Preserved spatial coding in hippocampal CA1 pyramidal cells during reversible suppression of CA3c output: evidence for pattern completion in hippocampus

Medial septal modulation of hippocampal single-unit activity was examined by assessing the behavioral and physiological consequences of reversibly inactivating the medial septum via microinjection of a local anesthetic (tetracaine) in freely behaving rats trained to solve a working memory problem on a radial maze. Reversible septal inactivation resulted in a dramatic, but temporary (15-20 min), impairment in choice accuracy. In addition, movement-induced theta (theta) modulation of the hippocampal EEG was eliminated. Septal injection of tetracaine also produced a significant reduction in location-specific firing by hilar/CA3c complex-spike cells (about 50%), with no significant change in the place-specific firing properties of CA1 complex-spike units. The mean spontaneous rates of stratum granulosum and CA1 theta cells were temporarily reduced by about 50% following septal injection of tetracaine. Although there was a significant reduction in the activities of inhibitory interneurons (theta cells) in CA1, there was no loss of spatial selectivity in the CA1 pyramidal cell discharge patterns. We interpret these results as support for the proposal originally put forth by Marr (1969, 1971) that hippocampal circuits perform pattern completion on fragmentary input information as a result of a normalization operation carried out by inhibitory interneurons. A second major finding in this study was that location specific firing of CA1 cells can be maintained in the virtual absence of the hippocampal theta-rhythm.     

Hippocampal spatial representations require vestibular input

The hippocampal formation is essential for forming declarative representations of the relationships among multiple stimuli. The rodent hippocampal formation, including the entorhinal cortex and subicular complex, is critical for spatial memory. Two classes of hippocampal neurons fire in relation to spatial features. Place cells collectively map spatial locations, with each cell firing only when the animal occupies that cell's "place field," a particular subregion of the larger environment. Head direction (HD) cells encode directional heading, with each HD cell firing when the rat's head is oriented in that cell's particular "preferred firing direction." Both landmarks and internal cues (e.g., vestibular, motor efference copy) influence place and HD cell activity. However, as is the case for navigation, landmarks are believed to exert greater influence over place and HD cell activity. Here we show that temporary inactivation of the vestibular system led to the disruption of location-specific firing in hippocampal place cells and direction-specific discharge of postsubicular HD cells, without altering motor function. Place and HD cell activity recovered over a time course similar to that of the restoration of vestibular function. These results indicate that vestibular signals provide an important influence over the expression of hippocampal spatial representations, and may explain the navigational deficits of humans with vestibular dysfunction.     

Reversible inactivation of the medial septum differentially affects two forms of learning in rats

The contribution of the medial septum to different aspects of spatial information processing was assessed by examining the effects of reversible septal inactivation on radial maze performance of rats. In addition, the selectivity with which the medial septum affects learning was studied by testing the effects of septal inactivation on the acquisition of non-spatial information. Rats were first trained according to a spatial working memory procedure that included a 30-min delay between the first 4 (forced) choices and subsequent test (free) choices. The forced choices comprised the sample phase of the experiment while the free choices comprised the test phase. Saline or tetracaine (a local anesthetic) was injected into the medial septal area either before the sample phase, after the sample phase (i.e. at the beginning of the delay period), or just before the test phase. In contrast to the saline injections, tetracaine injected just before the sample or test phases produced a significant increase in errors at test. Tetracaine injection at the beginning of the delay period did not affect test choice accuracy. EEG records showed that septal inactivation drastically, yet temporarily, reduced the hippocampal theta rhythm. Thus, when septal inactivation occurred either before the sample phase or at the beginning of the delay period, hippocampal theta recovered by the time of the test phase. Septal inactivation also produced a significant retardation of learning on a non-spatial reference memory task, although clear improvement over trials did occur. Moreover, the results of subsequent saline injections suggest that at least some of the performance deficit was due to variables other than learning per se.(ABSTRACT TRUNCATED AT 250 WORDS)     

Preservation of topography in the connections between the subiculum,field CA1, and the entorhinal cortex in rats

