Download Connections Between the Retrosplenial Cortex and the

HIPPOCAMPUS, VOL. 2, NO. 1, PAGES 1-12, JANUARY 1992
COMMENTARY
Connections Between the Retrosplenial Cortex and the
Hippocampal Formation in the Rat: A Review
J. Michael Wyss and Thomas Van Groen
Department of Cell Biology, University of Alabama at Birmingham, UAB
Station, Birmingham, AL 35294 U.S.A.
ABSTRACT
The retrosplenial cortex is situated at the crossroads between the hippocampal formation and
many areas of the neocortex, but few studies have examined the connections between the hippocampal formation and the retrosplenial cortex in detail. Each subdivision of the retrosplenial
cortex projects to a discrete terminal field in the hippocampal formation. The retrosplenial dysgranular cortex (Rdg) projects to the postsubiculum, caudal parts of parasubiculum, caudal and
lateral parts of the entorhinal cortex, and the perirhinal cortex. The retrosplenial granular b
cortex (Rgb) projects only to the postsubiculum, but the retrosplenial granular a cortex (Rga)
projects to the postsubiculum, rostra1 presubiculum, parasubiculum, and caudal medial entorhinal cortex. Reciprocating projections from the hippocampal formation to Rdg originate in septal
parts of C A I ,postsubiculum, and caudal parts of the entorhinal cortex, but these are only sparse
projections. In contrast, Rgb and Rga receive dense projections from the hippocampal formation.
The hippocampal projection to Rgb originates in area C A I ,dorsal (septal) subiculum, and postsubiculum. Conversely, Rga is innervated by ventral (temporal) subiculum and postsubiculum.
Further, the connections between the retrosplenial cortex and the hippocampal formation are
topographically organized. Rostra1 retrosplenial cortex is connected primarily to the septal (rostrodorsal) hippocampal formation, while caudal parts of the retrosplenial cortex are connected
with temporal (caudoventral) areas of the hippocampal formation. Together, the elaborate connections between the retrosplenial cortex and the hippocampal formation suggest that this projection provides an important pathway by which the hippocampus affects learning, memory, and
emotional behavior.
Key words: cingulate cortex, hippocampus, limbic system, Papez circuit
hippocampal formation has long been recognized as having
an important role in these functions (e.g., O’Keefe and Nadel,
1978; Olton, 1983; McNaughton and Morris, 1987). In light
of this evidence, the elucidation of the interconnections between the retrosplenial cortex and hippocampal formation
take on an added importance.
While anatomical data documenting the cortical connections of the retrosplenial cortex have been limited, recent
studies have indicated that the retrosplenial cortex has extensive connections (e.g., Domesick, 1969; Vogt and Miller,
1983; Van Groen and Wyss, 1990c; 1991a). For instance, several studies have shown that reciprocal connections exist between the retrosplenial cortex and the anterior nuclei of the
thalamus (Domesick, 1969; Robertson and Kaitz, 1981) and
that the retrosplenial and subicular cortices are interconnected (Sgrensen, 1980; Vogt and Miller, 1983; Vogt et al.,
1986). Our recent studies have elucidated the cortical and
thalamic connections of the retrosplenial granular b cortex
The retrosplenial cortex is a nodal point for the transfer of
information between the hippocampal formation, many neocortical regions, and the thalamus. Early studies demonstrated that the cingulate (including the retrosplenial) cortex
was innervated by the anterior thalamic nuclei and the neocortex and that it had a significant projection both to the hippocampal formation and via the hippocampal formation to
the hypothalamus. This led Papez (1937) to suggest that this
circuit subserved the elaboration of emotional “experience.”
In addition to the elaboration of “emotional experience,” the
retrosplenial cortex also appears to contribute significantly
to the processes of learning and memory (Gabriel and Sparenborg, 1986; 1987; Valenstein et al., 1987; Sutherland et al.,
1988; Matsunami et al., 1989; Sif et al., 1989). Further, the
Correspondenceand reprint requests to J. Michael Wyss, Department
of Cell Biology, University of Alabama at Birmingham, UAB Station
Box VH 302, Birmingham, AL 35294 U.S.A.
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(Rgb) and a cortex (Rga) (Wyss and Sripanidkulchai, 1984;
Sripanidkulchai and Wyss, 1986b; 1987; Wyss et al., 1990;
Van Groen and Wyss, 1990c), and recent studies document
the cortical and subcortical connections of the retrosplenial
dysgranular (Rdg) cortex (Sripanidkulchai and Wyss, 1986b;
Van Groen and Wyss, 1991a).
Whereas several recent studies document connections between individual regions of the retrosplenial cortex and hippocampal formation, the present commentary takes a broader
focus by considering the interconnections between the entire
retrosplenial cortex and hippocampal formation in the rat.
The results demonstrate that these interconnections provide
the anatomical basis for the retrosplenial cortex’s role in processing and integrating information related to memory, learning, and emotional functions.
Our recent data are based on studies using two anterograde
tracers and two retrograde tracers in over 100 male SpragueDawley rats. The anterograde tracing experiments have relied
primarily on the very sensitive anterograde transport of Phaseolus vulgaris leucoagglutinin (PHA-L; Gerfen and Sawchenko, 1984) to study the pattern of axonal terminals. For
retrograde transport experiments, small amounts of a fluorescent dye (fast blue [FBI or fluorogold [FG]) have been
injected by pressure into a defined region of the brain
(Schmued and Fallon, 1986; Sripanidkulchai and Wyss,
1986a).
