Our previous report put forward the hypothesis that the

correct functioning of episodic memory requires efficient

transmission of signals in each component of the trisynap-
tic pathway through the hippocampus, to allow neural rep-
resentations of the context to be generated within the hip-
pocampus [1]. This study noted that further development of
this model would take cognizance of the connections of the
hippocampus with different areas of the parahippocampal
complex, through which spatial and non-spatial information
arrives in the hippocampus and which is known [27] to play
an important role in information processing and episodic
memory. The parahippocampal complex consists of the pe-
rirhinal and postrhinal areas of the cortex, as well as the
entorhinal cortex (EC), through which excitation from
the first two areas is transferred to the hippocampus.
The postrhinal area of the cortex in rodents is homologous
to the parahippocampal cortex in primates [30]. Existing
data indicate that the cortical inputs to these rhinal areas are
Neuroscience and Behavioral Physiology, Vol. 41, No. 2, 2011
Involvement of the Trisynaptic Hippocampal Pathway
in Generating Neural Representations of ObjectPlace
Associations (an analytical review)
I. G. Silkis UDC 612.822.3
0097-0549/11/4102-0117

2011 Springer Science+Business Media, Inc.

117
Translated from Zhurnal Vysshei Nervnoi Deyatelnosti imeni I. P. Pavlova, Vol. 59, No. 6, pp. 643659,
NovemberDecember, 2009. Original article submitted February 28, 2009. Accepted April 28, 2009.
The possible mechanisms by which neural representations of objectplace associations are generated in
different parts of the network consisting of the hippocampus and the parahippocampal complex are ana-
lyzed. Spatial and non-spatial information arrives in the hippocampus via two streams from the parahip-
pocampal complex, which consists of the perirhinal, postrhinal, and entorhinal areas of the cortex. It can
be suggested that because there are no connections between the lateral and medial areas of the entorhinal
cortex, these representations, as particular patterns of connected and discharging neurons, are generated
mainly in the hippocampus, though they may also be generated in the entorhinal cortex because of the
input from the postrhinal cortex. As both information streams converge on neurons in the dentate gyrus
and field CA3, the trisynaptic pathway through the hippocampus may play a key role in generating these
representations. As spatial information arrives in the neocortex and passes from there via the parahip-
pocampal complex to the hippocampus about 20 msec earlier than non-spatial information, spatial infor-
mation is processed first in the dentate gyrus and field CA3. Later, because of the return of excitation from
field CA3c to the dentate gyrus, neural representations of objectplace associations start to be generated
in the dentate gyrus. Signals are transferred from the dentate gyrus to field CA3, where information arriv-
ing from the entorhinal cortex is superimposed on the neuronal patterns activated by these signals. As a
result, more complex neural representations are generated in field CA3 and signals are sent to field CA1.
In the dorsal (ventral) part of field CA1, non-spatial (spatial) information arriving from the lateral (medi-
al) part of the entorhinal cortex is superimposed on the activated neuronal pattern. The result is that high-
er-order representations are generated in field CA1. In the parahippocampal cortex, the generation of neu-
ronal representations of objectplace associations can result from the transfer of activity from the dorsal
part of hippocampal field CA1.
KEY WORDS: hippocampus, parahippocampal complex, trisynaptic pathway, objectplace associations.
Institute of Higher Nervous Activity and Neurophysiology,
Russian Academy of Sciences, Moscow;
e-mail: isa-silkis@mail.ru.
dominated by polymodal sensory and visuospatial inputs,
respectively. As a result, the perirhinal cortex is involved in
processing information about objects and in the perception
of complex stimuli [9, 71] and encodes behaviorally signif-
icant information on the properties of the spatial context,
while the postrhinal/pararhinal cortex is involved in identi-
fying changes in the spatial components of the context [11].
Information from the peri- and postrhinal areas of the cortex
is transferred to the hippocampus predominantly via the lat-
eral and medial areas of the EC (EClat and ECmed) respec-
tively [53]. Non-spatial information about objects and con-
ditioned signals passes to the hippocampus via the EClat,
which is part of the ventral information processing stream
(the what stream), while spatial information passes to the
hippocampus via the ECmed, which is part of the dorsal
information processing stream (the where stream) [53].
It has been suggested that neural representations of
objectplace associations can be generated in the parahip-
pocampal complex [8]. Another point of view [63] holds
that as the what and where streams converge on the
input into the hippocampus, its fundamental function is to
combine spatial and non-spatial information. It has been
suggested that as a result, this combination in the hip-
pocampus can create representations [53], which consist of
patterns of discharging neurons with particular connections.
For example, the discharge pattern of neurons, including
place cells, in hippocampal field CA1 depends both on the
geometry of the space and on the nature of the abstract task,
as demonstrated in [83]. Furthermore, place cells are sensi-
tive to changes in the nature of the task without any alter-
ations to the spatial context [83]. Place cells in field CA1
respond not only to the distance or direction of movement,
but also to color and odors [4]. The purpose of the task
being performed also affects neural representations of space
in hippocampal field CA3 [45]. In rodents, neural
objectplace representations are analogous to neural event
+ context representations in humans, which are required
for maintaining episodic memory [53].
In the light of the suggestion that the hippocampus is
involved in constructing the neural representation of an
episode and considering that the convergence of spatial and
non-spatial inputs occurs at the beginning of the trisynaptic
pathway through the hippocampus, the aim of the present
work was to analyze the mechanisms whereby this pathway
is involved in generating neural representations of object
place associations.
Characteristics of the Organization of the Two
Information Inputs to the Hippocampus
via the Parahippocampal Areas of the Cortex
A scheme of the organization of the two information
inputs to the hippocampus were constructed (Fig. 1) using
contemporary experimental data as reviewed in [30, 53, 63].
