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• W1515214283 abstract "The hippocampus is composed of several regions, each of which is a network of 105 to 106 neurons. The pattern of excitatory synaptic connections within and between regions has been determined, and the “wiring diagram” is shown in Figure 1. The intricacies are striking and beg for explanation, but it remains unclear how the connections work together to perform a function. Indeed, more generally, the goal of relating network connectivity to function has not been achieved for any region of the vertebrate central nervous system, with the exception of the retina. For many brain regions, the goal is a distant one, because not even the function of the region is known. For the hippocampus, the goal appears attainable, because the general function of the hippocampus in memory processes is established. Many models that relate aspects of hippocampal circuitry to memory function have have been proposed, and these have become more refined as new information has been learned about the cellular, network, and functional properties of the hippocampus (31Jarrard L.E On the role of the hippocampus in learning and memory in the rat.Behav. Neural Biol. 1993; 60: 9-26Crossref PubMed Scopus (809) Google Scholar, 57O’Keefe J Recce M.L Phase relationship between hippocampal place units and the EEG theta rhythm.Hippocampus. 1993; 3: 317-330Crossref PubMed Scopus (1654) Google Scholar, 9Buzsáki G Chrobak J.J Temporal structure in spatially organized neuronal ensembles a role for interneuronal networks.Curr. Opin. Neurobiol. 1995; 5: 504-510Crossref PubMed Scopus (646) Google Scholar, 52Muller R A quarter of a century of place cells.Neuron. 1996; 17: 813-822Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar, 19Eichenbaum H How does the brain organize memories?.Science. 1997; 277: 330-332Crossref PubMed Scopus (132) Google Scholar, 55Nadel L Moscovitch M Memory consolidation, retrograde amnesia and the hippocampal complex.Curr. Opin. Neurobiol. 1997; 7: 217-227Crossref PubMed Scopus (1262) Google Scholar, 72Squire L.R Zola S.M Episodic memory, semantic memory, and amnesia.Hippocampus. 1998; 8: 205-211Crossref PubMed Scopus (369) Google Scholar, 77Tulving E Markowitsch H.J Episodic and declarative memory role of the hippocampus.Hippocampus. 1998; 8: 198-204Crossref PubMed Scopus (807) Google Scholar). In this paper, I propose a model that builds on several previous ones and is the first attempt to provide a coherent explanation of all of the connections shown in Figure 1. The early view of the hippocampus was that information flowed serially through its regions and that the CA3 region was the most critical for memory storage. As shown in Figure 1, axons from the entorhinal cortex excite the granule cells of the first hippocampal region, the dentate gyrus; the granule cells then excite the pyramidal cells of the CA3 region, which then excite the pyramidal cells of the CA1 region (Figure 1). CA1 cells provide an output of the hippocampus back to the cortex. First generation models of the hippocampus (46Marr D Simple memory a theory for archicortex.Proc. R. Soc. Lond. B Biol. Sci. 1971; 262: 23-81Crossref Scopus (1779) Google Scholar, 48McNaughton B.L Morris R.G Hippocampal synaptic enhancement and information.Trends Neurosci. 1987; 10: 408-415Abstract Full Text PDF Scopus (897) Google Scholar, 74Treves A Rolls E.T Computational constraints suggest the need for two distinct input systems to the hippocampal CA3 network.Hippocampus. 1992; 2: 189-199Crossref PubMed Scopus (487) Google Scholar, 49McNaughton N Morris R.G Chlordiazepoxide, an anxiolytic benzodiazepine, impairs place navigation in rats.Behav. Brain Res. 1987; 24: 39-46Crossref PubMed Scopus (151) Google Scholar) proposed that memories were stored in the CA3 region and that the storage was “autoassociative.” The term autoassociative means that synaptic links are strengthened between cells that represent different components of the same memory. These links allow a complete memory to be recalled when only a few components are presented. The proposal that CA3 is an autoassociative memory network was based on three observations. First, the axons of CA3 pyramidal cells make excitatory synapses with numerous other pyramidal cells of the CA3 region, thus