequency of theta. By analogy, then, non-theta components of
SuM may also receive input from areas involved in the
detection of, or response, to emotionally significant events and
produce output in proportion to the level of input.
The reciprocal connections from SuM to these emotionprocessing areas could fulfill either of the two functions.
They could involve an initial crude attempt to modulate
these structures, or an attempt to prime them, in anticipation
of the outputs from the caudal limbic group of structures.
Alternatively it could involve a fast feedback control of the
activity of SuM that altered its output to the caudal limbic
group of structures depending on the relative balance
between activities in the structures of the reciprocal network.
However, there is an extra dimension to the asymmetry of
the ascending and descending connections to be considered.
In the parallel system suggested by Heidbreder and
Groenewegen (see previous section, solid lines in Fig. 10)
only one strand nominally projects to SuM with the other
strands targeting other areas of the hypothalamus. Further,
from a hippocampal perspective, this feedback is associated
with the septal rather than the temporal pole. The septal pole
receives relatively little input from the amygdala compared
to the temporal pole (Amaral et al., 1992). Consistent with
this the septal pole appears to be more selectively involved in
spatial processing and the temporal pole more selectively
involved in anxiety (Richmond et al., 1999). Yet SuM, itself,
seems to have a relatively lesser involvement in spatial
processing than anxiety. Thus the ascending connections
from SuM may be more concerned with adding an emotional
influence to cognitive processing while its descending
connections may be more concerned with adding a cognitive
influence to emotional processing.
Both more detailed anatomy and more, less hippocampally oriented, physiology and behavioural analysis will be
required before we can fully understand the complex web of
neural interactions within which the supramammillary area
must be embedded.
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