The diagram shows the hippocampal formation, consisting
of the dentate gyrus (DG), fields CA3 and CA1, and the
subiculum, as well as individual areas of the parahip-
pocampal complex. The main sources of cerebral cortical
inputs to the EC are field 35 of the perirhinal area and the
temporal visual fields, which are among the post-/pararhi-
nal fields. Only spatial information passes to the hippocam-
pus via the post-/pararhinal areas. However, the rostral part
of the postrhinal cortex projects to the dorsal area of field
36, which in turn projects to the ventral part of field 36, this
latter projecting to field 35, which is connected with the EC
[15]. As a result of these projections, not only non-spatial
information, but also some spatial information can pass to
the hippocampus through the perirhinal cortex. Recurrent
projections from field 36 of the perirhinal cortex to the
postrhinal cortex are few in number [30]. The parahip-
pocampal areas are connected with the EC topographically:
the perirhinal cortex projects mainly to the EClat and the
postrhinal to the ECmed and the caudal part of the EClat
[14] (Fig. 1). In primates, the perirhinal cortex projects
mainly to the rostral part of the EC (which is homologous
to the ventral or temporal area in rodents), while the tem-
poral visual areas project mainly to the caudal area (which
is homologous to the dorsal or septal area in rodents) [42].
The EC also receives fibers from the neocortex, which is
also organized topographically. For example, in macaques,
the rostral part of the EC receives projections from the
orbitofrontal and unimodal visual associative areas, while
afferents from the retrosplenial and parietal areas terminate
in the caudal part of the EC [65]. In rats, the EClat receives
projections mainly from the piriform and insular areas of
the cortex, while the ECmed receives projections from the
retrosplenial, visual, and posterior parietal areas of the cor-
tex [49]. Some afferent terminals overlap, particularly in the
rostrolateral part of the EC, while some cortical afferents
terminate mainly in either the upper layers (IIII) of the EC
or in the lower layers (VVI) [65] (Fig. 2).
The connections of the EC with different parts of the hip-
pocampus are also organized topographically. Thus, the ven-
tromedial part of the EC is connected mainly with the ventral
hippocampus, which performs functions which are qualita-
tively different and independent from the functions performed
by the dorsal hippocampus [67]. Most of the visuospatial
inputs to the dorsal hippocampus run from the dorsolateral
part of the EC, and lesions to the dorsal but not the ventral part
of the hippocampus produce strong impairment to spatial
memory in rodents [74]. In primates, the posterior part of the
hippocampus (corresponding to the dorsal part in rodents) is
also more important for spatial memory than the anterior (cor-
responding to the ventral area in rodents) [67]. The ventral
part of hippocampal field CA1, like the ventral part of the EC,
has been shown to be more adapted to processing non-spatial
information than the dorsal part [47]. A place field in the ven-
tral part of field CA1 has been found only in a small propor-
tion of pyramidal cells and their spatial resolution was signif-
icantly lower than that of place cells in the dorsal part of this
field [47]. The ventral part of the hippocampus is not con-
Silkis 118
nected to its other areas by either intrahippocampal or
extrahippocampal connections [67]. Differences in the nature
of information processing have been observed in the EC.
Thus, grid cells, which are present in the ECmed [49] and are
connected with the dorsal part of the hippocampus, respond to
each angle of a spatial grid and can precisely represent the dis-
position of the object, while neurons in the EClat, connected
with the more ventral part of the hippocampus, represent the
grid on a wider spatial scale [53].
Current data indicate that non-spatial information
passes to the upper layers of the perirhinal cortex and then
(via its lower layers) to the upper layers of the EClat, run-
ning from there to the distal part of field CA1 and the prox-
imal part of the subiculum [22] (Fig. 1). Signals from these
areas of the hippocampal formation may return to the deep
layers of the perirhinal cortex via the deep layers of the
EClat [22]. There is also a direct monosynaptic input from
the perirhinal cortex to the dorsal part of field CA1, fibers
passing in the lateral perforant pathway [62]. This input is
quite strong, as it can be potentiated [62]. Spatial informa-
tion arrives in the upper layers of the postrhinal cortex and
then passes via its lower layers to the upper layers of the
Involvement of the Trisynaptic Hippocampal Pathway in Generating Neural Representations 119
Non-spatial
information
Perirhinal
cortex
Field 35
Field 36
To insular
cortex
To TE
and TEO
Spatial
information
Postrhinal
cortex
To parietal
cortex and V4
Entorhinal
cortex,
lateral
part
Entorhinal
cortex,
medial
part
CA1,
distal
part
Subiculum,
proximal
part
CA1,
proximal
part
Subiculum,
proximal
part
DG
CA3
Fig. 1. Scheme showing the organization of the two information inputs to the hippocampus. DG is the dentate gyrus; CA1 and CA3
are hippocampal fields. Arrows show excitatory inputs; double lines show the transmission of combined spatial and non-spatial infor-
mation; dotted lines show the weak input.
Fig. 2. Scheme of open hippocampus-entorhinal cortex-hippocampus circuits. EC is the entorhinal cortex; I, II, III, IV, V,
and VI are the layers of the entorhinal cortex. For further details see caption to Fig. 1.
ECmed and then on to the proximal part of field CA1 and
the distal part of the subiculum [22]. From field CA1 and the
subiculum, signals pass through the deep layers the ECmed
in the return direction to the deep layers of the postrhinal
cortex [22]. The projections from the peri- and postrhinal
cortex to the EC can be regarded as direct, while those from
the EC to these areas as recurrent [84]. Recurrent projec-
tions from the hippocampus to the EC are also organized
topographically. Thus, responses in the EClat were greater
on stimulation of the distal part of CA1 and the proximal
part of the subiculum, while responses in the ECmed were
greater on stimulation of the proximal part of CA1 [22].
Projections from field CA1 to the neocortex are also topo-
graphical in nature [20]. In particular, the visual and other
sensory areas receive projections from the ventral two thirds
of field CA1 [20].