In order to examine whether the entorhinal-hippocampal-entorhinal circuit is reciprocal and topographic, the connections between the subiculum, the CA1 field, and the entorhinal cortex were studied with the carbocyanine dye (Dil), which moves in both retrograde and anterograde directions. We investigated the organization of reciprocal connections revealed by injections of Dil in the entorhinal cortex along the rhinal sulcus. Anterograde fluorescent labeling showed the same pattern reported in previous studies of the dorsal hippocampus. When the injection site of DiI extended into the deep layers (IV–VI) of the same cortical column, the anterograde labeling of the perforant path was accompanied by retrograde labeling of the subicular neurons and the CA1 neurons. The distribution of labeled cells overlapped the distribution of labeled fibers, and the distribution of labeled cells paralleled that of the labeled fibers in the CA1 field. DiI injection into the medial entorhinal cortex revealed fewer retrogradely labeled subicular neurons than injection into the lateral entorhinal cortex, whereas the number of labeled CA1 neurons was not dependent on the injection site. The number of labeled CA1 neurons was always several times greater than the number of subicular neurons. Thus, the amount of information conveyed by the CA1 projection might be higher than that conveyed by the subicular projection. These results indicate that the entorhinal cortex, CA1, and the subiculum are connected reciprocally and topographically. We believe that the framework of the major hippocampal circuit proposed in previous studies should be reconsidered. We propose that the CA1 projection, rather than the subicular projection, is the main projection that feeds back information from the hippocampus to the entorhinal cortex. © 1995 Wiley-Liss, Inc.     

Place cell firing cannot support navigation without intact septal circuits

Though it has been known for over half a century that interference with the normal activity of septohippocampal neurons can abolish hippocampal theta rhythmicity, a definitive answer to the question of its function has remained elusive. To clarify the role of septal circuits and theta in location‐specific activity of place cells and spatial behavior, three drugs were delivered to the medial septum of rats: Tetracaine, a local anesthetic; muscimol, a GABA‐A agonist; and gabazine, a GABA‐A antagonist. All three drugs disrupted normal oscillatory activity in the hippocampus. However, tetracaine and muscimol both reduced spatial firing and interfered with the rat's ability to navigate to a hidden goal. After gabazine, location‐specific firing was preserved in the absence of theta, but rats were unable to accurately locate the hidden goal. These results indicate that theta is unnecessary for location‐specific firing of hippocampal cells, and that place cell activity cannot support accurate navigation when septal circuits are disrupted.     

Medial septal modulation of hippocampal theta cell discharges

The effect of small electrolytic lesions in various areas of the septum on the behavioral correlates and firing repertoires of hippocampal theta cells, was investigated in the freely moving rabbit. Lesions localized to the medial septum were found to abolish both slow wave theta and the rhythmic firing of CA1 and dentate layer theta cells, in both the type 1 theta (movement) and type 2 theta (sensory processing) behavior conditions. Small lesions of the diagonal band, lateral septum and fimbria/fornix regions only affected rhythmicity to the extent that they also involved the medial septal region. The same medial septal lesions that abolished rhythmicity were also shown to reduce the mean discharge rate of theta cells occurring during the type 1 movement condition by approximately 50%, while the discharge rate occurring during the type 2 sensory processing condition did not change significantly. Behavioral changes were also only observed for lesions involving the medial septum. The importance of afferent input from the medial septum in the generation of hippocampal theta cell rhythmicity was discussed.     

Efferent connections of the hippocampal formation in the rat.