forming a “recurrent” network. Second, these synapses undergo an activity-dependent modification of synaptic strength termed long-term potentiation (LTP). Third, the particular kind of LTP found at these synapses has a “Hebbian” property whereby a synapse is strengthened if there is both presynaptic and strong postsynaptic activity. According to neural network theory (41Kohonen T Associative Memory. Springer-Verlag, Berlin1978Google Scholar, 27Hopfield J.J Neural networks and physical systems with emergent collective computational abilities.Proc. Natl. Acad. Sci. USA. 1982; 79: 2554-2558Crossref PubMed Scopus (11044) Google Scholar), networks having these properties are capable of storing large numbers of autoassociative memories in their recurrent synapses. Over time, it has become clear that the flow of information through the hippocampus is not strictly serial and that the CA3 network is not the only recurrent network. Specifically, it was found that CA3 and CA1 pyramidal cells cannot only be excited by the preceding network but also by direct inputs from the entorhinal cortex (Figure 1). It was also discovered that the dentate region is a recurrent network, although a more complicated one than CA3 (7Buckmaster P.S Schwartzkroin P.A Hippocampal mossy cell function a speculative view.Hippocampus. 1994; 4: 393-402Crossref PubMed Scopus (104) Google Scholar). Dentate granule cells excite mossy cells, another type of cell in the dentate gyrus (66Scharfman H.E Kunkel D.D Schwartzkroin P.A Synaptic connections of dentate granule cells and hilar neurons results of paired intracellular recordings and intracellular horseradish peroxidase injections.Neuroscience. 1990; 37: 693-707Crossref PubMed Scopus (183) Google Scholar). These cells make modifiable excitatory connections back onto granule cells (25Hetherington P.A Austin K.B Shapiro M.L Ipsilateral associational pathway in the dentate gyrus an excitatory feedback system that supports N-methyl-D-aspartate-dependent long-term potentiation.Hippocampus. 1994; 4: 422-438Crossref PubMed Scopus (42) Google Scholar, 30Jackson M.B Scharfman H.E Positive feedback from hilar mossy cells to granule cells in the dentate gyrus revealed by voltage-sensitive dye and microelectrode recording.J. Neurophysiol. 1996; 76: 601-616PubMed Google Scholar), thus forming a recurrent network. The final major finding was that the pyramidal cells of CA3 have axon branches that produce excitatory feedback to the dentate network (29Ishizuka N Weber J Amaral D.G Organization of intrahippocampal projections originating from CA3 pyramidal cells in the rat.J. Comp. Neurol. 1990; 295: 580-623Crossref PubMed Scopus (639) Google Scholar, 60Penttonen M Kamondi A Sik A Acsady L Buzsáki G Feed-forward and feed-back activation of the dentate gyrus in vivo during dentate spikes and sharp wave bursts.Hippocampus. 1997; 7: 437-450Crossref PubMed Scopus (107) Google Scholar). Thus, the hippocampus has two recurrent networks, and these are reciprocally connected (Figure 1). There has been no previous proposal for the function of this reciprocal connectivity. In trying to relate hippocampal circuitry to memory function, it is important to understand that there are several different kinds of memory and that the hippocampus stores only “episodic memories,” memories that can be formed during a single occurrence, can be articulated (in humans), and that are linked to the particular context in which the event(s) occurred (17Dore F.Y Thornton J.A White N.M Murray E.A Selective hippocampal lesions yield nonspatial memory impairments in rhesus monkeys.Hippocampus. 1998; 8: 323-329Crossref PubMed Scopus (25) Google Scholar, 77Tulving E Markowitsch H.J Episodic and declarative memory role of the hippocampus.Hippocampus. 1998; 8: 198-204Crossref PubMed Scopus (807) Google Scholar). The hippocampus appears to be a long lasting and perhaps permanent repository of a high-level representation of these memories (reviewed by 55Nadel L Moscovitch M Memory consolidation, retrograde amnesia and the hippocampal complex.Curr. Opin. Neurobiol. 