Initial studies showed that fibers originating in layers
III and V of the peri- or postrhinal cortex terminate in lay-
ers II and III of the EC [15]. However, subsequent investi-
gations demonstrated that some parts of the parahippocam-
pal areas projects to layers IIII of the EC, while others
project to layers VVI of the EC [42]. Neurons in layers II
and VI of the EC project to the dentate gyrus (DG) and field
CA3, while neurons in layers III and V project to field CA1
[93] (Fig. 2). This means, firstly, that different groups of EC
neurons excite the DG/CA3 and field CA1 and, secondly,
that each component of the trisynaptic hippocampal path-
way receives projections not only from neurons in the upper
layers of the EC, which receive information from the
parahippocampal areas, but also from neurons in the lower
layers, which receive information from field CA1, i.e., after
processing in the hippocampus.
Neurons in any part of the EC (lateral and medial) have
been shown to project mainly to this same part of the EC
and that EC neurons projecting to the temporal (ventral)
part of the DG, are not directly connected to EC neurons
projecting to the septal (dorsal) part of the DG [26].
Electrophysiological studies have also demonstrated that
stimulation of the upper layers of the EC lead to activation
of neurons mainly in this same part of the EC, and interac-
tions between neurons in the upper layers of these areas
occur only at the boundary between the lateral and medial
areas [10]. It follows from these data that the streams of
spatial and non-spatial information do not interact in the
EC. The topographical character of interneuronal interac-
tions in the EC suggests that cells located in the medial-lat-
eral direction of the plane of the EC may integrate informa-
tion on the basis of connections within the strip and that
information processed in different strips remains separate
[14]. Separation of information processing also appears to
be supported by propagation via perforant fibers to the hip-
pocampus as, despite the divergent distribution of perforant
fibers in field CA1/subiculum, only a small proportion of
CA1/subiculum neurons receiving common innervation are
connected together [69]. In the trisynaptic pathway to the
hippocampus, information processing also occurs via sepa-
rate pathways supported by the topographic organization of
the inputs. Thus, it has been shown that field CA3 cells
located closer to the DG (the proximal part of field CA3)
send larger projections to the septal part of field CA1, while
field CA3 cells located closer to CA1 project mainly to the
temporal part of field CA1 [44]. Separation of the process-
ing circuits in the trisynaptic pathway is also indicated by
the fact that although Schffer collaterals branch extensive-
ly in field CA1, stimulation of a small locus in field CA3
evoked the greatest response in only a narrow, inclined strip
running through field CA1 to the subiculum [3].
Judging from existing experimental data, the EC-hip-
pocampus-EC neuronal circuit is closed only in rare cases.
Thus, only a small proportion of field CA1 neurons inner-
vate those loci in the deep layers of the EC which send pro-
jections to a restricted area of the upper layers of the EC
which project recurrently to field CA1 [69]. Furthermore,
orthodromic and antidromic responses evoked by stimula-
tion of a single area of the EClat have been shown to be
located in different parts of field CA1 [90]. Antidromic
responses were seen in the more septal part of CA1 than
orthodromic responses, as a single EC locus receiving infor-
mation from the septally located area of field CA1 forwards
this information to an area in field CA1 located more tem-
porally (Fig. 2). Thus, activation initially involves the septal
part of field CA1 and then propagates via the EC to the tem-
poral part. The authors of [90] came to the conclusion that
information in the EC-hippocampus-EC network propagates
via the three-dimensional spiral pathway, i.e., along open
circuits. This is evidently one of the reasons why reverbera-
tion in this circuit is hindered. Another reason may be the
powerful inhibitory effect of the lower layers of the ECmed
(receiving inputs from the hippocampus) on the upper layers
(projecting to the hippocampus) identified in [34].
Functional Organization of Spatial and Non-Spatial
Visual Inputs to the Hippocampus
The main flow of sensory, particularly visual, informa-
tion arrives in the hippocampus from different areas of the
neocortex via the peri- and postrhinal/parahippocampal cor-
tex [21]. Only minor afferentation of non-visual modality
arrives in the postrhinal cortex, while the perirhinal cortex
receives afferentation from both the visual and other senso-
ry areas of the neocortex [30]. Visual information arrives
predominantly in the caudal parts of the peri- and postrhi-
nal cortex [70]. The temporal field (TF) of the parahip-
pocampal cortex receives visual afferentation from the sec-
ondary visual area V2 [31], area V4 (associated with color
processing) [87], and from the inferior temporal area (TEO)
and the caudal part of the anterior temporal cortex (TE)
[85]. The perirhinal cortex receives fibers from the uni-
modal visual areas of the TE and the rostral part of the TEO,
as well as from the TF [85]. The connections of the visual
areas with the peri- and pararhinal cortex are reciprocal.
Silkis 120
Thus, field 36 of the perirhinal cortex projects recurrently to
the visual fields TE and TEO, while field TF sends fibers to
the posterior parietal cortex and visual area V4 [58] (Fig. 1).
Cells from the TF and TH also project to the TE and TEO
[7]. The postrhinal area is characterized by strong recipro-
cal connections with the associative visual areas of the cor-
tex, the superior colliculi, and the lateral posterior thalamic
nuclei in rodents (these nuclei are homologous to the pulv-
inar of the thalamus in primates, which conducts visual
information) [30].
Visual information arriving in the peri- and postrhinal
areas is transmitted to the hippocampus via the lateral and
medial entorhinal cortex respectively. Along with afferenta-
tion from the postrhinal cortex, the ECmed receives fibers
from the posterior parietal (spatial visual) and visual asso-
ciative cortical areas [16]. It has been suggested that the
neural representation of space in grid cells in the dorsocau-
dal part of the ECmed results from integration in the path-
way located outside the hippocampal formation, presump-
tively in the retrosplenial and/or parietal cortex [32].
The visuospatial area of field TF and the ventromedial part
of field TE may project to field CA1, also indirectly [77].