NOMENCLATURE
The retrosplenial cortex is divided into two parts, granular
and dysgranular, and the retrosplenial granular cortex is further subdivided into granular a (Rga) and granular b (Rgb)
regions according to the mapping of Wyss and Sripanidkulchai (1984) following the classification suggested by Rose
(1927a; 1927b; Figures 1 and 2). Retrosplenial granular a cortex corresponds to areas 29a and 29b, and Rgb corresponds
to area 29c of Vogt and Peters (1981). The retrosplenial dysgranular cortex (Rose 1927a; 1927b) is designated
area 29d by Brodmann (1909) and Vogt and Peters (1981) and
29c by Krieg (1946).
Retrosplenial dysgranular cortex has a staining pattern in
Nissl preparations that distinguishes it from the adjacent cortical areas (Fig. 1). Laterally and rostrally Rdg is bordered
by lateral agranular (motor) cortex (Donoghue and Wise,
1982) and caudally and laterally Rdg is bounded by area 18b
(Fig. 1); the border between Rdg and area 18b is characterized
by a change in Nissl staining. While layer IV of Rdg is occupied by few granule cells, this layer in 18b contains many
granular cells. The border between the Rdg and the more
ventral Rgb is characterized by two changes in Nissl staining.
First, in Rdg compared to Rgb, layers I1 and I11 are wider,
and in Rgb layer I1 cells are more darkly stained and form
prominent clumps. Second, in Rdg compared to Rgb, layer
1V is wider, and in Rdg the layer V neuronal cell bodies tend
to be larger. The border between Rgb and the more ventral
Rga is characterized by two changes in Nissl staining. First,
in Rgb compared to Rga, layer I1 is wider and contains smaller
and more darkly staining cells, and in Rgb these cells form
more prominent clumps. Second, in Rgb compared to Rga,
layer 111 is thin and the pyramidal cell bodies are randomly
spaced; in Rga the layer I11 neuronal cell bodies tend to be
arranged in bands parallel to the pial surface. Ventrally and
caudally Rga is bounded by the postsubiculum (the dorsal
part of the subicular cortex [Van Groen and Wyss, 1990bl:
Fig. 1); the border between Rga and postsubiculum is characterized by a change in Nissl staining. While layer IV of Rga
is occupied by granule cells, this layer in postsubiculum contains the lamina dissecans superficially and small pyramidal
cells in its deeper half.
This study employs the subdivision of the hippocampal formation suggested by Lorente de NO (1934). The hippocampal
formation consists of the hippocampus proper (Ammon’s
horn, i.e., cornu Ammonis fields CA,-CA,), the area dentata,
and the subicular complex (Fig. I ) . For our study, CA3 consists of all of regio inferior as defined by Ramon y Cajal
(1911), including CAZ of Lorente de NO (1934) and Swanson
and Cowan (1977). CAI corresponds to the area that Ramon
y Cajal (191 1 ) termed regio superior. The subicular complex
is subdivided into subiculum proper, presubiculum, parasubiculum. and postsubiculum (Van Groen and Wyss, 1990a;
1990b; Figs. I , 2).
HIPPOCAMPAL CONNECTIONS OF
RETROSPLENIAL CORTEX
Rdg, efferent projections
Rostral Rdg sends out a group of axons that turn caudally
in the cingulum bundle to terminate in the postsubicular, parasubicular, entorhinal, and perirhinal cortices (Fig. 3). At the
splenium of the corpus callosum a number of these axons
extend ventrally to rostral postsubiculum, where they form
a dense terminal plexus in layers 1-11 and V-VI, with less
dense terminations in layers 111-IV (Fig. 4A) and a very
sparse terminal field in the dorsocaudal subiculum. A small
number of axons extends further ventrally to form a terminal
plexus in layer I of caudal parts of parasubiculum and in the
deep layers (IV-VI) of the caudal lateral entorhinal and perirhinal cortices. Contralaterally, a few axons and terminals
project to layer V of postsubiculum.
Caudal Rdg gives rise to a group of axons that runs caudally
in the cingulum bundle to terminate in the postsubicular, parasubicular, and perirhinal cortices (Fig. 3). At the splenium
of the corpus callosum these axons extend ventrally to form
a dense terminal plexus in layers 1-11 and V-VI of the caudal,
ventral part of postsubiculum. A small number of axons extends ventrally to end in the superficial layer (I) of the caudal
part of parasubiculum, and the deep layers (IV-VI) of the
caudal perirhinal cortex. Contralaterally, a few axons and
terminals project to layer V of postsubiculum.
Rdg, afferent connections
Rostral Rdg receives hippocampal formation projections
from subiculum, postsubiculum, and entorhinal cortex (Fig.
5). The Rdg receives a limited input from the septa1 (dorsal)
part of the subiculum. Most neuronal cell bodies that project
to Rdg are in the deep layers (V-VI) of the rostral part of
the postsubicular cortex and the caudal part of the entorhinal
cortex.