In this investigation the projections of the hippocampal formation to the septal area and hypothalamus were studied in the rat with the combined use of 3H-amino acid radioautography and horseradish peroxidase histochemistry. The results indicate that all of the fibers which project to the hypothalamus and the majority of fibers which project to the septum arise from the subicular cortex and not from hippocampal pyramidal cells. The projection to both of these areas are topographically organized along the longitudinal axis of the hippocampal formation. Specifically, fibers from subicular cortical cells situated at the septal end of the hippocampal formation which project through the medial part of the dorsal fornix terminate in the dorsomedial quadrant of the lateral septal nucleus and in the dorsal portion of the pars posterior of the medial mammillary nucleus. Fibers from progressively more posteroventral levels of the hippocampal formation which project through more lateral portions of the dorsal fornix and fimbria terminate in progressively lateral and ventral quadrants of the lateral septal nucleus and in progressively more ventral portions of the pars posterior. Concerning the specific origin of the fornix system, fibers from only the prosubiculum and subiculum project through both the pre- and postcommissural fornix. Hippocampal pyramidal cells from all CA fields have a restricted projection through the precommissural fornix and terminate in the caudal half of the septum while the presubiculum projects solely through the postcommissural fornix. The medial corticohypothalamic tract (MCHT) was found to arise from cells located in anterior ventral levels of the subicular cortex. Fibers from this tract appeared to be distributed throughout the pericellular region of the entire ventromedial extent of the hypothalamus from the level of the suprachiasmatic nucleus through the level of the medial mammillary nucleus. In this way, the mammillary bodies receive input from the subicular cortex via two routes: the descending column of the fornix and the MCHT.     

GABAergic contributions to gating,timing, and phase precession of hippocampal neuronal activity during theta oscillations

Successful spatial exploration requires gating, storage, and retrieval of spatial memories in the correct order. The hippocampus is known to play an important role in the temporal organization of spatial information. Temporally ordered spatial memories are encoded and retrieved by the firing rate and phase of hippocampal pyramidal cells and inhibitory interneurons with respect to ongoing network theta oscillations paced by intra‐ and extrahippocampal areas. Much is known about the anatomical, physiological, and molecular characteristics as well as the connectivity and synaptic properties of various cell types in the hippocampal microcircuits, but how these detailed properties of individual neurons give rise to temporal organization of spatial memories remains unclear. We present a model of the hippocampal CA1 microcircuit based on observed biophysical properties of pyramidal cells and six types of inhibitory interneurons: axo‐axonic, basket, bistratistified, neurogliaform, ivy, and oriens lacunosum‐moleculare cells. The model simulates a virtual rat running on a linear track. Excitatory transient inputs come from the entorhinal cortex (EC) and the CA3 Schaffer collaterals and impinge on both the pyramidal cells and inhibitory interneurons, whereas inhibitory inputs from the medial septum impinge only on the inhibitory interneurons. Dopamine operates as a gate‐keeper modulating the spatial memory flow to the PC distal dendrites in a frequency‐dependent manner. A mechanism for spike‐timing‐dependent plasticity in distal and proximal PC dendrites consisting of three calcium detectors, which responds to the instantaneous calcium level and its time course in the dendrite, is used to model the plasticity effects. The model simulates the timing of firing of different hippocampal cell types relative to theta oscillations, and proposes functional roles for the different classes of the hippocampal and septal inhibitory interneurons in the correct ordering of spatial memories as well as in the generation and maintenance of theta phase precession of pyramidal cells (place cells) in CA1. The model leads to a number of experimentally testable predictions that may lead to a better understanding of the biophysical computations in the hippocampus and medial septum. © 2012 Wiley Periodicals, Inc.     

Spatial Memory Sequence Encoding and Replay During Modeled Theta and Ripple Oscillations

Spatial learning involves the storage and replay of temporally ordered spatial information. The hippocampus is a key brain structure involved in spatial learning in rats. Temporally ordered spatial memories are encoded and replayed by the firing rate and phase of hippocampal pyramidal cells and inhibitory interneurons with respect to ongoing network theta and ripple oscillations paced by intra- and extrahippocampal areas. Theta oscillations (4–7 Hz) may contribute to memory formation, whereas fast ripple oscillations to temporally compressed forward and reverse replay of previously stored memories. Different classes of CA1 excitatory and inhibitory neurons and medial septal inhibitory neurons have been shown to differentially phase their activities with respect to theta and ripples. Understanding how the different hippocampal and extrahippocampal areas and their neuronal classes interact during these network oscillations and how they facilitate the storage and replay of spatiotemporal memories is of great importance. A computational model of the hippocampal CA1 microcircuit that uses biophysical representations of the major cell types, including pyramidal cells and four types of inhibitory interneurons, is extended. Inputs to the network come from the entorhinal cortex (EC), the CA3 Schaffer collaterals and the medial septum. A biophysical mechanism of spike timing-dependent plasticity (STDP) is used for learning spatial memory patterns in the correct order. The model addresses two important issues: (1) How are the storage and replay (forward and reverse) of temporally ordered memory patterns controlled in the CA1 microcircuit during theta and ripples? (2) What roles do the various types of inhibitory interneurons play in these processes?     