It would appear that the existence of these neurons has the
result that neurons in the temporal lobe in monkeys and
humans have selectivity in relation to particular types of
visual stimuli and even for the images of specific individu-
als [66]. In the anterior inferior temporal cortex of the TE
and rhinal (perirhinal) cortex in monkeys, the proportion of
neurons responding to visual stimuli and neurons selective-
ly responding to shape or color (but not size) was signifi-
cantly greater than that in the pararhinal cortex or hippo-
campus [76]. Neurons in the place area of the pararhinal
cortex responded to the three-dimensional geometry of the
scene but did not respond to faces [40]. The firing of indi-
vidual neurons in the human EC and hippocampus also
showed significant specificity in relation to the stimulus cat-
egory [56]. Some 14% of neurons (activity was recorded
from more than 400 cells) responded selectively to stimuli
of categories such as faces, natural scenes, and houses, and
known persons and animals [56].
Understanding of the mechanisms generating neural
representations of objectplace associations in the hip-
pocampus requires consideration of the features of the pro-
cessing of visual information in those cortical areas from
which the hippocampus receives this information. The
latent periods (LP) of responses to visual stimuli in the dor-
sal and ventral visual streams, by which spatial and non-
spatial information respectively reaches the brain, are
known to differ, with signals propagating faster in the dor-
sal stream [80]. In the magnocellular layer of the lateral
geniculate body (LGB) of macaques, response LP values
were 1020 msec shorter than those in the parvocellular
layer. The same difference of 20 msec was also characteris-
tic of the LP of the responses of retinal X and Y cells, which
project to the magnocellular and parvocellular layers of the
LGB respectively, and for 4C-alpha and 4C-beta cells of the
primary visual cortex (field V1) [72]. Neurons in other areas
of the cortex innervated by cells in the magnocellular layer
of the LGB are also activated earlier than neurons innervat-
ed by cells in the parvocellular layer [80]. In the dorsal
stream to field V1, the LP of responses of 4C-alpha cells
were 6 msec longer than the LP of responses of cells in the
magnocellular layer of the LGB. The latent periods of the
responses of neurons in fields V3, MT (medial temporal),
MST (medial superior temporal), and FEF (frontal eye
field) were 69 msec longer than the LP of the responses of
neurons in field V1. In contrast with the ventral stream, in
areas V1, V2, and V4, which are classically regarded as
hierarchical, the LP of responses increased progressively as
signals moved through the hierarchy, differences between
response LP in fields V1 and V2 or V2 and V4 averaging
about 20 msec. As the LP of the responses of different neu-
rons in fields V2 and V4 overlapped, it was suggested that
this hierarchy also includes fast and slow streams [80].
Although area V1 neurons of the magnocellular pathway
are activated an average of 20 msec earlier than neurons in
the parvocellular pathway, rapid processes (like slow pro-
cesses) in fields V1 and V2 start at essentially the same
times [72]. It is of note that the LP of responses in the FEF,
at the eighth level of the hierarchy, are of comparable mag-
nitude to the LP of responses in field V2 (second level), V3
(third level), MT (fifth level), and MST (seventh level), and
are sometimes even shorter than the LP of responses of neu-
rons in field V1, which is at the first level of the hierarchy
[80]. The LP of responses of many field V2 cells were
greater than the LP of the responses of neurons in fields MT
and MST. This result corresponds to anatomical connec-
tions, as there are direct projections from field V1 to the MT
and FEF [80]. Thus, the previously accepted hierarchy does
not reflect the functional hierarchy and it is incorrect to sug-
gest that the LP of visual responses in the higher cortical
areas are longer than those in the primary areas, because of
the time required for propagation across the cortex on trans-
fer through the hierarchical levels of processing.
As there are no data on different conduction velocities
via the medial and lateral perforant pathways, it is natural to
suggest that signals from the neocortex passing through the
post- and perirhinal cortex and then through the ECmed and
EClat arrive in the hippocampus with a time shift of about
20 msec.
The Possibility that Hippocampal Neurons Integrate
Spatial and Non-Spatial Information
Previous studies have not assessed the time shift
between streams of spatial and non-spatial information. We
suggest that signal integration does not occur at the initial
stages of processing in the DG as, in the area in which per-
forant fibers terminate on the dendrites of granule cells,
only those signals arriving in a time range of about 10 msec
can be summed [79]. The excitatory responses of pyramidal
Involvement of the Trisynaptic Hippocampal Pathway in Generating Neural Representations 121
cells in field CA3 can also be significantly enhanced, but
only if signals arriving from the DG and EC have time dis-
placements of no more than 10 msec [18]. It would appear
that what information can initially be processed in the DG
and CA3 only after processing of where information, i.e.,
sequentially.
Processing is also influenced by the efficiency of hip-
pocampal excitation by the EC, induced by the spatial and
non-spatial inputs. This differs, because there are differ-
ences in the membrane properties of projection neurons in
layer II of the EClat and layer II of the ECmed and in their
firing characteristics [91]. The medial perforant pathway is
known to terminate in the DG in the middle third of the
molecular layer, while the lateral perforant pathway termi-
nates in its upper third; in field CA3, the medial perforant
pathway terminates in the deep part of the lacunar-molecu-
lar layer, while the lateral perforant pathway terminates in
its upper part [88]. This provides grounds for suggesting
that the input from the ECmed can excite DG and field CA3
neurons more effectively than the input from the EClat. The
greater effectiveness of the input from the ECmed may also
be facilitated by the fact that unlike the input from the
EClat, it acts on sensitive N-methyl-D-aspartate receptors in
the DG and field CA3 [55].
Stimulation of the medial perforant pathway can elicit
excitatory postsynaptic potentials (EPSP) with LP of 23
msec (presumptively monosynaptic) in field CA3 neurons in
the lacunar molecular layer and with LP of >7 msec (pre-
sumptively disynaptic) in the radial layer [94]. As population
spikes evoked by stimulation of perforant fibers can appear
in field CA3 even earlier than in the molecular layer of the
DG [19], spatial information arriving from the EC can be
processed in field CA3 and the DG almost simultaneously.