Caudal parts of Rdg also receive a small projection from
the dorsal part of subiculum. A larger number of projections
arise from the deep layers (V-VI) of the caudal part of post-
RETROSPLENIAL-HIPPOCAMPAL CONNECTIONS / Wyss and Van Croen
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Fig. 1 . Four low-power photomicrographs of Nissl stained coronal sections of the hippocampal and retrosplenial cortices
(A to D, rostra1 to caudal) to demonstrate the cytoarchitectonic divisions. Scale bar, 500 pm. Ca, cornu Ammonis; Para,
parasubiculum; Post, postsubiculum; Pre, presubiculum; Rdg, retrosplenial dysgranular cortex; Rga, retrosplenial granular
a cortex; Rgb, retrosplenial granular b cortex; SUB, subiculum.
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postsubiculum, whereas caudal parts of Rgb project to more
ventrocaudal parts of postsubiculum (Fig. 7).
Rgb, afferent connections
Fig. 2 . Unfolded, schematic maps to demonstrate the position of the retrosplenial (inset, Wyss and Sripanidkulchai,
1984) and hippocampal cortices (Swanson et al.. 1978). Scale
bars, 1,000 pm. CA, cornu Ammonis; IEA, intermediate entorhinal cortex; L E A , lateral entorhinal cortex: MEA, medical entorhinal cortex; Para, parasubiculum: Post, postsubiculum: Pre, presubiculum; Rdg, retrosplenial dysgranular
cortex; Rga. retrosplenial granular a cortex: Rgb, retrosplenial granular b cortex: SUB, subiculum.
subiculum (Fig. 6B) and the deep layers (V-VI) of the caudal
part of the entorhinal cortex. The termination of these projections in Rdg has been documented using the PHA-L
method (Van Groen and Wyss, 1991a).
Rgb, efferent connections
Retrosplenial granular b cortex axons terminate in the postsubicular cortex, where they form a dense terminal plexus in
superficial layer I, layer 111-IV, and Vl (Fig. 4B). Rostra1
parts of Rgb predominantly project to dorsoanterior parts of
Retrosplenial granular b cortex is innervated by a small
number of pyramidal neurons in the dorfal, medial part of
area C A I , and a small number of nonpyramidal neurons at
the border of stratum radiatum and stratum moleculare, predominantly in area C A I (Fig. 6D). A dense cluster of neurons
in the dorsal (septal) one-third of the subiculum (Fig. 6A) also
projects to Rgb, as does a band of neurons in the deep layers
(i.e., layers V and VI) of postsubiculum. Contralateral neurons in the deep layers (i.e., layers V and VI) of postsubiculum also project to Rgb. Rostral parts of Rgb receive a
projection predominantly from area C A I ,the dorsalmost part
of subiculum, and rostral parts of postsubiculum. In contrast,
caudal parts of Rgb receive input predominately from more
ventral parts of the dorsal subiculum and more caudal parts
of the postsubiculum (Fig. 8). These connections have been
verified by anterograde tracing experiments (Fig. 4F).
Rga, efferent connections
Rostral Rga gives rise to two groups of axons that course
ventrally into the caudal postsubiculum, presubiculum, parasubiculum, and entorhinal cortex. One group of axons terminates in the deep (i.e., IV-VI) layers of the postsubiculum
(Fig. 4C), presubiculum, and parasubiculum (Fig. 4D). The
second group of axons courses through layer I of the postsubiculum to the presubiculum, where the majority of these
axons appear to terminate in layer I , but a small number of
terminals also extend to postsubiculum and parasubiculum.
Retrosplenial granular a cortex also projects to the contralateral postsubiculum and presubiculum in layers V and VI.
Caudal Rga gives rise to terminals in the same general areas
as the rostral Rga, but the terminal field in postsubiculum is
considerably more caudal (Fig. 9).
Rga, afferent connections
Retrosplenial granular a cortex receives a small input from
a small number of pyramidal and nonpyramidal neurons in
field CAI of the dorsal hippocampus; the nonpyramidal neurons mainly are at the border of stratum radiatum and stratum
moleculare. Rostral (compared to caudal) Rga receives projections from slightly different areas of the hippocampal formation (Fig. 10). Cell bodies in the ventral part of the temporal third of the subiculum (Fig. 6C) project to rostral Rga,
in contrast to the dorsal part of the temporal third of the
subiculum, which projects primarily to more caudal parts of
Rga. The terminations of these projections in Rga have been
documented using the PHA-L method (Van Groen and Wyss,
1990c; Fig. 4E).
laminar termination of hippocampal projections
Fig. 3 . Schematic maps to demonstrate the labeling pattern
in the hippocampal formation following injections of PHA-L
into rostral (vertical hatching) and caudal (horizontal hatching) Rdg (inset).
Neurons in the septal (dorsal) third of CAI project a few
axons and terminals to Rgb, predominantly in layer 11. Ventral subiculum projects to layers 1, 11, and I11 of Rga, with
the greater part of the axons and terminals in layer I1 (Fig.
4E). Dorsal subiculum projects mainly to Rgb, with small
RETROSPLENIAL-HIPPOCAMPAL CONNECTIONS / Wyss and Van Groen
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Fig. 4. High-power photomicrographs of coronal sections to demonstrate PHA-L labeling. (A-C) Labeled axons and terminals
in postsubiculum following an injection into (A) Rdg, (B) Rgb, and (C) Rga. (D) Labeled axons and terminals in the deep
layers of parasubiculum and presubiculum following an injection into Rga. (E) Labeled axons and terminals in the superficial
layers of Rga following an injection into ventral subiculum. (F) Labeled axons and terminals in Rgb following an injection
into dorsal subiculum. Scale bars, 100 pm.