Reversible inactivation of the medial septum: selective effects on the spontaneous unit activity of different hippocampal cell types

The contribution of septal afferents to spontaneous hippocampal single unit activity was examined by reversibly inactivating the medial septal nucleus using microinjections of the local anethetic lidocaine. Septal inactivation reduced spontaneous firing of cells in stratum granulosum and in the hilar/CA3 region for periods of up to about 15 min. The firing rates of CA1 complex-spike (pyramidal) cells, however, were not changed, although CA1 theta cells (inhibitory interneurons) exhibited a significant reduction in spontaneous rate. One interpretation of this pattern of results is that the output of CA1 pyramidal cells is maintained roughly constant in spite of reduced input from CA3 because of a proportional reduction in feedforward inhibition. This interpretation is consistent with Marr's²² formulation of the manner in which the hippocampus implements distributed associative memory. Alternatively, afferents to CA1 originating from regions other than CA3 may play a larger role in regulating CA1 output than previously assumed.     

Effect of electric stimulation of the septum of the rabbit brain on subiculum cells with different types of spontaneous activity

Neuronal activity was recorded extracellularly in subiculum of unanaesthetized rabbits during stimulation of the medial septal nucleus and hippocampal field CA1. According to the pattern of the background activity subicular cells were divided into three groups: cells with theta-modulation, cells with delta-modulation and complex spikes, cells with irregular single-spike activity. The theta-cells were specifically related to the septal input: their reactivity to septal stimulation was higher and the latencies of their responses significantly shorter than those of the other groups of cells. Stability of the theta-modulation was increased during and after septal stimulation. Reactivity to CA1 stimulation, as well as latencies of responses were identical for all groups of subicular cells. Rhythmic theta-modulation was damped after CA1 stimulation. The data indicate specific properties of the septal input to the subicular cells with theta-modulation.     

Enhanced acetylcholinesterase staining in the hippocampal perforant pathway zone after combined lesions of the septum and entorhinal cortex

A lesion of the septum or a transection of the fimbria-fornix diminishes most, but not all, acetylcholinesterase (AChE) staining in the hippocampal formation. The residual AChE is located in the outer part of the molecular layer of the hippocampal CA1 zone and adjacent subicular field (zone 31). We report that following combined lesions of the septum and entorhinal cortex, the residual hippocampal AChE staining pattern expands and occupies the zone innervated normally by perforant pathway terminals from the entorhinal cortex.     