It follows from the electrophysiological characteristics
of DG granule cells identified above that temporal summa-
tion of non-spatial information with spatial information
requires excitation evoked by activation of the medial per-
forant pathway to return to DG neurons. We suggest that
this condition can be fulfilled by, for example, the input
from field CA1 returning to the DG via the mossy cells of
the hilus [78]. The recurrent action on the DG is exerted
mainly by neurons in area CA3c [50, 78]. The ventral hip-
pocampus also has direct recurrent projections from field
CA3c and the DG [78]. The action of field CA3 on granule
cells can be either excitatory or inhibitory, due to the
involvement of input GABAergic interneurons in the DG.
However, in vivo experiments have demonstrated that in
some physiological conditions, the excitatory CA3-mossy
cell-DG granule cell pathway can be efficient, while gran-
ule cell discharges are associated with trains of discharges
of CA3 neurons in sharp waves [96]. It appears that return
of excitation takes about 20 msec while, judging from the
illustrations presented in [78], stimulation of the fimbriae
(evoked by discharges of mossy cells in the hilus) leads to
EPSP in the DG with LP of about 2030 msec. The signif-
icant contribution of area CA3c to the processing of spatial
information is evidenced by the fact that lesions to this area
are apparent in behavior as larger deficits in the perception
of space than seen with lesions to areas CA3c and CA3b
[41]. It can be suggested that as a result of the functioning
of autoassociative connections, areas CA3a and CA3b are
involved in encoding spatial information, including relative
associations [50]. In addition, areas CA3a and CA3b are
involved in the sequential processing of information in
cooperation with field CA1. It remains possible that the
dorsal part of the DG is required for processing spatial
information because of the pattern separation or orthogo-
nalization of the sensory inputs to create a metric represen-
tation, while the dorsal parts of fields CA3 and CA1 receive
this representation via the di- and trisynaptic pathways [35].
The perforant input to field CA1 evidently carries addition-
al information, as it has been found that the dorsal part of
field CA1 is involved in remembering topological informa-
tion, while the dorsal parts of field CA3 and the DG do not
have a role [35].
Summation on the distal dendrites of pyramidal neu-
rons in field CA1 (in the area of the perforant endings)
increases linearly only for EPSP separated from each other
by 5 msec, compared with 20 msec for summation on the
proximal dendrites (in the area at which Schffer collaterals
terminate) [95]. However, it should be noted that the per-
forant inputs are not sufficiently strong [60]. Stimulation of
the lateral or medial perforant pathways, although often
eliciting excitation in the distal dendrites of field CA1 pyra-
midal cells, does not lead to population spikes [19]. The LP
of discharges of individual field CA1 neurons amounts to
some 917 msec, i.e., excitation sufficient for discharges
arrive via the di- or trisynaptic pathway [60]. It was sug-
gested that the role of each of the perforant inputs to pyra-
midal cells in fields CA3 and CA1 consists of facilitation of
other inputs, for example, those from DG and CA3, respec-
tively [17].
There is no recurrent excitatory circuit from field CA1
to CA3, though recurrent inhibition does occur, as CA1
contains GABAergic interneurons innervating neurons both
in this field and in field CA3 [81]. Furthermore, the axons
of these cells can reach the hilus. The functional role of this
inhibition may be to synchronize the activity of neurons in
different parts of the hippocampus. This in turn may pro-
mote the generation of particular associations in the neu-
ronal ensemble, preventing the simultaneous generation of
other associations.
Processing of Spatial Information and the Generation
of Neural Representations of ObjectPlace Associations
in the Hippocampus
Data showing that although lesioning of neurons in the
DG leads to severe impairments to spatial learning and
alters the nature of the discharges of neurons in fields CA3
and CA1, the spatial selectivity of place cells in fields
Silkis 122
CA3 and CA1 changes little as compared with controls [64]
are interesting in relation to the aim of the present work.
The authors of this study believed that the effect identified
resulted from the fact that some spatial information bypass-
es the DG, reaching fields CA1 and CA3 via other path-
ways, particularly the perforant. It would appear that
because of the input from the EC, the place field in area
CA1 is present even when there are lesions to the DG and
CA3 [53]. The arrival of information on the positions of
objects directly to fields CA3 and CA1 allows neuronal rep-
resentations of contexts to be created with lesser expendi-
ture in terms of processing. The individual contribution of
the perforant pathways in forming the place fields in fields
CA3 and CA1 is indicated by data showing some indepen-
dence in the generation of neural representations of space
within them [61, 89]. From our point of view, this effect
may be associated with the differences in the organization
of the inputs from the EC to fields CA3 and CA1. Thus,
neurons in areas CA3 and CA1 are excited by cells in dif-
ferent layers of the EC, which have different dynamic char-
acteristics [29] and can therefore have different influences
on the activity of postsynaptic neurons in the hippocampus.
Nonetheless, some spatial information arrives in field CA1
from field CA3. This suggestion is supported by evidence
reported in [12], where it was demonstrated that following
selective lesioning of layer III of the ECmed (from which
the neural representation of space can be transmitted direct-
ly to field CA1), the receptive fields of field CA1 cells
became larger and more blurred, while the receptive fields
of field CA3 cells (receiving spatial information from cells
in layer II of the ECmed) remained clearly delineated. It
follows from these data that the direct perforant input to
field CA1 from the ECmed is required for more accurate
spatial firing of place cells.