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Fig. 5. Schematic maps to demonstrate the pattern of retrograde labeling in the hippocampal formation following injections into rostra1 (filled circles) and caudal (diamonds)
Rdg.
numbers of fibers going to Rga and Rdg. In Rgb most of the
axons and terminals are in deep layer I1 and layer 111 (Fig.
4F), with smaller numbers of axons in layers I and 111. Both
in Rgb and in Rga most of the axons in layer I are fibers of
passage. Postsubiculum projects to Rga and Rgb, with a small
number of fibers in Rdg. These projections end in layers I
(predominantly in Ib and Ic) and 111-IV. Both in Rga and in
caudal Rgb a large number of these axons in layer I are fibers
of passage.
NONHIPPOCAMPAL CONNECTIONS OF
RETROSPLENIAL CORTEX
In addition to the output of the retrosplenial cortex to the
hippocampal formation, this region also projects to widespread areas of the brain (Domesick, 1969; Vogt and Miller,
1983; Wyss and Sripanidkulchai, 1984; Vogt et al., 1986; Sripanidkulchai and Wyss, 1987: Van Groen and Wyss, 1990c;
1991a). Retrosplenial dysgranular cortex projects to orbital,
IR, retrosplenia, 18b, 17, postsubicular, parasubicular, entorhinal, and perirhinal cortices. Subcortically, Rdg projects
to caudatelputamen, anterior (anteromedial, AM), lateral (laterodorsal, LD; lateroposterior, LP), reticular, and reuniens
nuclei of the thalamus, zona incerta, superior colliculus, periaqueductal gray, and ventral pontine nuclei. Retrosplenial
dysgranular cortex has contralateral projections to Rdg, Rgb,
Rga, IR, and postsubicular cortices. Retrosplenial granular b
cortex projects to IR, Rdg, Rga, and postsubicular cortices.
Subcortically, Rgb projects to claustrum, anterodorsal (AD),
LD, and reticular nuclei of the thalamus, superior colliculus,
periaqueductal gray, and the ventral pontine nuclei. Most of
the contralateral projections of Rgb are to Rgb, Rdg, Rga,
and postsubicular cortices. Retrosplenial granular a cortex
projects to IR, Rdg, Rgb, entorhinal, postsubicular, presubicular, and parasubicular cortices. Subcortical projections
from Rga are to anteroventral (AV), LD, reticular and reuniens nuclei of the thalamus, the superior colliculus, and the
ventral pontine nuclei. Most of the contralateral projections
of Rga are to Rga, Rdg, Rgb, subicular, and entorhinal cortices, and to AV.
The retrosplenial cortex is innervated by axons from a wide
variety of brain regions (Rose and Woolsey, 1948; Meibach
and Siegel, 1977a; 1977b; Niimi, 1978; Robertson and Kaitz,
1981; Finch et al., 1984a; Sripanidkulchai and Wyss, 1986b;
Vogt et al., 1986; Thompson and Robertson, 1987; Van Groen
and Wyss, 1990c; 1991a). Retrosplenial dysgranular cortex
receives projections from orbital, IR, retrosplenial, 18b, 17,
postsubicular, and entorhinal cortices. Contralateral projections originate in Rdg, Rgb, and Rga cortices, and subcortical
projections originate in claustrum, diagonal band of Broca,
medial septal nucleus, anterior (AM), lateral (LD and LP),
and reuniens nuclei of the thalamus, the raphe nuclei, and
the locus ceruleus. Retrosplenial granular b cortex is innervated by axons from IR, Rdg, and Rga cortices, area CAI,
the subiculum, and postsubiculum. Subcortical, neuronal cell
bodies project to Rgb from claustrum, diagonal band of
Broca, medial septal nucleus, AD, AV, LD, and reuniens
nuclei of the thalamus, raphe nuclei and locus ceruleus. Contralateral projections to Rgb arise from neurons in Rgb, Rdg,
and postsubiculum. Retrosplenial granular a cortex receives
ipsilateral projections from Rga and Rgb, area 18b, area infraradiata, postsubiculum, hippocampus, rostroventral subiculum, presubiculum, and contralateral Rga. Subcortical
projections to Rga arise from the claustrum, diagonal band
of Broca, (both vertical and horizontal limbs), the reuniens,
AD, AV, and LD nuclei of the thalamus, the midbrain raphe
nuclei, and the locus ceruleus.
DIFFERENTIAL PROJECTIONSTO EACH
REGION OF RETROSPLENIAL CORTEX
One element in the circuitry of the medial limbic structures
proposed by Papez (1937) was a cortical connection between
the retrosplenial and hippocampal cortices. Although direct
connections with the hippocampus proper (i.e., area CAICA4) were not observed in subsequent studies (however, see
Van Groen and Wyss, 1990c), pathways between the retrosplenial and the subicular cortices have been documented
(Adey, 1951; Swanson and Cowan, 1977; Meibach and Siegel,
1977a; 1977b; Spirensen, 1980; Van Groen and Wyss, 1990a;
1990b; Witter et al., 1990; Van Groen and Wyss, 1991a). Our
studies demonstrate that ventral subiculum and presubiculum
project to the Rga cortex, the dorsal part of the subiculum
projects to the Rgb cortex, and the postsubiculum projects
to Rga, Rgb, and Rdg cortices (Fig. 11). The retrosplenial cortex also receives widespread cortical innervation
from infraradiata, visual, and motor cortices (Vogt and
Miller, 1983; Van Groen and Wyss, 1 9 9 0 ~ 1991a).