1997; 7: 217-227Crossref PubMed Scopus (1262) Google Scholar). Through feedback connections to the cortex, hippocampal neurons can activate a more detailed, lower-level representation that is stored in the cortex. Evidence that will be summarized in the following paragraphs indicates that the hippocampus may be especially important in the episodic memory of sequences. An example of such a memory would be: at the zoo (context), Jerry dropped his candy (memory 1), the monkey in the cage grabbed it (memory 2), and Jerry was sad (memory 3). One line of evidence for the storage of sequences in the hippocampus comes from the effect of hippocampal lesions on sequence learning in the rat (26Honey R.C Watt A Good M Hippocampal lesions disrupt an associative mismatch process.J. Neurosci. 1998; 18: 2226-2230PubMed Google Scholar). Normal rats can learn multiple two item sequences and orient to items that are out of their normal sequence. Rats with hippocampal lesions orient to altogether novel stimuli but do not orient when only the sequence of familiar items is changed. Other tests of sequence learning also reveal impairments in animals with hippocampal lesions (W. E. DeCoteau and R. P. Kesner, 1998, Soc. Neurosci., abstract; 80Wallenstein G.V Eichenbaum H Hasselmo M.E The hippocampus as an associator of discontiguous events.Trends Neurosci. 1998; 21: 317-323Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar). A second line of evidence indicating the importance of sequences comes from the study of hippocampal place cells. These cells fire when the animal is in a particular location in the environment. Different place cells have different place fields and collectively map the environment (56O’Keefe J Dostrovsky J The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat.Brain Res. 1971; 34: 171-175Crossref PubMed Scopus (3398) Google Scholar). During sleep, there is a tendency of place cells to fire in the same sequence as they fired during the movement of the rat in the earlier awake state (68Skaggs W.E McNaughton B.L Replay of neuronal firing sequences in rat hippocampus during sleep following spatial experience.Science. 1996; 271: 1870-1873Crossref PubMed Scopus (698) Google Scholar, 61Qin Y.-L McNaughton B.L Skaggs W.E Barnes C.A Memory reprocessing in corticocortical and hippocampocortical neuronal ensembles.Philos. Trans. R. Soc. Lond. B Biol. Sci. 1997; 352: 1525-1533Crossref PubMed Scopus (204) Google Scholar). It is thought that this sequence replay may be important for memory consolidation. Finally, recordings from hippocampal place cells show a firing pattern termed the “phase-advance” that has been interpreted as a prediction of sequential upcoming positions along a well known path. This pattern occurs as the rat moves and while its hippocampus is generating a network oscillation at theta frequency (4–10 Hz). The key observation is that as the rat moves through a cell’s place field, the cell fires with progressively earlier phase (Figure 2A) on successive theta cycles (57O’Keefe J Recce M.L Phase relationship between hippocampal place units and the EEG theta rhythm.Hippocampus. 1993; 3: 317-330Crossref PubMed Scopus (1654) Google Scholar, 69Skaggs W.E McNaughton B.L Wilson M.A Barnes C.A Theta phase precession in hippocampal neuronal populations and the compression of temporal sequences.Hippocampus. 1996; 6: 149-172Crossref PubMed Scopus (1039) Google Scholar). A simple interpretation of this phase-advance (see Figure 2A and Figure 2B) is that it reflects a prediction of the sequence of upcoming places cued by the rat’s current position (32Jensen O Lisman J Hippocampal CA3 region predicts memory sequences accounting for the phase precession of place cells.Learn. Mem. 1996; 3 (a): 279-287Crossref PubMed Scopus (274) Google Scholar, 76Tsodyks M.V Skaggs W.E Sejnowski T.J McNaughton B.L Population dynamics and theta rhythm phase precession of hippocampal place cell firing a spiking neuron model.Hippocampus. 1996; 6: 271-280Crossref PubMed Scopus (257) Google Scholar; but see 38Kamondi A Acsady L Wang X.J Buzsáki G Theta oscillations in somata and dendrites of hippocampal pyramidal cells in vivo activity-dependent phase-precession of action potentials.Hippocampus. 1998; 8: 244-261Crossref PubMed Scopus (386) Google Scholar). The sequence is said to be “time-compressed,” because it is played out within a theta cycle at a rate more rapid than the actual traversal of the places. Theta oscillations are subdivided by faster gamma oscillations (40 Hz) (4Bragin A Jando G Nadasdy Z Hetke J Wise K Buzsáki G Gamma (40–100 Hz) oscillation in the hippocampus of the behaving rat.J. Neurosci. 