It can be suggested that deficit in spatial learning
induced by lesions to the DG reported in [64] are associat-
ed not with errors in the processing of spatial information
but with the impossibility of generating neuronal represen-
tations of objectplace associations in field CA1 without
the DG. As information on objects arrives at the ventral part
of field CA1 via the EClat and information on the spatial
positions of objects arrive in the dorsal part of field CA1 via
the ECmed [22], i.e., to different cells, it is natural to sup-
pose that integrated information linking an object with its
position in space can arrive at pyramidal cells in field CA1
only after processing in the DG and/or field CA3 (where,
because of the recurrent circuit, summation of the inputs
from the EClat and ECmed converging on a single neuron
can occur), with transfer of activity from representations of
objectplace associations generated in the DG and field
CA3 then being via the trisynaptic pathway. It is of note that
pyramidal neurons in field CA3 and granule cells in the DG
in the hippocampus in rats, whose activity was recorded in
identical conditions, were characterized by similar spatial and
directional selectivity and similar trains of discharges [46].
From our point of view, this effect may be based on the
mutual influences of areas CA3c and DG on each other.
Experimental evidence has been obtained showing that
the DG maintains the separation of spatial patterns [33]. In
particular, this was apparent as the absence of a spatial cor-
relation between simultaneously recorded DG granule cells
[46]. This effect may be associated with the topical organi-
zation of the inputs from grid cells in the ECmed to the DG.
It would appear that as a result, the DG, which receives con-
verging information from different parts of an episode, may
not only operate simultaneously with field CA3 in main-
taining the spatial separation of stimuli [52], but may also
maintain the process of orthogonalization of sensory inputs.
It has been suggested that field CA3, which also receives
convergent information about the episode, is involved not
only in generating a complex spatial pattern, but also in
generating associations between spatial stimuli [59].
Experimental evidence has also been obtained showing that
field CA3 is involved in episodic memory and learning as a
result of the generation of certain associations between the
object serving as the conditioned signal and the spatial posi-
tion of this object [51].
From the point of view of the mechanism suggested
here, excitation of DG and field CA3 neurons by fibers of the
lateral perforant pathway, which carries non-spatial informa-
tion, occurs after initial processing by these cells of spatial
information arriving 20 msec later via the fibers of the medi-
al perforant pathway. As a result, non-spatial information is
superimposed on already processed spatial information, i.e.,
on the neural representation of space. Thus a new neural pat-
tern is generated, whose activity is the representation of the
objectplace association. Signals from the representation of
the objectplace association from field CA3 are then trans-
mitted via Schffer collaterals to neurons in field CA1.
Schffer collaterals terminate on the proximal dendrites of
pyramidal cells, where EPSP delayed by 20 msec may be
summed linearly if they are evoked by signals strong enough
to induce long-term potentiation [95]. As a result, neural rep-
resentations of objectplace associations of a higher order
may be generated in field CA1 neurons, including associa-
tions generated in the DG with a 20-msec delay.
It was suggested in [4] that the input from area CA3
modulates previously generated place fields of pyramidal
cells in area CA1. The initial formation of place fields in
CA1 may be based, for example, on the inputs from grid
cells in the dorsocaudal part of the ECmed, whose activity
represents a directionally oriented, topographically orga-
nized neuronal map of the spatial environment [37]. Signals
arising in layer II of the EC and arriving in field CA1 via
the trisynaptic pathway may converge on a given pyramidal
neuron with signals arriving directly from layer III of the
EC via the perforant pathway [48]. Although the perforant
input is relatively weak, facilitation of spatial and temporal
summation of EPSP in field CA1 may promote sufficiently
strong neuronal activity at another input, leading to long-
Involvement of the Trisynaptic Hippocampal Pathway in Generating Neural Representations 123
term potentiation [95]. The result is that the potentiated
input is summed with another synchronous or asynchronous
input with marked selectivity for the time interval between
the inputs and specificity for the position on the dendrite
[95]. This allows detection of the coincidence of objects (or
the coincidence of spatial loci). The integration of different
spatial signals on field CA1 neurons is evidenced by data
showing that some neurons react selectively only to coinci-
dence in a particular position in space, the start position,
and the target disposition [83]. It is of note that even these
complex responses depend on the context [83]. This effect,
pointing to the generation of neural representations of more
complex objectplace associations, appears to be induced
by the influence of the input from field CA3. The effect of
this input also explains the fact that field CA1 neurons
respond predominantly to the coincidence of stimuli such as
a conditioned signal and a place [83]. The important contri-
bution of the DG to the generation of neural representations
of associations between the place fields and sensory
information in field CA1 is evidenced by results reported in
[36], which demonstrated similarity between the place
field of DG neurons and field CA1 neurons when the target
of the animals movement consisted of visual stimuli. If
only field CA3 played a special role in the generation of
associations between the visual signal and spatial position,
(because of numerous internal connections), and informa-
tion were then transmitted to field CA1, then the effect
noted above would not be seen.
Possible Mechanisms for the Generation of Neural
Representations of Associations in the
Parahippocampal Areas
Various points of evidence have now been obtained for
the existence of contextual associations in the parahip-
pocampal complex. A specific contribution was identified
for each of the structures in the medial temporal lobe
(the hippocampus, perirhinal cortex, and TF field, i.e., the
postrhinal cortex) to solving tasks based on the existence of
objectplace associations. On comparison of pictures of
five objects, four of which the subject was familiar with and
one was new, subjects with lesions to field TF produced
errors on substitution of the positions of two objects [6].
Not only did lesions to the perirhinal cortex produce impair-
ments to the solution of spatial tasks, but hippocampal
lesions led to impairment of learning only for tasks requir-
ing generation of objectplace associations [6]. In another
series of experiments, the perirhinal cortex was activated
only when the task required integration of the properties of
the visual object into an invariant representation, though not
when assessment of individual object properties (color or
shape) was required [24]. Studies reported in [13] showed
that the perirhinal cortex was active in encoding not only
information about objects, but also spatial information,
while the postrhinal cortex was active only in encoding spa-
tial information. These data were consistent with the results
reported in [6], in which neurons in area TF also responded
predominantly to changes in the positions of objects.