;
Our experiments (Sripanidkulchai and Wyss, 1986b; Van Groen and
Wyss, 1990c; 1991a) have demonstrated that Rdg is innervated by infraradiata, Rga, 18b, 17, and contralateral Rdg
cortices, Rgb is innervated by infraradiata, Rdg, and contralateral Rgb cortices, and Rga is innervated by infraradiata,
Rgb, Rdg, and contralateral Rga cortices. Thus, each part of
the retrosplenial cortex receives a somewhat different neocortical and limbic cortex projection (Fig. 1I).
The thalamic nuclei also project distinctly to each retrosplenial region (Rose and Woolsey, 1948; Niimi, 1978; Niimi
RETROSPLENIAL-HIPPOCAMPAL CONNECTIONS / Wyss and Van Groen
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Fig. 6. Four photomicrographs of coronal sections of the hippocampal formation following injections of retrogradely transported fluorescent tracers. (A) Labeled neurons in the dorsal subiculum following an injection into Rgb. (B) Labeled neurons
in the deep layers of postsubiculum following an injection into Rdg. (C) Labeled neurons in ventral subiculum following an
injection of Rga. (D) A labeled nonpyramidal neuron in area CAI following an injection of Rgb. Scale bars (A-C), 50 pm;
scale bar (D), 20 pm.
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HIPPOCAMPUS VOL. 2, NO. 1, JANUARY 1992
A
I
Fig. 7. Schematic maps to demonstrate the labeling pattern
in the hippocampal formation following injections of PHA-L
into rostral (vertical hatching) and caudal (horizontal hatching) Rgb.
Fig. 8. Schematic maps to demonstrate the pattern of retrograde labeling in the hippocampal formation following injections of PHA-L into rostral (filled circles) and caudal (diamonds) Rgb.
et al., 1978; Thompson and Robertson, 1987; Van Groen and
Wyss, 1991a; 1991b). AD projects primarily to Rga and Rgb,
AV projects predominantly to Rgb, and LD projects primarily
to Rdg, with smaller terminal fields in Rgb and Rga (vide infra;
Sripanidkulchai and Wyss, 1986b; Van Groen and Wyss,
1988; 1991a; 1991b). In contrast, thalamic projections from
AM only terminate in Rdg. Thalamic projections to Rdg, Rgb,
and Rga terminate primarily in layer I , 111, and IV (Vogt,
1985; Sripanidkulchai and Wyss, 1986b; Van Groen and
Wyss, 1988).
Each region of the retrosplenial cortex has distinct terminal
fields within the cortex (Fig. 1 I). Retrosplenial dysgranular
cortex projects to IR, Rga, 18b, postsubiculum, and para-
subiculum, while projections from Rgb terminate predominantly in infraradiata, Rdg, Rgb, and postsubiculum. The
major efferent projections of Rga are to the caudal Rdg, and
the postsubiculum. Further, contralateral projections of each
region are predominantly homotypic, i.e., Rdg to Rdg, Rgb
to Rgb, and Rga to Rga. These connections confirm that the
retrosplenial cortex plays an intimate role in the transfer of
neocortical and limbic cortex information, and the differences
in connections between Rga, Rgb, and Rdg suggest that each
area contributes uniquely.
The connections documented in this commentary further
clarify the role of the retrosplenial cortex in the so-called
“Papez circuit” (Papez, 1937); most prominent inputs and
outputs of the retrosplenial cortex are to areas in the limbic
Fig. 9. Schematic maps to demonstrate the labeling pattern
in the hippocampal formation following injections of PHA-L
into rostral (vertical hatching)
- and caudal (horizontal hatching) Rga.
Fig. 10. Schematic maps to demonstrate the pattern of retrograde labeling in the hiuoocamual formation following injeitions into rostra1 (filled circles) and caudal (diamonds) gga.
RETROSPLENIAL-HIPPOCAMPAL CONNECTIONS / Wyss and Van Groen
9
the areas of the retrosplenial granular cortex to which subiculum projects. In the retrosplenial granular cortex thalamic
inputs end predominantly in layer Ia, the subicular input ends
primarily in layer 11, and the postsubicular input terminates
predominantly in layers Ib, Ic, and 11-111. Such an anatomical
organization is ideally suited for integration of these three
inputs by the retrosplenial, layer V, pyramidal neurons. The
electrophysiological study of Finch and colleagues indicates
that such a thalamocortical integration occurs in these layer
of the retrosplenial granular cortex (Finch
FUNCTIONAL IMPORTANCE OF THE
RETROSPLENIAL-HIPPOCAMPAL
INTERCONNECTIONS
Functional studies demonstrate that lesions of the retrosplenial cortex impair place learning of rats in a water maze;
however the animals are not impaired in learning (including
visual tasks) p e r se. Thus “posterior cingulate areas are essential to the ability to move accurately to points in space
using the relationships among distal cues” (Sutherland et al.,
1988). Other recent studies demonstrate that Rdg contains
“head direction cells,” i.e., neurons that discharge as a function of the rat’s head direction in the horizontal plane (Chen
DSub
et al., 1990), while the hippocampus proper contains “place
cells” (i.e., neurons that fire when a rat is in a specific place;
O’Keefe and Nadel, 1978). It should be noted that the postsubiculum, which receives a dense projection from Rdg, also
contains “head direction cells” (Taube et al., 199%; 1990b).