1995; 15: 47-60PubMed Google Scholar), and these may organize the readout of sequential locations during a theta cycle, as diagrammed in Figure 2. According to this view, the memory of a particular location (or more generally, an event or object) is encoded by a group of cells that fire synchronously during a particular gamma cycle that has a particular phase within the theta cycle. The hippocampus thus uses what is termed a phase code. A model based on this idea (Figure 2B) leads to the prediction that the average phase-advance should be one gamma cycle per theta cycle, a prediction in reasonable accord with experiments (34Jensen O Lisman J.E Theta/Gamma networks with slow NMDA channels learn sequences and encode episodic memory role of NMDA channels in recall.Learn. Mem. 1996; 3 (c): 264-278Crossref PubMed Scopus (120) Google Scholar). Having a rapid, time-compressed readout of memory sequences is of obvious utility in preparing the animal for what is to come (the next time Jerry drops his candy at the zoo, he may pick it up more quickly). The ability of the CA3 recurrent network to synaptically encode sequence information during learning follows straightforwardly from what is known about the biophysical basis of LTP. At the recurrent synapses of CA3, LTP depends on the NMDA class of glutamate-activated receptors (NMDAR). These receptors mediate a Hebbian form of plasticity that is triggered when released glutamate binds to the NMDAR, and there is substantial postsynaptic depolarization. Because NMDARs in the CA1–CA3 region deactivate slowly (>100 ms) (15Debanne D Guerineau N.C Gahwiler B.H Thompson S.M Physiology and pharmacology of unitary synaptic connections between pairs of cells in areas CA3 and CA1 of rat hippocampal slice cultures.J. Neurophysiol. 1995; 73: 1282-1294PubMed Google Scholar), LTP can occur even if postsynaptic depolarization occurs with a 100 ms delay after glutamate release (20Gustafsson B Wigstrom H Abraham W.C Huang Y.Y Long-term potentiation in the hippocampus using depolarizing current pulses as the conditioning stimulus to single volley synaptic potentials.J. Neurosci. 1987; 7: 774-780PubMed Google Scholar). This delay window has important implications for sequence learning; if, as the animal moves, place cells A and B are sequentially activated within 100 ms, the synaptic connection from cell A to cell B will be strengthened (3Blum K.I Abbott L.F A model of spatial map formation in the hippocampus of the rat.Neural Comput. 1996; 8: 85-93Crossref PubMed Scopus (251) Google Scholar), and this would be similarly true for the elements in a longer sequence (A cells become strongly connected to B cells, which are strongly connected to C cells, etc.). It is important to note that the strengthening of connections is asymmetrical (B cells become strongly connected to C cells but not vice versa). Thus, if B cells were to be activated during a recall process, they would activate C cells, not A cells, thereby reproducing the sequence that was actually experienced. The mechanism described in the previous paragraph could lead to the encoding of memory sequences in which sequential events have a temporal separation of <100 ms, but what about the more common situation in which the temporal separation is much larger? The encoding of such sequences may depend on a short-term memory buffer that can extend the period of active firing for many seconds. Because hippocampal neurons tend to fire for many seconds after a brief stimulus (78Vinogradova O.S Functional organization of the limbic system in the process of registration of information facts and hypotheses.in: Isaakson R.L Pribram K.H The Hippocampus. Plenum Press, New York1984Google Scholar, 22Hampson R.E Heyser C.J Deadwyler S.A Hippocampal cell firing correlates of delayed-match-to-sample performance in rat.Behav. Neurosci. 1993; 107: 715-739Crossref PubMed Scopus (146) Google Scholar, 13Colombo M Gross C.G Responses of inferior temporal cortex and hippocampal neurons during delayed matching to sample in monkeys (Macaca fascicularis).Behav. Neurosci. 