Download Subicular and CA1 hippocampal projections to the accessory

HIPPOCAMPUS 19:124–129 (2009)
RAPID COMMUNICATION
Subicular and CA1 Hippocampal Projections to the
Accessory Olfactory Bulb
C. de la Rosa-Prieto, I. Ubeda-Banon, A. Mohedano-Moriano, P. Pro-Sistiaga,
D. Saiz-Sanchez, R. Insausti, and A. Martinez-Marcos*
ABSTRACT:
The hippocampal formation is anatomically and functionally related to the olfactory structures especially in rodents. The entorhinal cortex (EC) receives afferent projections from the main olfactory
bulb; this constitutes an olfactory pathway to the hippocampus. In addition to the olfactory system, most mammals possess an accessory olfactory (or vomeronasal) system. The relationships between the hippocampal formation and the vomeronasal system are virtually unexplored.
Recently, a centrifugal projection from CA1 to the accessory olfactory
bulb has been identified using anterograde tracers. In the study reported
herein, experiments using anterograde tracers confirm this projection,
and injections of retrograde tracers show the distribution and morphology of a population of CA1 and ventral subicular neurons projecting to
the accessory olfactory bulb of rats. These results extend previous
descriptions of hippocampal projections to the accessory olfactory bulb
by including the ventral subiculum and characterizing the morphology,
neurochemistry (double labeling with somatostatin), and distribution of
such neurons. These data suggest feedback hippocampal control of chemosensory stimuli in the accessory olfactory bulb. Whether this projection processes spatial information on conspecifics or is involved in
learning and memory processes associated with chemical stimuli
remains to be elucidated. V 2008 Wiley-Liss, Inc.
C
KEY WORDS:
vomeronasal
hippocampus; pheromone; subiculum; tract-tracing;
INTRODUCTION
The hippocampal formation is anatomically and functionally related
to the olfactory system. The ancient view of the hippocampus as an olfactory-related structure alone, however, has been discarded for decades
(Seress, 2007). Nevertheless, the hippocampal formation appears to be
essential for olfactory identification (Holscher, 2003) and for the expression of odor memory representations in novel situations (Eichenbaum,
1998).
Laboratorio de Neuroanatomı́a Humana, Departamento de Ciencias
Médicas, Facultad de Medicina, Centro Regional de Investigaciones Biomédicas, Universidad de Castilla-La Mancha, Albacete, Spain
Grant sponsor: Health Council JCCM; Grant numbers: GCS-2006_E/03;
PI-2006/15; Grant sponsor: Education and Science Council JCCM; Grant
number: PCC08-0064; Grant sponsor: Spanish Education and Science
Ministry; Grant number: BFU2007-62290/BFI.
*Correspondence to: Alino Martinez-Marcos, Dpto. CC. Médicas, Fac.
Medicina, Univ. Castilla-La Mancha, Avda. Almansa 14, 02006 Albacete,
Spain. E-mail: [email protected]
Accepted for publication 30 July 2008
DOI 10.1002/hipo.20495
Published online 5 September 2008 in Wiley InterScience (www.
interscience.wiley.com).
C 2008
V
WILEY-LISS, INC.
Anatomically, the hippocampus receives olfactory
information through several different routes. The
main olfactory bulb projects directly through the
medial olfactory tract to the hippocampal rudiment
(LeGross Clark and Meyer, 1947; Scalia, 1966; Davis
et al., 1978; Shipley and Adamek, 1984; MartinezMarcos and Halpern, 2006). Indirectly, but probably
most importantly, the main olfactory bulb also projects to the entorhinal cortex (EC) (Scalia, 1966;
Price, 1973; Scalia and Winans, 1975; Kosel et al.,
1981; Martinez-Marcos and Halpern, 2006), which
through the perforant path to the dentate gyrus (DG)
provides the main input of olfactory information to
the hippocampus itself (Insausti, 1993; Insausti et al.,
2002; Witter, 2007). The hippocampal formation
provides feedback inputs to the olfactory system by
means of centrifugal projections. Historically, a projection from the temporal third of the subiculum to
the anterior olfactory nucleus has been described
(Swanson and Cowan, 1977). Retrogradely labeled
cells were found in the ventral CA1 after large injections affecting the main and accessory olfactory bulbs
and anterior olfactory nucleus (de Olmos et al.,
1978). Anterograde tracing experiments in the ventral
CA1 revealed a projection to the main olfactory bulb
and anterior olfactory nucleus (van Groen and Wyss,
1990). The main olfactory bulb also receives centrifugal projections from the EC (Insausti et al., 1997).