Further, studies by Sikes et al. (1985; 1988) indicate that Rdg
may be involved in the processing of visual information in
relation to eye movements. Thus, in addition to the anatomical evidence (Van Groen and Wyss, 1991a), there is functional evidence that Rdg plays a role in visual-spatial behavior.
Together with the studies of others, these data suggest that
the
retrosplenial cortex contributes to the role of the hipPara
pocampus in memory and learning (Matsunami et al., 1989;
Fig. 11. Schematic summary of the main connections of Rdg, Sif et al., 1989). Gabriel and colleagues (Gabriel et al., 1980;
Rgb, and Rga. AD, anterodorsal nucleus of the thalamus; 1989; Gabriel and Sparenborg, 1986; 1987) have demonstrated
AM, anteromedial nucleus of the thalamus; AV, anteroven- that the response of retrosplenial cortex neurons in a learning
tral nucleus of the thalamus; DSub, dorsal subiculum; IR, paradigm is in part dependent on intact connections from the
area infraradiata (anterior cingulate cortex); LD, laterodorsal hippocampal formation to the retrospleniai cortex. SutherOf the
Lp, lateroPosterior
Of the
land et al. (1988; 1989) have demonstrated that an intact rethalamus; Para, parasubiculum; Post, postsubiculum; Pre,
for the
to move accutrosPlenia1
cortex is
presubiculum; Rdg, retrosplenial dysgranular cortex; Rga, retrosplenial granular a cortex; Rgb, retrosplenial granular b rately to Points in space using distal cues, i.e., place
cortex; S Ctx, sensory cortex; SUB, subiculum; VSub, ven- navigation. Bilateral lesions of the retrosplenial cortex impair
rabbits in their ability to reverse discrimination in a nictating
tral subiculum.
membrane response paradigm (Berger et al., 1986). Further,
cortex and thalamus (Fig. 11). The retrosplenial cortex is in- Markowska et al. (1989) have demonstrated that retrosplenial
terconnected with the infraradiata cortex (Bassett and Ber- Cortex lesions induce Spatial memoQ‘ impairments in rats, and
ger, 1982; Vogt and Miller, 1983; Finch and Babb, 1984a; Using an identical experimental design, Murray et al. (1989)
SripanidkUlchai and wYss, 1987; Van Green and WYSS, have demonstrated a similar defect in monkeys. Finally, Val1990~;1991a), the retrosplenial cortex projects to and re- enstein et al. (1987) have demonstrated the development of
ceives projections from the rostra1 thalamic nuclei, and the amnesia in a patient after lesions in the retrosplenial Cortex.
retrosplenial cortex projects to and receives projections from Thus, the retrosplenial cortex appears to be important for
learning and memory in a broad spectrum of mammalian spethe hippocampal formation (i.e., subicular cortex).
The subiculum proper projects to the retrosplenial granular cies. In light of these findings, the elucidation of the anatomy
cortex and postsubiculum. Postsubiculum in turn projects to and physiology of the interconnections between the hippo-
Fl
10
HIPPOCAMPUS VOL. 2, NO. 1, JANUARY 1992
ory-related structures of the monkey during a delayed response.
Brain Res. Bull. 22:829-838.
McNaughton, B. L., and R. G . M. Morris (1987) Hippocampal synaptic enhancement and information storage within a distributed
ACKNOWLEDGMENTS
memory system. TINS. 10:408-415.
This study was supported by NIH grants HL 34315 and HL Meibach, R. C., and A . Siegel (1977a) Subicular projections to the
posterior cingulate cortex in rats. Exp. Neurol. 57:264-274.
37722.
Meibach, R. C., and A. Siegel (1977b) Efferent connections of the
hippocampal formation in the rat. Brain Res. 124:197-224.
Literature
Murray, E. A,, M. Davidson, D. Gaffan, D. S . Olton, and S. Suomi
(1989) Effects of fornix transection and cingulate cortical ablation
Adey, W. R. (1951) An experimental study of the hippocampal conon spatial memory in rhesus monkeys. Exp. Brain Res. 74:173-nexions of the cingulate cortex in the rabbit. Brain 74:233-247.
Bassett, J. L., and T. W. Berger (1982) Associational connections
186.
between the anterior and posterior cingulate gyrus in rabbit. Brain Niimi, M. (1978) Cortical projections of the anterior thalamic nuclei
Res. 248:371-376.
in the cat. Exp. Brain Res. 31:403-416.
Berger, T. W., C. L. Weikart, J . L. Bassett, and W. B. Orr (1986) Niimi, K . , M. Niimi, and Y. Okada (1978) Thalamic afferents to the
Lesions of the retrosplenial cortex produce deficits in reversal
limbic cortex in the cat studied with the method of retrograde axonal transport of horseradish peroxidase. Brain Res. 145:225-238.
learning of the rabbit nictating membrane response: Implications
for potential interactions between hippocampal and cerebellar brain O'Keefe, J., and L. Nadel (1978) The hippocampus as a cognitive
map. Clarendon Press, Oxford.
systems. Behav. Neurosci. 100:802-809.