Cortical projection patterns of the medial septum-diagonal band complex

A detailed analysis of the cortical projections of the medial septum-diagonal band (MS/DB) complex was carried out by means of anterograde transport of Phaseolus vulgaris leucoagglutinin (PHA-L). The tracer was injected iontophoretically into cell groups of the medial septum (MS) and the vertical and horizontal limbs of the diagonal band of Broca (VDB and HDB), and sections were processed immunohistochemically for the intra-axonally transported PHA-L. The labeled efferents showed remarkable differences in regional distribution in the cortical mantle dependent on the position of the injection site in the MS/DB complex, revealing a topographic organization of the MS/DB-cortical projection. In brief, the lateral and intermediate aspects of the HDB, also referred to as the magnocellular preoptic area, predominantly project to the olfactory nuclei and the lateral entorhinal cortex. The medial part of the HDB and adjacent caudal (angular) part of the VDB are characterized by widespread, abundant projections to medial mesolimbic, occipital, and lateral entorhinal cortices, olfactory bulb, and dorsal aspects of the subicular and hippocampal areas. Projections from the rostromedial part of the VDB and from the MS are preponderantly aimed at the entire hippocampal and retrohippocampal regions and to a lesser degree at the medial mesolimbic cortex. Furthermore, the MS projections are subject to a clear mediolateral topographic arrangement, such that the lateral MS predominantly projects to the ventral/temporal aspects of the subicular complex and hippocampus and to the medial portion of the entorhinal cortex, whereas more medially located cells in the MS innervate more septal/dorsal parts of the hippocampal and subicular areas and more lateral parts of the entorhinal cortex. PHA-L filled axons have been observed to course through a number of pathways, i.e., the fimbria-fornix system, supracallosal stria, olfactory peduncle, and lateral piriform route (the latter two mainly by the HDB and caudal VDB). Generally, labeled projections were distributed throughout all cortical layers, although clear patterns of lamination were present in several target areas. The richly branching fibers were abundantly provided with both "boutons en passant" and terminal boutons. Both distribution and morphology of the labeled basal forebrain efferents in the prefrontal, cingulate, and occipital cortices closely resemble the distribution and morphology of the cholinergic innervation as revealed by immunohistochemical demonstration of choline acetyltransferase. In contrast, the labeled projections to the olfactory, hippocampal, subicular, and entorhinal areas showed a heterogeneous morphology. Here, the distribution of only the thin varicose projections resembled the distribution of cholinergic fibers.     

Topographical and laminar organization of subicular projections to the parahippocampal region of the rat

In this study, we analyzed in detail the topographic organization of the subiculoparahippocampal projection in the rat. The anterograde tracers Phaseolus vulgaris leucoagglutinin-L and biotinylated dextran amine were injected into the subiculum at different septotemporal and transverse levels. Deep layers of the ento-, peri-, and postrhinal cortices are the main recipients of subicular projections, but in all cases we noted that a small fraction of the projections also terminates in the superficial layers II and III. Analysis of the fiber patterns in the parahippocampal region revealed a topographic organization, depending on the location of the cells of origin along both the transverse and the septotemporal axes of the subiculum. Projections originating from subicular cells close to CA1, i.e., proximal part of subiculum, terminate exclusively in the lateral entorhinal cortex and in the perirhinal cortex. In contrast, projections from cells closer to the subiculum-presubiculum border, i.e., distal part of subiculum, terminate in the medial entorhinal cortex and in the postrhinal cortex. In addition, cells in septal portions of the subiculum project to a lateral band of entorhinal cortex parallel to the rhinal sulcus and to peri- or postrhinal cortices, whereas cells in more temporal portions project to more medial parts of the entorhinal cortex. These results indicate that subicular projections to the parahippocampal region precisely reciprocate the known inputs from this region to the hippocampal formation. We thus suggest that the reciprocal connectivity between the subiculum and the parahippocampal region is organized as parallel pathways that serve to segregate information flow and thus maintain the identity of processed information. Although this parallel organization is comparable to that of the CA1-parahippocampal projections, differences exist with respect to the degree of collateralization.     

A [C]2-Deoxyglucose analysis of the functional neural pathways of the limbic forebrain in the rat. III. The hippocampal formation