However, other investigators found that the postrhinal cor-
tex cannot be regarded as an area sensitive exclusively to
scenes, as it can also respond to the non-spatial category of
stimuli (for example, faces and colored shapes) [25].
It is of note that when humans learn the generation of
new associations between visual stimuli, which should
include spatial or non-spatial contexts, both types of con-
texts produced stronger activation of the parahippocampal
complex than individual stimuli [2]. As the parahippocam-
pal complex produces significantly more active responses to
scenes rich in associations than scenes of the same visual
quality but less associative, it can be suggested that the
parahippocampal complex supports not merely the process-
ing of placescene information, as accepted, but forms
associations regarding the context [8]. It was suggested that
highly integrated information arrives in the hippocampus as
a result of associative connections in the rhinal areas [57].
We propose that as there is an input from the postrhinal cor-
tex to field 36 of the perirhinal cortex, this, like the DG,
may be a site of generation of neural representations of
objectplace associations if the conditions for temporal
summation are created. The activity and temporal summa-
tion in the perirhinal cortex may be supported by the recur-
rent excitatory circuits which apparently exist in field 36
and other areas of the cortex. The need for this condition to
be fulfilled is shown by the facts that not only does the
perirhinal cortex contain associations linked with the spatial
position of an object, but also that these have been shown to
influence the activity of place cells in the hippocampus.
Thus, lesions to the perirhinal cortex were found to lead to
instability of the fields of place cells in field CA1, which
was apparent, for example, in displacements of the recep-
tive fields towards other loci, though the characteristics of
their neuron spike activity and their field sizes did not
change [68]. The authors of this study proposed that
although the fields of place cells in field CA1 can also be
generated without the involvement of the perirhinal cortex,
this field is subsequently transformed under the influence of
the sensory context.
It appears that associations cannot be generated in the
EC, as cells in the EClat and ECmed involved in propagat-
ing activity from the peri- and postrhinal cortex respective-
ly do not interact with each other. As the perirhinal cortex
does not project to the postrhinal, it is unlikely that neural
representations of objectplace associations are generated
in the latter. If they were generated, signals from them
might be propagated to the hippocampus via the ECmed.
However, although the upper layers of the ECmed (project-
ing to the hippocampus) contains place cells, the experi-
mental data indicate that the ability to discriminate different
contexts is characteristic only of the hippocampus and not
the ECmed [75]. It seems entirely possible that signals from
neural representations of objectplace associations generat-
Silkis 124
ed in the hippocampus are propagated from there to the
postrhinal cortex either via recurrent pathways or directly
via the axons of pyramidal cells in field CA1 or via the
lower layers of the EC. If this suggestion is correct, then
those layers of the postrhinal cortex which project to the EC
and hippocampus should not show changes in activity
linked with the generation of neural representations, while
such changes should appear in those layers which receive
information from the EC and hippocampus. This suggestion
can be tested experimentally.
As projections from the EC to the perirhinal cortex are
more intense than those to the postrhinal cortex [43], the
largest number of recurrent entorhinal-cortical influences
may be mediated via the perirhinal cortex. However, it was
found that synchronized discharges from EC neurons do not
propagate to this area of the cortex and that during stimula-
tion of the EC, spikes reach the temporal areas of the neo-
cortex only at very low probability [73]. These data allowed
the authors of [73] to suggest that that the rhinal areas of the
cortex have less a relay function between the hippocam-
pus and neocortex than a gating role. However, it remains
possible that spike activity from the neural representations
of objectplace associations generated in the hippocampus
arrive in the neocortex directly from the EC, bypassing the
parahippocampal complex, as there are projections from
neurons in layer V of the EC to the occipital (visual), tem-
poral (auditory), parietal (somatosensory), lateral frontal
(motor), and the insular and cingulate areas of the cortex
[43]. Furthermore, signals from field CA1 from neural rep-
resentations of objectplace associations may be transmit-
ted to the neocortex directly, as the ventral parts of this field
project to the visual and other sensory areas [20].
A Neural Network in Which Neural Representations of
an Episode May Be Generated and Stored
Imagination in patients with bilateral hippocampal
lesions is known to consist of fragmentary images, without
complete representation of the context [38]. These patients
cannot remember past episodes or imagine new episodes.
These data led to the conclusion that that the hippocampus
makes a critical contribution to creating representations of
an episode combining separately perceived elements [38].
In our preceding report [1], we discussed experimental data
indicating that the same individual hippocampal neurons
may take part in the generation of neural representations of
context which can be stored and then extracted from mem-
ory (for example, on imagining an episode during waking or
during dreams). Comparison of hippocampal functioning in
the states of waking and paradoxical sleep, in which con-
textual memory is disrupted, led us to suggest the hypothe-
sis that the generation of the neural representation of the
context of an episode and its correct extraction from mem-
ory require potentiated propagation of signals along the
trisynaptic pathway from the EC through the whole hip-
pocampal field [1]. We suggested that remembering or
imagining an episode in the state of waking produces acti-
vation of the neural representation of the context of an
episode, stored in the activity of a particular group of neu-
rons in the DG, fields CA3 and CA1 (connections between
which are mediated via the trisynaptic pathway), matching
the neural representation of the details of this episode stored
in those cortical areas in which information on these details
was processed when they were perceived [1].
Like the hippocampus, the parahippocampal complex
is involved not only in the processing and encoding of
information on episodes, but also takes part in extracting
information about it from memory [25, 39]. In particular,
the place area in the pararhinal cortex has been shown to
be activated when there is a need to remember a previous-
ly known position [28, 54]. Furthermore, this area of the
cortex has been shown to be activated on recognition
(which requires memory) of different details of a scene
[54]. It has been suggested that this activation may involve
the parietal and occipital-temporal areas of the cortex,
which are connected to the pararhinal cortex (in which
information on scene details appears to be processed) [54].