1994; 108: 443-455Crossref PubMed Scopus (95) Google Scholar), the hippocampus must either itself be a buffer or be driven by a network that has buffering ability (Figure 2B). Such persistent firing allows a single brief presentation to be synaptically encoded by an LTP-type process that requires repetitive firing to produce synaptic modification. Of particular relevance to sequence learning is the possibility that such buffers can hold multiple items active at the same time by a multiplexing mechanism (44Lisman J.E Idiart M.A Storage of 7 +/− 2 short-term memories in oscillatory subcycles.Science. 1995; 267: 1512-1515Crossref PubMed Scopus (957) Google Scholar, 33Jensen O Lisman J.E Novel lists of 7+−2 known items can be reliably stored in an oscillatory short-term memory network interaction with long-term memory.Learn. Mem. 1996; 3 (b): 257-263Crossref PubMed Scopus (120) Google Scholar). According to the multiplexing model, items that are presented sequentially during learning are represented in sequential gamma cycles, as illustrated in Figure 2C, and the entire pattern repeats for many seconds in every theta cycle (see Figure 2C legend for a description of possible physiological mechanisms). A buffer of this kind would allow an LTP-type process (with a delay window of 100 ms) to form asymmetrical memory linkages between sequential memory items in a manner consistent with psychophysical results (Figure 3D), even if the events occurred seconds apart (as in Jerry’s story) (34Jensen O Lisman J.E Theta/Gamma networks with slow NMDA channels learn sequences and encode episodic memory role of NMDA channels in recall.Learn. Mem. 1996; 3 (c): 264-278Crossref PubMed Scopus (120) Google Scholar, 35Jensen O Lisman J.E An oscillatory short-term memory buffer model can account for data on the sternberg task.J. Neurosci. 1998; 18: 10688-10699PubMed Google Scholar). There are thus physiologically plausible mechanisms by which realistic sequences of events could be encoded into long-term memory. The findings summarized in the preceding paragraphs form the basis of the view that the CA3 region is not an autoassociative network, as previously proposed (autoassociation would symmetrically link Jerry and dropped and candy). Rather, according to second generation models (3Blum K.I Abbott L.F A model of spatial map formation in the hippocampus of the rat.Neural Comput. 1996; 8: 85-93Crossref PubMed Scopus (251) Google Scholar, 32Jensen O Lisman J Hippocampal CA3 region predicts memory sequences accounting for the phase precession of place cells.Learn. Mem. 1996; 3 (a): 279-287Crossref PubMed Scopus (274) Google Scholar, 42Levy W.B A sequence predicting CA3 is a flexible associator that learns and uses context to solve hippocampal-like tasks.Hippocampus. 1996; 6: 579-590Crossref PubMed Scopus (300) Google Scholar, 76Tsodyks M.V Skaggs W.E Sejnowski T.J McNaughton B.L Population dynamics and theta rhythm phase precession of hippocampal place cell firing a spiking neuron model.Hippocampus. 1996; 6: 271-280Crossref PubMed Scopus (257) Google Scholar, 79Wallenstein G.V Hasselmo M.E GABAergic modulation of hippocampal population activity sequence learning, place field development, and the phase precession effect.J. Neurophysiol. 1997; 78: 393-408PubMed Google Scholar), CA3 is a heteroassociative network that links different memories that occurred at different times (heteroassociation asymmetrically links “Jerry dropped candy” to “monkey reached through cage and grabbed it”). The next section will develop the idea that the reciprocally connected dentate and CA3 networks provide a solution to the special problems that arise when attempting to accurately recall sequences. One observation that at first did not seem to fit with the idea that the phase-advance is generated in CA3 is that it is also observed in the preceding region, the dentate gyrus (68Skaggs W.E McNaughton B.L Replay of neuronal firing sequences in rat hippocampus during sleep following spatial experience.Science. 