In addition to the main olfactory system, most
mammals possess an accessory olfactory (or vomeronasal) system specialized for the detection of chemical
substances such as pheromones that are involved in
social interactions (Halpern and Martinez-Marcos,
2003). The relationship between the vomeronasal system and the hippocampal formation has received little
attention. Vomeronasal information could reach the
hippocampal formation through projections from the
accessory olfactory bulb to the posteromedial cortical
amygdala (Winans and Scalia, 1970; Raisman, 1972;
Scalia and Winans, 1975; Davis et al., 1978; Martinez-Marcos and Halpern, 1999b; Mohedano-Moriano
et al., 2007), which in turn projects to CA1, the subiculum, and the EC (Kemppainen et al., 2002). Using
anterograde tracers, Cenquizca and Swanson (2007)
recently described a projection, previously unknown,
HIPPOCAMPAL PROJECTIONS TO THE ACCESSORY OLFACTORY BULB
125
FIGURE 1.
Projections from the hippocampal formation to
the accessory olfactory bulb. Coronal (A, B) and parasagittal (C,
D) sections of rat brain showing anterogradely labeled fibers in
the granule cell layer of the accessory olfactory bulb (D, not visible in C) after a biotinylated dextran-amine injection into CA3,
ventral CA1, and ventral subiculum (A, B). Some sections were
nissl-counterstained (B, C). AON, anterior olfactory nucleus; CA1,
CA3, fields from the hippocampus; DG, dentate gyrus; dlo, dorsal
lateral olfactory tract; FC, frontal cortex; GL, glomerular layer of
the accessory olfactory bulb; Gr, granule cell layer of the accessory
olfactory bulb; MOB, main olfactory bubl; M/T, mitral/tufted cell
layer of the accessory olfactory bulb; PMCo, posteromedial cortical
amygdaloid nucleus; VS, ventral subiculum. Calibration bar for:
A–C 400 lm; D 40 lm.
from the ventral field of CA1 to the granule cell layer of the
accessory olfactory bulb. Earlier studies on centrifugal projections to the accessory olfactory bulb using retrograde tracers, however, had failed to reveal such projections (Raisman, 1972; Broadwell and Jacobowitz, 1976; Davis et al., 1978; Barber, 1982;
Martinez-Marcos and Halpern, 1999a). Only large injections also
affecting the main olfactory bulb and anterior olfactory nucleus
yielded labeling in the ventral CA1 (de Olmos et al., 1978).
This work aims to identify the origin of centrifugal afferents
from the CA1 and subiculum to the accessory olfactory bulb in
order to further explore the connectivity between these systems.
These data could eventually increase our understanding of the
influence of the hippocampal formation on the processing of
chemical cues.
Twenty-three adult female Sprague-Dawley rats were used in
this study. Throughout the study, the guidelines of the European Community on Welfare of Research Animals (directive
86/609/EEC) and the Ethical Committee for Animal Research
at the University of Castilla-La Mancha were followed. Animals
were injected intraperitoneally with a combined dose of ketamine hydrochloride (Ketolar, Parke-Davis, Madrid, 75 mg/kg)
and xylazine (Xilagesic, Barcelona, 10 mg/kg). Iontophoretic
injections of dextran-amines conjugated to biotin (BDA) or tetramethylrhodamine (RDA, Molecular Probes, Eugene, OR) or
FluoroGold (FG, Biotium, Hayward, CA) were placed into
ventral CA1/ventral subiculum or the accessory olfactory bulb.
Five days later, the animals were anesthetized (as above) and
perfused with 4% paraformaldehyde. Sagittal (olfactory bulbs)
or coronal sections were obtained using a freezing microtome.
Biotinylated dextran-amine (BDA) was revealed using the ABC
kit (Vector Laboratories, Burlingame, CA). Some sections of
RDA experiments were reacted for immunofluorescence against
somatostatin (1:1,000, goat antisomatostatin D-20, Santa Cruz;
1:200 chicken anti-goat Alexa 488, Molecular Probes) to analyze the possible correspondence with the two types of subicular neurons (Witter and Amaral, 2004). For further details of
the protocols see related articles (Pro-Sistiaga et al., 2007;
Ubeda-Banon et al., 2007, 2008).
A total of 23 injections of different tracers were performed
at different locations. Five injections of BDA were aimed at the
ventral portion of CA1 and/or the ventral subiculum; all
yielded comparable results. Case B10207 is described as representative. The injection site was small, involving an area
between ventral CA1 and the ventral subiculum and a portion
of CA3 (Figs. 1A,B). It is important to note that the posteromedial cortical amygdala was completely unaffected by the
injection site. Fine beaded fibers were observed in the granule
cell layer of the accessory olfactory bulb (Fig. 1C-not observable at this magnification-, arrowheads in D). Abundant anterograde labeling was observed in the anterior olfactory nuHippocampus
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FIGURE 2.