From our point of view, it is entirely possible that the basis
of these points is the fact that spike activity from the neu-
ral representation of the episode, generated mainly in the
hippocampus and partially in the perirhinal cortex, is also
transmitted to the postrhinal cortex. Thus, neural represen-
tations of objectplace associations are generated and
stored in the whole of the neural network, including the
hippocampus and parahippocampal complex. As already
noted, experimental data indicate that the hippocampus and
parahippocampal areas have different roles in generating
objectplace associations [6], the hippocampus encoding
the more complex associations linking different episodes
[23]. From the point of view of our proposed mechanism,
the generation of these complex associations may be based
on the convergence of the perforant inputs and inputs from
the DG to neurons in field CA3, the presence of interac-
tions between these neurons, convergence of the perforant
inputs and the inputs from field CA3 to pyramidal neurons
in field CA1, and also the possibility that temporal sum-
mation of the inputs from Schffer collaterals converging
on the proximal dendrites of field CA1 pyramidal cells
may occur.
Our previous report [1] indicated that in the state of
paradoxical sleep, changes in the neurotransmitter compo-
sition as compared with the waking state should lead to
degradation of the conditions for induction of long-term
potentiation of the efficiency of synaptic transmission in
both the lateral and medial perforant pathways to the DG, as
well as in all areas of the trisynaptic pathway. As a result,
excitation of neural ensembles analogous to the excitation
occurring during waking, when neural representations of
objectplace associations are generated with the involvement
of both information streams converging on DG neurons,
becomes impossible during paradoxical sleep. The result of
Involvement of the Trisynaptic Hippocampal Pathway in Generating Neural Representations 125
this is that extraction of previously generated neural repre-
sentations of objectplace associations from memory
becomes inaccurate, and this may be one of the causes of
the bizarre nature of dreams. (Distorted extraction of infor-
mation occurs because of the residual effectiveness of con-
nections between the EC and field CA1 [1].)
Episodic memory is known to be impaired not only in
dreams, but also in schizophrenia. Schizophrenia patients
have difficulty remembering contextual information [92].
It is also known that the volumes of not only the hippocam-
pus, but also the rhinal areas are reduced in schizophrenia
[82]. Significant changes occurring in layer II of the EC in
patients with schizophrenia are indicated by decreases in
activity in this layer [5]. It remains possible that decreases
in the excitatory input from the EC to the hippocampus are
among the underlying causes of deteriorations in the gener-
ation of associations and impairments to contextual memo-
ry in schizophrenia. This suggestion is supported by simu-
lation results. Thus, the connections of the peri- and
postrhinal areas with the EC and the connections of the EC
with the hippocampus were decreased in models developed
in [86], and this led to impairments imitating those seen in
schizophrenia.
CONCLUSIONS
The present report develops the existing concept that
the neural network on which episode memory is based
includes not only the hippocampal formation, but also the
parahippocampal complex with which it is connected and
though which spatial and non-spatial information streams
reach the hippocampus. We propose a mechanism whereby
these information streams are combined and neural repre-
sentations of objectplace associations are generated in the
neural network including the hippocampus and parahip-
pocampal complex, which consists of the perirhinal,
postrhinal/parahippocampal, and entorhinal areas of the
cortex. Non-spatial information arrives at the hippocampus
via the perirhinal cortex and the lateral part of the entorhinal
cortex, while spatial information arrives via the postrhinal/
parahippocampal and medial entorhinal areas. According to
this mechanism, the small number of projections from the
peri- to the postrhinal area and the absence of connections
between the lateral and medial areas of the entorhinal cor-
tex have the result that the generation of neural representa-
tions of objectplace associations occurs mainly in the hip-
pocampus, but include sensory-spatial associations
generated in field 36 of the perirhinal cortex because of the
input from the postrhinal area to field 36 of the perirhinal
cortex. From our point of view, the trisynaptic pathway
through the hippocampus plays a special role in generating
neural representations of objectplace associations, as it is
at the beginning of this pathway, at neurons in the dentate
gyrus and field CA3, that convergence of the spatial and
non-spatial inputs occurs. In contrast to earlier models, we
propose that signals carrying spatial information arrive at
the cortex and, thus, at the parahippocampal complex, and
thence to the hippocampus, some 20 msec earlier than sig-
nals carrying non-spatial information. Dentate gyrus gran-
ule cells may therefore initially process only spatial infor-
mation, the subsequent generation of neural representations
of objectplace associations in the dentate gyrus occurring
as a result of the return of excitation from field CA3c
(part of field CA3). Signals from neural representations of
objectplace associations generated in the dentate gyrus
arrive in field CA3, where information arriving via per-
forant fibers from the entorhinal cortex is superimposed on
them. As a result, more complex neural representations of
objectplace associations are generated in field CA3, these
then being transmitted to field CA1. Spike activity arriving
from the lateral (medial) part of the entorhinal cortex and
carrying non-spatial (spatial) information is superimposed
on these neural representations in the dorsal (ventral) part of
field CA1. The result is that neural representations of high-
er-order associations are generated in field CA1. As neural
representations of objectplace associations are very
unlikely to be generated in the parahippocampal cortex, but
are nonetheless observed, it seems likely that they result
from the transfer of spike activity from neural representa-
tions of associations generated in the dorsal part of hip-
pocampal field CA1.
As the parahippocampal complex, like the hippocam-
pus, is involved not only in memorization, but also in recall-
ing episodes, we suggested that the neural representations
of episodes are stored in the whole of the neural network,
including the hippocampus and the parahippocampal com-
plex. This neural network appears to be so efficient for the
functioning of episodic memory in humans and spatial
memory in animals that many of the anatomical character-
istics of the hippocampus and the adjacent parahippocam-
pal areas, as well as the functional roles of these areas in
declarative memory have remained unaltered during the
development of the mammals [63].
This study was supported by the Russian Foundation for
Basic Research (Grant No. 08-04-00218a) and the Russian
Humanities Scientific Foundation (Grant No. 07-06-00336a).
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