The regions metabolically activated in the rat brain following focal electrical stimulation of various components of the hippocampal formation were identified with the use of [¹⁴C]2-deoxyglucose (2-DG) autoradiography. The results of these experiments, conducted in the rat, showed that in the absence of elicited afterdischarge activity, stimulation of either the CA1 or CA3 field of the dorsal hippocampus resulted in bilateral metabolic activation of only the dorsal hippocampus as well as of a relatively restricted region within the dorsomedial aspect of the lateral septal nucleus, bilaterally. In contrast, stimulation of either the CA1 or CA3 field of the ventral hippocampus resulted in bilateral activation of the ventral hippocampus and no region of the dorsal hippocampus. Following such stimulation, the lateral septal nucleus was also labeled bilaterally, but the activated regions were situated in a position ventrolateral to those resulting from stimulation at dorsal levels. Stimulation of the subicular cortex, in contrast, resulted in only ipsilateral activation of the hippocampal formation and lateral septal nucleus. Further rostral levels of the lateral septal nucleus were noted to be activated following stimulation of subicular cortex as compared to stimulation of the cornu Ammonis.The hypothalamus was directly activated by two pathways, the postcommissural fornix and the medial corticohypothalamic tract. Following stimulation at dorsal and posterior levels of CA1 and the subiculum, the mammillary bodies were demonstrably labeled by input from the postcommissural fornix. Regions of the medial hypothalamus were activated via the medial corticohypothalamic tract following stimulation of the ventral subiculum.The amygdala, stria terminalis and its bed nucleus were also shown to be demonstrably activated following stimulation of the ventral subiculum, ventral CAl field and posterior prosubiculum. This pathway may represent an additional route by which hippocampal modulation may indirectly modulate hypothalamic function.The presence of elicited afterdischarges resulted in more extensive patterns of metabolic labeling within the hippocampal formation and lateral septal nuclei as compared to experiments in which afterdischarges were not elicited. The extent of the demonstrable labeling, both within, and extrinsic to the hippocampal formation appeared to be a function of the duration and severity of the elicited seizure discharge. Additional structures which were demonstrably labeled following the elicitation of seizure activity include the entorhinal cortex-prepyriform area, amygdala, substantia innominata, putamen, substantia nigra, olfactory and prefrontal cortices and medial thalamic nuclei.     

The topography of activity transmission between lateral entorhinal cortex and subfield CA1 of the hippocampus

It is important to establish how information is transmitted through the hippocampal formation because of the structure's critical role in memory and spatial processing. Here we provide evidence that challenges the hypothesis that information is processed in parallel closed entorhinal-CA1 loops. We tested the hypothesis by mapping, throughout hippocampal subfield CA1, field potentials evoked by stimulation of different sites in lateral entorhinal cortex in awake rats, thereby establishing the topography of electrophysiological transmission between the entorhinal cortex and CA1. The results established that antidromic and orthodromic responses evoked from the same entorhinal site occurred in spatially separated CA1 areas, with antidromic responses being located more septally than orthodromic responses. Thus, an entorhinal site receives information from a CA1 area located closer to the septal pole of the hippocampus and transmits it to the next CA1 area located closer to the temporal pole. Accordingly, processing in the hippocampal formation is by open rather than closed loops. Activation occurred first in CA1 close to its septal pole and spread towards its temporal pole. Four successively activated CA1 areas, oriented at an angle to the longitudinal axis of the hippocampus, were distinguished. Overall, the findings indicate that information can potentially be transmitted from the septal to the temporal end of the hippocampal formation via an ordered succession of hippocampal and entorhinal areas that form a three-dimensional spiral pathway.     

The perforant path projection from the medial entorhinal cortex layer III to the subiculum in the rat combined hippocampal–entorhinal cortex slice

Intracellular recordings were performed to examine the perforant path projection from layer III of the entorhinal cortex to the subiculum in rat combined hippocampal–entorhinal cortex slices. Electrical stimulation in the medial entorhinal cortex layer III caused short latency combined excitatory and inhibitory synaptic responses in subicular cells. In the presence of the GABA_A antagonist bicuculline and the GABA_B antagonist CGP-55845 A inhibition was blocked and isolated AMPA- or NMDA receptor-mediated EPSPs could be elicited. After application of the non-NMDA antagonist NBQX and the NMDA antagonist APV excitatory responses were completely blocked indicating a glutamatergic input from the neurons of the medial entorhinal cortex layer III. By stimulation from a close (< 0.2 mm) position in the presence of NBQX and APV and either CGP-55845 A or bicuculline we could record monosynaptic fast GABA_A or slow GABA_B receptor-mediated IPSPs, respectively. We compared synaptic responses in subicular cells induced by stimulation in the medial entorhinal cortex layer III with responses elicited by stimulation of afferent fibres in the alveus. The EPSPs of subicular cells induced by stimulation of alvear fibres could be significantly augmented by simultaneous activation of perforant path fibres originating in the medial entorhinal cortex layer III, while delayed activation of alvear fibres after stimulation of the perforant path resulted in a weak inhibition of the alveus evoked EPSPs. Thus, the perforant path projection activates monosynaptic excitation of subicular neurons. Therefore the entorhinal cortex does not only function as an important input structure of the hippocampal formation but is also able to modulate the hippocampal output via the entorhinal–subicular circuit.     