Projections to the accessory olfactory bulb from
the hippocampal formation. Parasagittal (A) and coronal (B–F)
sections of rat brain showing retrograde and anterograde labeling
(B–F) after a tetramethylrhodamine-labeled dextran-amine injection into deep layers (mitral/tufted and granule cell layers) of the
accessory olfactory bulb (A). Double labeling with somatostatin
immunofluorescence (F). CA1, CA3, fields from the hippocampus;
DG, dentate gyrus; dlo, dorsal lateral olfactory tract; FC, frontal
cortex; Gr, granule cell layer of the accessory olfactory bulb; M/T,
mitral/tufted cell layer of the accessory olfactory bulb; PMCo,
posteromedial cortical amygdaloid nucleus; VS, ventral subiculum.
Calibration bar for: A, B 400 lm; C–F: 80 lm. [Color figure can
be viewed in the online issue, which is available at www.
interscience.wiley.com.]
cleus, but only scattered fibers were observed in the main olfactory bulb (data not shown).
A total of six injections of FG were targeted to the accessory
olfactory bulb. This tracer produced relatively large injection
sites involving most of the cell layers of the accessory olfactory
bulb often extending to the main olfactory bulb. These injections resulted in retrogradely labeled cells in the ventral subiculum and the ventral portion of CA1 (data not shown). As
expected, the pattern of retrograde labeling was similar to that
described in the literature, including the anterior medial amygdala,
the bed nucleus of the accessory olfactory tract, and the posteromedial cortical amygdaloid nucleus (de Olmos et al., 1978).
Tetramethylrhodamine-labeled dextran-amine is an anterograde tracer that under certain circumstances is a very reliable
retrograde tracer from very small injection sites (Martinez-Marcos and Halpern, 1999a). Six injections involved the superficial
layers of the accessory olfactory bulb including the mitral/
tufted cell layer, i.e., above the dorsal lateral olfactory tract.
These injections gave rise to retrograde-labeled cells in areas
such as the bed nucleus of the accessory olfactory tract and the
anterior medial amygdala, but not in the posteromedial medial
amygdala or CA1/ventral subiculum (data not shown). Six
injections affected the deep layers of the accessory olfactory
bulb, i.e., including the granule cell layer; all yielded consistent
results. As example, case R6807 showed a small injection site
involving the mitral/tufted cell layer, the dorsal lateral olfactory
tract, and the granule cell layer (Fig. 2A). As expected from a
predominantly anterograde tracer, layer I of the posteromedial
Hippocampus
HIPPOCAMPAL PROJECTIONS TO THE ACCESSORY OLFACTORY BULB
127
FIGURE 3.
Mapping of distribution of labeled cells. Schematic
sections of the brain illustrating one example of the distribution of
retrogradely labeled cells after a rhodamine-labeled dextran-amine
injection into the granule cell layer of the accessory olfactory bulb.
Numbers indicate the distance from Bregma according to Paxinos
and Watson (2005). The Insausti et al.’ (1997) nomenclature for
the entorhinal cortex has been adopted. Abbreviations: APir, amygdalo-piriform transition area; CA1, CA2, CA3, fields from the hippocampus; DG, dentate gyrus; DIE, dorsal intermediate entorhinal
field; DLE, dorsal lateral entorhinal field; Pir, piriform cortex;
PMCo, posteromedial cortical amygdaloid nucleus; rf, rhinal fissure; VS, ventral subiculum.
cortical amygdaloid nucleus showed numerous terminal fibers
(Fig. 2B). This injection gave rise to retrograde-labeled cells in
the bed nucleus of the accessory olfactory tract and anterior
medial amygdala (data not shown) as well as in the posteromedial cortical amygdaloid nucleus, ventral CA1, and ventral subiculum (Fig. 2B). In ventral CA1, cells were deeply located in
the stratum oriens and showed a main ascending dendrite (Fig.
2C). This pattern was similar in the ventral subiculum (Fig.
2D), although some cells were superficially placed and showed
apical dendrites and proximal branches near the cell somata
(arrows in Fig. 2E). Labeled cells did not coexpress somatostatin (Fig. 2F). Topographically, these cells were restricted to the
ventral CA1 and ventral subiculum at mid rostrocaudal levels
from 24.80 to 25.88 mm from bregma according to Paxinos
and Watson (2005) (Figs. 3A–C). Scattered cells were observed
in the piriform and entorhinal cortices (Fig. 3).