Brodmann, K. (1909) Vergleichende Lokalisationslehre der Gros- Olton, D. S . (1983) Memory functions and the hippocampus. I n
shirnrinde in ihren Prinzipien dargestellt auf Grund des ZellenNeurobiology of the h i p p o u m p u s , W. Seifert, ed., Academic
baues. Barth, Leipzig.
Press, New York, NY.
Chen, L. L . , B. L . McNaughton, C. A. Barnes, and E . R. Ortiz (1990) Papez, J . W . (1937) A proposed mechanismofemotion. Arch. Neurol.
Head-directional and behavioral correlates of posterior cingulate
Psychiat. 38:725-734.
and medial prestriate cortex neurons in freely moving rats. SOC. Ramon y Cajal, S. (191 1) Histologie du systeme nerveux de I'homme
Neurosci. Abstr. 16:441.
et des vertebres. A. Maloine, Paris.
Domesick, V. B. (1969) Projections from the cingulate cortex in the Robertson, R. T . , and S. S. Kaitz (1981) Thalamic connections with
rat. Brain Res. 12:296-320.
limbic cortex. 1. Thalamocortical projections. J . Comp. Neurol.
Donoghue, J . P . , and S. P. Wise (1982) The motor cortex of the rat:
195:50l-525.
Cytoarchitecture and microstimulation mapping. J. Comp. Neurol.
Rose, M. (1927a) Der Allocortex bei Tier und Mensch. J . Psychol.
2 12~76-88.
Neurol. 34: 1-1 1 1 .
Finch, D. M., E . L. Derian, and T. L . Babb (1984a) Afferent fibers Rose, M. (1927b) Gyrus limbicus anterior und Regio retrosplenialis
to rat cingulate cortex. Exp. Neurol. 83:468-485.
(Cortex holoprotoptychos quinquestrdtificatus) Vergleichende ArFinch, D. M., E. L . Derian, and T . L. Babb (1984b) Excitatory prochitektonik bei Tier und Mensch. J . Psychol. Neurol. 35:65-17:3.
jection of the rat subicular complex to the cingulate cortex and Rose, J. E., and C. N. Woolsey (1948) Structure and relations of
synaptic integration with thalamic afferents. Brain Res. 301 :25-37.
limbic cortex and anterior thakdmic nuclei in rabbit and cat. J .
Gabriel, M., and S. Sparenborg (1986) Anterior thalamic discrimiCornp. Neurol. 89:279-347.
native neuronal responses enhanced during learning in rabbits with
Schmued, L., and J. H. Fallon (1986) Fluoro-Gold: A new fluorescent
subicular and cingulate cortical lesions. Brain Res. 384: 195-198.
retrograde axonal tracer with numerous unique properties. Brain
Gabriel, M., and S. Sparenborg (1987) Posterior cingulate cortical
Res. 377:147-154.
lesions eliminate learning-related unit activity in the anterior cin- Sif, J., M. Meunier, C. Messier, A . Calas, and C. Destrade (1989)
gulate cortex. Brain Res. 409:151-157.
Quantitative ['4C12-deoxyglucosestudy of a functional dissociation
Gabriel, M., K. Foster, and E. Orona (1980) Interaction of the laminae
between anterior and posterior cingulate cortices in mice. Neuof cingulate cortex and the anteroventral thalamus during behavrosci. Lett. 101:223-228.
ioral learning. Science 208: 1050-1052.
Sikes, R. W., B. A. Vogt, and H. A. Swadlow (1985) Limbic cortex
Gabriel, M., S. Sparenborg, and Y. Kubota (1989) Anterior and meneuronal activity associated with saccadic eye movements in awake
dial thalamic lesions, discriminative avoidance learning. and cinrabbits and possible underlying afferents. SOC.Neurosci. Abstr.
gulate cortical neuronal activity in rabbits. Exp. Brain Res. 76:44111:1042.
457.
Sikes, R. W., B. A. Vogt, and H. A. Swadlow (1988) Neuronal reGerfen, C. R. and P. E. Sawchenko (1984) An anterograde neuroansponses in rabbit cingulate cortex linked to quick-phase eye moveatomical tracing method that shows the detailed morphology of
ments during nystagmus. J. Neurophysiol. 59:922-936.
neurons, their axons and terminals: Immunohistochemical locali- S@rensen,K. E. (1980) Ipsilateral projection from the subiculum to
zation of an axonally transported plant lectin, Phaseolus vulgaris
the retrosplenial cortex in the guinea pig. J. Comp. Neurol.
leucoagglutinin (PHA-L). Brain Res. 290:219-238.
193:893-911.
Krieg, W. J. S. (1946) Connections of the cerebral cortex. I. The Sripanidkulchai, K., and J . M. Wyss (1986a) Two rapid methods of
albino rat. A. Topography of the cortical areas. J. Comp. Neurol.
counterstaining fluorescent dye tracer containing sections without
84:221-275.
reducing the fluorescence. Brain Res. 397:117-129.