Unstable CA1 place cell representation in rats with entorhinal cortex lesions

Recent studies emphasize the importance of the entorhinal cortex in spatial representation and navigation. Furthermore, evidence is accumulating to show that spatial processing depends on interactions between the entorhinal cortex and the hippocampus. To investigate these interactions, we examined the effects of entorhinal cortex lesions on the activity of hippocampal CA1 place cells. Rats received bilateral radiofrequency lesions of the entorhinal cortex or sham lesions before place cell recording. Place cells were recorded as the rats performed a pellet-chasing task in a cylinder containing three cue-objects. Entorhinal cortex lesions did not abolish place cell spatial firing but reduced noticeably discharge rate and field size. Most importantly, the lesions affected firing field stability when cells were recorded both in constant conditions and following cue manipulations (object rotation, object removal). These findings indicate that the entorhinal cortex is necessary for the stability of hippocampal representations across exposures to a familiar environment. Consistent with the recent discovery of grid cells in the medial entorhinal cortex, our results suggest that the entorhinal cortex contributes to providing a spatial framework that would enable the hippocampus to maintain stable environment-specific representations.     

Organizational connectivity among the CA1, subiculum,presubiculum, and entorhinal cortex in the rabbit

The laminar and topographical organization of connections between the hippocampal formation and parahippocampal regions was investigated in the rabbit following in vivo injection of cholera toxin B subunit as a retro‐ and antero‐grade tracer and biotinylated dextran amine as an anterograde tracer. We confirmed several connectional features different from those of the rat, that is, the rabbit presubiculum received abundant afferents from CA1 and had many reciprocal connections with the entorhinal cortex. On the other hand, we identified many similarities with the rat: both the CA1 and subicular afferents that originated from the entorhinal cortex were abundant; moreover, the presubiculum received many inputs from the subiculum and sent massive projections to the entorhinal cortex. By plotting retrograde and anterograde labels in two‐dimensional unfolded maps of the entire hippocampal and parahippocampal regions, we found that each group of entorhinal cells that project to CA1, subiculum, and presubiculum, and also the termination of the presubiculo‐entorhinal projection, was distributed in band‐like zones in layers II–III, extending across the medial and lateral entorhinal cortex. Our results suggest that the rabbit has a basic connectivity that is common with that of the rat, and also has additional hippocampal–presubicular and entorhino–presubicular connections that may reflect functional evolution in learning and memory.     

Temporal firing characteristics and the strategic role of subicular neurons in short-term memory

The role of subicular neurons is explored with respect to their participation in short-term memory during performance of a spatial Delayed-Nonmatch-to-Sample (DNMS) task by well-trained rats. Subicular and CA1 neuron firing was examined in the same animals in relation to the encoding of task-relevant events during the DNMS trial. The results indicate that subicular neurons have completely different firing signatures than well-characterized hippocampal neurons in this task. Firing patterns of subicular neurons consisted of five different categories spanning all three phases of the DNMS trial, but concentrated mostly within the Sample and early portion of the Delay period. Unlike hippocampal neurons, subicular cells did not exhibit conjunctive firing correlates with respect to particular combinations of task events; rather, subicular cell firing was differentiated primarily on the basis of temporal specificity within the trial. Only two of the five subicular cell types fired differentially on correct versus error trials; however, one cell type exhibited such differential firing as an inverse function of duration of delay interval. Experiments employing gamma-aminobutyric acid GABA(B) receptor agonists and antagonists showed that both behavioral performance as well as subicular cell firing were disrupted significantly by baclofen at short delays, while performance at long delays and hippocampal cell firing were relatively immune to this effect. The relevance of subicular cell firing in the task with respect to its temporal relation to delay-dependent hippocampal neuronal activity suggests that the structures have complementary roles in the encoding and representation of items in short-term memory.