Collectively, these results demonstrate only recently and partially known feedback projection from the ventral area of CA1
of the hippocampus and from ventral subiculum to the granule
cell layer of the accessory olfactory bulb. This projection was
shown to arise from the ventral field of CA1 using anterograde
tracing (Cenquizca and Swanson, 2007). Our results are interesting and novel for four reasons: (1) we have retrogradely confirmed such a projection for the first time; (2) we have demonstrated not only the projection of CA1 but also that of the ventral
subiculum to the accessory olfactory bulb; (3) considering the
number of retrograde-labeled cells, these results show that the
hippocampus may have an influence on the vomeronasal system,
which has been underestimated previously; (4) the data on cell
position (deep and superficial), dendritic morphology (narrow and
wide), and double labeling with somatostatin (no coexpression)
suggest that labeled cells could correspond to the two cell types
described in the subiculum (Harris et al., 2001): intrinsically
bursting cells tend to be deeply located, have a narrow dendritic
tree, and preferentially express somatostatin; whereas regular spiking neurons tend to be located superficially, have a wider dendritic
tree, and preferentially express NADPH diaphorase/nitric oxide
synthetase (NOS) (Witter and Amaral, 2004). Therefore, according to our data on position and cell morphology, and although
we have not found double-labeled cells with somatostatin and this
is unconclusive, we believe that both cell types could be projecting
to the accessory olfactory bulb although eletrophysiological data
would be necessary to asses this point.
Prior to discussing these results, it is necessary to include
some technical considerations. Injections in the accessory olfactory bulb involved the dorsal portion of the lateral olfactory
tract and the possibility arises that axons traveling to the main
olfactory bulb were affected by the injection site. Regarding
this possibility, it is necessary to distinguish the labeling in the
ventral CA1 and ventral subiculum from the labeling in the
piriform and entorhinal cortices. The labeling in CA1 and ventral subiculum likely corresponds to axons ending in the accessory olfactory bulb based in three reasons: (1) the retrograde
labeling in CA1 and ventral subiculum was abundant after
injections in the accessory olfactory bulb (Figs. 2 and 3), but
absent after injections in the main olfactory bulb (Insausti
et al., 1997; unpublished results); (2) the anterograde labeling
in the accessory olfactory bulb was terminal-like (Cenquizca
and Swanson, 2007) (Fig. 1D) after injections in CA1 and ventral subiculum (Figs. 1A,B); (3) according to the literature, the
ventral CA1 and ventral subiculum projects to the main olfactory bulb (van Groen and Wyss, 1990), but this projection is
Hippocampus
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much reduced when compared with the projections to the anterior olfactory nucleus and accessory olfactory bulb (Cenquizca
and Swanson, 2007) (this report). On the other hand, the
labeling in the piriform and entorhinal cortices after injections
in the accessory olfactory bulb is likely due to involvement of
axons in the lateral olfactory tract traveling to the main olfactory bulb based in two reasons: (1) only scattered cells were
seen in the piriform and entorhinal cortices after injections in
the accessory olfactory bulb (Figs. 2 and 3); (2) this pattern of
labeling in the piriform and entorhinal cortices is comparable,
although more abundant, after injections in the main olfactory
bulb (Insausti et al., 1997; unpublished results). Therefore, we
are confident that regrogradely labeled cells in the ventral CA1
and ventral subiculum originate from axons ending in the granule cell layer of the accessory olfactory bulb.
It is interesting to speculate why the projection from the
ventral CA1 and ventral subiculum to the accessory olfactory
bulb has not been revealed by previous studies of the afferent
connections. Studies using lesion-degeneration methods
(Raisman, 1972), autoradiography with tritiated amino acids
(Barber and Field, 1975; Davis et al., 1978; Barber, 1982), tracers such as horseradish peroxidase (HRP) (Broadwell and Jacobowitz, 1976; Davis et al., 1978) or dextran-amines (MartinezMarcos and Halpern, 1999a) have not shown retrograde labeling
in CA1 or subiculum. Only injections of HRP affecting the
main and accessory olfactory bulbs and anterior olfactory nucleus
yielded retrograde-labeled cells in the ventral CA1 (de Olmos
et al., 1978), although authors were unsure of this projection
due to the large sizes of their injections. The reason could be
methodological and/or due to species differences. Sensitive retrograde tracers such as FG gave rise to retrogradely labeled cells in
ventral CA1 and ventral subiculum, but injections of RDA only
produced such retrograde labeling when the tracer was greatly
concentrated and affected the granule cell layer (present results).