Lorente de NO, R. (1934) Studies on the structure of the cerebral Sripanidkulchai, K., and J. M. Wyss (1986b) Thalamic projections to
cortex 11. Continuation of the study of the Ammonic system. J.
retrosplenial cortex in the rat. J . Comp. Neurol. 254:143-165.
Psychol. Neurol. 46:113-177.
Sripanidkulchai, K., and J. M. Wyss (1987) The laminar organization
Markowska, A. L., D. S. Olton, E. A. Murray, and D. Gaffan (1989)
of efferent neuronal cell bodies in the retrosplenial granular cortex.
A comparative analysis of the role of fornix and cingulate cortex
Brain Res. 406:255-269.
in memory: Rats. Exp. Brain Res. 74:187-201.,
Sutherland, R. J., I. Q. Whishaw, and B. Kolb (1988) Contributions
Matsunami, K., T . Kawashima, and H. Satake (1989) Mode of [I4C]
of cingulate cortex to two forms of spatial learning and memory.
2-deoxy-glucose uptake into retrosplenial cortex and other memJ. Neurosci. 8:1863-1872.
campal formation and the retrosplenial cortex takes on an
added importance.
RETROSPLENIAL-HIPPOCAMPAL CONNECTIONS / Wyss and Van Croen
Sutherland, R. J., and A. J. Rodriguez (1989) The role of fimbridfornix and some related subcortical structures in place learning
and memory. Behav. Brain Res. 32~265-277.
Swanson, L. W., and W. M. Cowan (1977) An autoradiographic study
of the organization of the efferent connections of the hippocampal
formation in the rat. J. Comp. Neurol. 172:49-84.
Swanson, L. W., J. M. Wyss, and W. M. Cowan (1978) An autoradiographic study of the organization of the intrahippocampal association pathways in the rat. J . Comp. Neurol. 181:681-716.
Taube, J. S . , R. U . Muller, and J. B. Ranck, Jr. (1990a) Head-direction cells recorded from the postsubiculum in freely moving rats.
I. Description and quantitative analysis. J. Neurosci. 10:420-435.
Taube, J. S . , R. U. Muller, and J . B. Ranck, Jr. (1990b) Head-direction cells recorded from the postsubiculum in freely moving rats.
11. Effects of environmental manipulations. J. Neurosci. 10:436447.
Thompson, S . M., and R. T. Robertson (1987) Organization of subcortical pathways for sensory projections to the limbic cortex. I.
Subcortical projections to the medial limbic cortex in the rat. J.
Comp. Neurol. 265~175-188.
Valenstein, E., D. Bowers, M. Verfaellie, K. M. Heilman, A . Day,
and R. T. Watson (1987) Retrosplenial amnesia. Brain 110:16311646.
Van Groen, T., and J. M. Wyss (1988) The distribution of projections
from the anterior thalamic nuclei to the subicular cortex. SOC.Neurosci. Abstr. 14:921.
Van Groen, T., and J . M. Wyss (1990a) The connections of presubiculum and parasubiculum in the rat. Brain Res. 518:227-243.
Van Groen, T., and J. M. Wyss (1990b) The postsubicular cortex in
the rat: Characterization of the fourth region of the subicular cortex
and its connections. Brain Res. 529: 165-177.
Van Groen, T., and J. M. Wyss (1990~)Connections of the retro-
11
splenial granular A cortex in the rat. J. Comp. Neurol. 300593606.
Van Groen, T., and J. M. Wyss (1991a) Connections of the retrosplenial dysgranular cortex in the rat. J. Comp. Neurol. In press.
Van Groen, T., and 1. M. Wyss (1991b) Projections from the laterodorsal nucleus of the thalamus to the limbic and visual cortices.
SOC. Neurosci. Abs. 17:1583.
Vogt, B. A. (1985) Cingulate Cortex. In Cerebral Cortex, A. Peters
and E. G. Jones, eds., pp. 89-149, Plenum Press, New York, NY.
Vogt, B. A., and A. Peters (1981) Form and distribution of neurons
in rat cingulate cortex: Areas 32, 24, and 29. J . Comp. Neurol.
195:603-625.
Vogt, B. A., and M. W. Miller (1983) Cortical connections between
rat cingulate cortex and visual, motor, and postsubicular cortices.
J. Comp. Neurol. 216:192-210.
Vogt, B. A . , R. W. Sikes, H. A . Swadlow, and T. G. Weyand (1986)
Rabbit cingulate cortex: Cytoarchitecture, physiological border
with visual cortex, and afferent cortical connections of visual,
motor, postsubicular, and intracingulate origin. J. Comp. Neurol.
248:74-94.
Witter, M. P., R. H. Ostendorf, and H. J. Groenewegen (1990) Heterogeneity in the dorsal subiculum of the rat: Distinct neuronal
zones project to different cortical and subcortical targets. Eur. J.
Neurosci. 2~718-725.
Wyss, J . M., and K. Sripanidkulchai (1984) The topography of the
mesencephalic and pontine projections from the cingulate cortex
of the rat. Brain Res. 293:l-15.
Wyss, J. M., T. Van Groen, and K. Sripanidkulchai (1990) Dendritic
bundling in layer I of granular retrosplenial cortex: Intracellular
labeling and selectivity of innervation. J. Comp. Neurol. 295:3342.