1996; 271: 1870-1873Crossref PubMed Scopus (698) Google Scholar). One possible explanation would be that the information is sent to the dentate from CA3 by the feedback connections (Figure 1). But what would be the purpose of such feedback, and, in the larger sense, what is the purpose of having two reciprocally connected recurrent networks? Abstract models of sequencing networks suggest an answer to these questions (39Kleinfeld D Sequential state generation by model neural networks.Proc. Natl. Acad. Sci. USA. 1986; 83: 9469-9473Crossref PubMed Scopus (179) Google Scholar, 71Sompolinksy H Kanter I Temporal association in asymmetric neural networks.Phys. Rev. Lett. 1986; 57: 2861-2864Crossref PubMed Scopus (315) Google Scholar). One might at first think that sequencing could be done by a simple heteroassociative recurrent network in which cells encoding memory A were connected to cells encoding memory B, which were then connected to cells encoding memory C, etc. (Figure 3A). However, it can easily be seen that this process will not lead to accurate sequence recall. Because of intrinsic and synaptic noise, memory A cells cannot perfectly activate memory B cells; some memory B cells don’t fire (false negatives), while other cells that are not part of memory B do fire (false positives). Memory B is thus somewhat degraded, a degradation signified as B′. The problem gets worse in the next step of sequence recall, when B′ is used to activate memory C cells. Because the starting point is inaccurate, the firing of C cells will be even more inaccurate, C′′. The result is a concatenation of errors that makes the replay of long sequences problematic. What Sompolinsky and Kleinfeld showed was that this problem could be avoided by a second set of synapses that contained autoassociative information about the specific memory items, i.e., about A, B, and C. A well established capability of autoassociative recurrent networks is to restore a degraded memory to its original form, i.e., convert B′ to B (Figure 3B). This corrected memory could then be used to predict C without a concatenation of errors. They proposed that a network could alternately use the autoassociative and heteroassociative synapses to produce accurate sequence recall. I propose that this principle underlies sequence recall in the hippocampus but that the two sets of synapses are in different recurrent networks; the autoassociative information about memory items may be stored in the dentate, whereas the heteroassociative information that links memory items into a sequence may be stored in CA3. These networks might interact during recall in the following way (Figure 3C): in CA3, memory B cells are fired by recurrent input from memory A cells, but with errors, resulting in pattern B′; this pattern is sent to the dentate, where it is corrected to B and sent back to CA3; there, it triggers the next cycle of sequence recall. In this way, the two reciprocally interconnected recurrent networks could produce accurate sequence recall. Although the influence of CA3 on the dentate has been demonstrated in vivo (60Penttonen M Kamondi A Sik A Acsady L Buzsáki G Feed-forward and feed-back activation of the dentate gyrus in vivo during dentate spikes and sharp wave bursts.Hippocampus. 1997; 7: 437-450Crossref PubMed Scopus (107) Google Scholar), this interaction has not yet been described in any detail. More data will therefore be required to determine whether the reciprocal interactions can perform the functions required by the model (see preliminary ideas in Figure 3C legend). What can be evaluated from available data is whether the proposed bidirectional interaction is feasible from a timing standpoint. If each step in sequence recall is linked to one gamma cycle (Figure 2), the bidirectional interaction must occur in less than the period of the oscillation (25 ms). The evidence suggests that this is feasible, since transmission from CA3 to the dentate takes <3 ms (82Wu K Canning K.J Leung L.S Functional interconnections between CA3 and the dentate gyrus revealed by current source density analysis.Hippocampus. 