It is therefore likely that these projections parallel the centrifugal
pathway from the posteromedial cortical amygdaloid nucleus
through the stria terminalis (Raisman, 1972; Barber, 1982).
In fact, the accessory olfactory bulb receives differential laminar projections: one bundle of fibers from the posteromedial
cortical amgydaloid nucleus traveling through the stria terminalis that reaches the internal granule cell layer, and a second
bundle of fibers from the medial amgydaloid nucleus and bed
nucleus of the accessory olfactory tract terminating in the internal plexiform layer and probably running in the accessory olfactory tract (Barber, 1982). These results are in line with a third
pathway from the hippocampal formation through the septal
complex and taenia tecta, as already described (van Groen and
Wyss, 1990; Cenquizca and Swanson, 2007), that would reach
exclusively the granule cell layer of the accessory olfactory bulb.
Therefore, the absence of labeling in previous studies could
be due to the sensitivity of the method used including the precise placement of the injection site (Raisman, 1972; Barber and
Field, 1975; Broadwell and Jacobowitz, 1976; Davis et al., 1978;
de Olmos et al., 1978; Barber, 1982) or to the fact that such projections are absent in marsupials mammals such as the short-tailed
opossum (Martinez-Marcos and Halpern, 1999a).
Hippocampus
Regarding anterograde tracing experiments aimed at the hippocampus, injections of tritiated amino acids into the ventral
subiculum yielded labeling in the anterior olfactory nucleus
(Swanson and Cowan, 1977); whereas injections of Phaseolus
vulgaris-leucoagglutinin (PHAL) in the ventral CA1 confirmed
the projection to the anterior olfactory nucleus and revealed a
projection to the olfactory bulb (it is assumed to the main olfactory bulb) (van Groen and Wyss, 1990). Only recently, similar
experiments with injections of PHAL in the ventral CA1 has
specifically described the projection to the granule cell layer of
the accessory olfactory bulb (Cenquizca and Swanson, 2007).
Although the ancient view of the hippocampus as a mainly
olfactory structure is not longer accepted (Seress, 2007), there
is a clear anatomical and functional relationship between the
hippocampus and the olfactory system. Anatomically, the main
olfactory bulb projects to the EC (Price, 1973; Scalia and
Winans, 1975; Davis et al., 1978; Shipley et al., 2004), which
in turn constitutes one of the main sources of afferents to the
hippocampus (Witter and Amaral, 2004; Witter, 2007). Functionally, a number of lines of evidence support the participation
of the hippocampal formation in olfactory learning and memory (Eichenbaum, 1998; Truchet et al., 2002; Roman et al.,
2004). However, data on the relationship between the hippocampal formation and the vomeronasal system are sparse
(Kemppainen et al., 2002; Cenquizca and Swanson, 2007).
The data available, however, allow proposing circuits
between the hippocampal formation and the vomeronasal system and hypothesizing about their functional significance. A
number of connections between the amygdaloid complex,
including the vomeronasal amygdala, and the hippocampal formation have been described (Pitkanen et al., 2000). For example, the posterior cortical nucleus of the amygdala receives
vomeronasal information from the accessory olfactory bulb
(Winans and Scalia, 1970; Scalia and Winans, 1975; Mohedano-Moriano et al., 2007) and projects to the EC, ventral
subiculum, and ventral CA1(Kemppainen et al., 2002). The
ventral subiculum and ventral CA1 project to the accessory olfactory bulb (Cenquizca and Swanson, 2007) (present results).
Therefore, these connections would constitute a feedback loop
from the accessory olfactory bulb to the posteromedial cortical
amygdaloid nucleus, from there to the ventral subiculum and
ventral CA1 and back to the accessory olfactory bulb. This circuit could participate in recognition and memory formation of
pheromones, in a manner similar to that of recognition and
memory formation of odors (Eichenbaum, 1998; Roman et al.,
2004). Alternatively, the projection from the ventral CA1 and
ventral subiculum to the accessory olfactory bulb could relay
spatial information on the location of conspecific chemical signals from the cognitive map elaborated by place cells (O’Keefe,
1979; Brun et al., 2002).
Acknowledgments
The authors thank members of LNH and Dr. Garcı́a Olmo
for her help with the animals. The assistance of International
Science Editing in revising the English version of the manu-
HIPPOCAMPAL PROJECTIONS TO THE ACCESSORY OLFACTORY BULB
script is also acknowledged. CRP is supported by a predoctoral
fellowship associated with Grant PCC08–0064.
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