1998; 8: 217-230Crossref PubMed Scopus (28) Google Scholar), and transmission back to CA3 takes <5 ms (83Yeckel M.F Berger T.W Feedforward excitation of the hippocampus by afferents from the entorhinal cortex redefinition of the role of the trisynaptic pathway.Proc. Natl. Acad. Sci. USA. 1990; 87: 5832-5836Crossref PubMed Scopus (225) Google Scholar). A key prediction is that the dentate and CA3 recurrent networks perform the different functions of autoassociation and heteroassociation, respectively. As discussed above, what suggests that the CA3 region is heteroassociative is that the time window of synaptic modification is sufficiently long (∼100 ms) to produce heteroassociative linkages (given the evidence that different information is active within this time window [Figure 2]). If the dentate network performs autoassociation, then the time window in this network must be shorter, specifically less than the period of a gamma cycle. One way this could occur would be if the NMDAR deactivation time was short (<30 ms) at either of the two synapses in the dentate recurrent network, and it would thus be of great interest to measure these times. At a more functional level, the model predicts that the accuracy of sequence recall should be reduced by interfering with the function of the dentate or by eliminating the feedback projections from CA3 to dentate. I now turn to the possible function of the direct input from the entorhinal cortex to CA3 (Figure 1). This input is called the perforant path input, and I argue that it has a key role in allowing memory sequences to be stored in context. Context refers to the general, relatively constant features of the environment. In our example, the zoo is the context. Cotton candy and animal smells are part of what makes up context. The importance of the hippocampus in encoding contextual information has been demonstrated in behavioral experiments. For instance, during aversive conditioning; given a choice of environments, normal animals will move to the environment in which they were not shocked when a conditioned stimulus is given. After hippocampal lesions, animals can still be conditioned, but actions based on context are absent (67Selden N.R Everitt B.J Jarrard L.E Robbins T.W Complementary roles for the amygdala and hippocampus in aversive conditioning to explicit and contextual cues.Neuroscience. 1991; 42: 335-350Crossref PubMed Scopus (428) Google Scholar). The importance of context is also evident in recordings from hippocampal place cells. In a given context, the environment is mapped out by a subset of place cells. In a different context (e.g., room), the environment will be mapped out by a different subset (53Muller R.U Kubie J.L The effects of changes in the environment on the spatial firing of hippocampal complex–spike cells.J. Neurosci. 1987; 7: 1951-1968PubMed Google Scholar). About one-third of the cells are potentially active in a given context (73Thompson L.T Best P.J Place cells and silent cells in the hippocampus of freely-behaving rats.J. Neurosci. 1989; 9: 2382-2390PubMed Google Scholar). This strong context dependence is not observed in the entorhinal cortex (62Quirk G.J Muller R.U Kubie J.L Ranck Jr., J.B The positional firing properties of medial entorhinal neurons description and comparison with hippocampal place cells.J. Neurosci. 1992; 12: 1945-1963PubMed Google Scholar). Importantly, there are no cells in the hippocampus that fire continuously in a particular context. One explanation is that contextual input to the hippocampus is itself subthreshold. Such a subthreshold depolarization could, however, have important consequences in enabling context-appropriate cells to be triggered by other inputs. The perforant path input to CA3 could play this enabling role. This pathway terminates in the most distal region of the dendritic tree and is thus the least effective input for firing cells. However, this input could produce a depolarizing bias in target cells that would allow a single axonal input from a dentate granule cell to fire the cell. These axons, which are termed mossy fibers, synapse onto CA3 cells at unusually large spines having multiple active zones (11Chicurel M.E Harris K.M Three-dimensional analysis of the structure and composition of CA3 branched dendritic spines and their synaptic relationships with mossy fiber boutons in the rat hippocampus.J. Comp. Neurol. 1992; 325: 169-182Crossref PubMed Scopus (319) Google Scholar), an observation that led to the proposal that a single mossy fiber might “detonate” (fire) the CA3 cell (48McNaughton B.L Morris R.G Hippocampal synaptic enhancement" @default.
• W1515214283 created "2016-06-24" @default.
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• W1515214283 date "1999-02-01" @default.
• W1515214283 modified "2023-10-14" @default.
• W1515214283 title "Relating Hippocampal Circuitry to Function" @default.
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