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Encoding and retrieval in the CA3 region of the hippocampus: a model of theta-phase separation.

Past research conducted by Hasselmo et al. in 2002 suggests that some fundamental tasks are better accomplished if memories are encoded and recovered during different parts of the theta cycle. A model of the CA3 subfield of the hippocampus is presented, using biophysical representations of the major cell types including pyramidal cells and two types of interneurons. Inputs to the network come from the septum and the entorhinal cortex (directly and by the dentate gyrus). A mechanism for parsing the theta rhythm into two epochs is proposed and simulated: in the first half, the strong, proximal input from the dentate to a subset of CA3 pyramidal cells and coincident, direct input from the entorhinal cortex to other pyramidal cells creates an environment for strengthening synapses between cells, thus encoding information. During the second half of theta, cueing signals from the entorhinal cortex, by the dentate, activate previously strengthened synapses, retrieving memories. Slow inhibitory neurons (O-LM cells) play a role in the disambiguation during retrieval. We compare and contrast our computational results with existing experimental data and other contemporary models.

Animals↗

Optical recording of rat entorhino-hippocampal system in organotypic culture.

It is difficult to comprehend the entorhino-hippocampal information processing using acute transverse hippocampal slice, because the dorsally inclined connections of the entorhino-hippocampal projections can be damaged easily. Therefore, we investigated the spatial-temporal propagation in organotypic cultures of the hippocampus attaching to the entorhinal cortex using a real-time optical recording system with a voltage-sensitive dye and suitability as an in vitro model. Real-time imaging demonstrated that the stimulation of the perforant pathway induced excitatory propagation in trisynaptic pathway of the hippocampus and sequentially in the layer V from the medial to the lateral entorhinal cortex. The horizontal propagation from the lateral to the medial site was also seen after the stimulation of the lateral entorhinal cortex. The analysis of the entorhino-hippocampal organotypic culture would contribute to understanding of the mechanism of learning and memory.

Animals↗

Postnatal maturation of cytochrome oxidase and lactate dehydrogenase activity and age-dependent consequences of lithium-pilocarpine status epilepticus in the rat: a regional histoenzymology study.

The lithium-pilocarpine (Li-Pilo) model of epilepsy reproduces some pathophysiological, temporal, and developmental features of human temporal lobe epilepsy. In this model, rates of cerebral glucose utilization measured by the [(14)C]2-deoxyglucose technique increased during the initial status epilepticus (SE) and decreased during the latent or chronic periods. To correlate these metabolic changes with the activities of the enzymes of the glycolytic and tricarboxylic acid cycle pathways, we measured by histoenzymology the regional activity of two key enzymes of glucose metabolism, lactate dehydrogenase (LDH) for the anaerobic pathway and cytochrome oxidase (CO) for the aerobic pathway coupled to oxidative phosphorylation, at various times after SE induced by Li-Pilo in 10- (P10), 21-d-old (P21) and adult rats for CO and in adult rats only for LDH. CO activity was slightly affected in P10 and P21 rats only at 4 and 24 h and normalized by 14 d after SE. In adult rats, CO activity decreased at 4 and 24 h in damaged areas, like entorhinal cortex, hippocampal CA3 area, amygdala, and thalamus. At 14 d after SE, CO activity was decreased only in entorhinal cortex and increased in brainstem regions involved in the remote control of seizures. In adult rats, LDH activity decreased at 24 h and 14 d after SE in sensorimotor and entorhinal cortex. These data show that the enzymatic equipment underlying the metabolism of glucose is not severely affected by Li-Pilo SE and confirm our previous observations concerning the relative metabolic hyperactivity of brain regions involved in the seizure circuit despite marked neuronal loss.

Age Factors↗

Differential effects of low doses of ethanol on the impulse activity in various regions of the limbic system.

This study was a follow-up to our earlier data which indicated that the hippocampus was one of the brain areas in which ethanol had a preferential action. Rabbits were chronically implanted with electrodes in 9 brain areas associated with the hippocampus. The EEG and multiple-unit activity were recorded simultaneously in each area before and for 15 min after i.p. injection of ethanol at dosages of 0, 150, 300, or 600 mg/kg, given in random order. Subjective evaluation of EEG tracings from all brain areas did not disclose any regional differences. The incidence of hippocampal theta rhythm was depressed transiently at the 2 lower doses and was increased in some rabbits at later post-injection times after the largest dose. Quantitative analysis of the unit activity revealed several major effects of ethanol. Individual rabbits varied significantly in their degree of response. The effects of ethanol included phasic decreases and increases, which varied with the brain area and the dose. A predominant depression of MUA occurred in the septum, fimbria/fornix, entorhinal cortex, and CA1 zone of the hippocampus. Large transient increases in MUA were noted in the CA1, hippocampal commissure, and entorhinal cortex. Overall, regional differences in unit activity consisted of a relatively greater effect in the septum, CA1, and the entorhinal cortex. Conspicuously smaller effects were evident in the CA3 and dentate zones of the hippocampus.

Animals↗

The OM series of terminal field-specific monoclonal antibodies demonstrate reinnervation of the adult rat dentate gyrus by embryonic entorhinal transplants.

Monoclonal antibodies OM-1 to OM-4 and IM-1 [Woodhams et al. (1991) Neuroscience 46, 57-69] have complementary immunostaining patterns in the molecular (dendritic) layer of the adult rat dentate gyrus, with OM-1 to OM-4 selectively recognizing the outer (distal) two-thirds (i.e. the entorhinal afferent zone), and IM-1 the inner (proximal) one-third (i.e. the hippocampal commissural/associational zone). Immunoblotting suggests that OM-1 recognizes a single glycoprotein antigen of mol. wt around 93,000, and OM-2, OM-3, and OM-4 all recognize a second glycoprotein antigen of mol. wt around 36,000. At four weeks after removal of the ipsilateral entorhinal cortex the background OM immunostaining of the entorhinal afferent zone is abolished and replaced by a network of densely stained granules, which we interpret as degenerating entorhinal afferent axons. At the same time, the proximal, IM immunoreactive zone expands by about 10 microns in width (while the distal deafferented zone shrinks by about 80 microns). Attempts were made to restore the OM immunoreactivity of the distal zone by grafting either small pieces or cell suspensions of embryonic day 18 entorhinal cortex directly into the dentate molecular layer of entorhinally deafferented adult hosts. About half (14/26) of the animals with successfully positioned grafts showed restoration of OM-2 to OM-4 immunostaining throughout the entire width of the outer two-thirds (entorhinal afferent zone) of the dentate molecular layer. Strikingly, however, in adjacent serial sections the restoration of OM-1 immunoreactivity was restricted to the "middle" molecular layer, i.e. the most proximal part of the distal (entorhinal) two-thirds of the dentate molecular layer. In no case did the OM-1 immunoreactivity extend to the outer margin of the molecular layer. This did not appear to be associated with incompleteness of the removal of the host entorhinal projection, since it occurred in grafted cases where the hippocampus had been completely isolated from the entorhinal area. The simplest explanation of the observed pattern of OM loss and restitution is that the epitopes are located on the entorhinodentate axons, but it is not clear whether the antigens recognized by OM-1 and OM-2 to OM-4 are expressed in different parts of the same group of axons, or in different subsets of entorhinodentate axons. Nor is it clear why the pattern of OM-1 is only restored to the "middle" molecular layer, while that of OM-2 to OM-4 is restored to the entire outer two-thirds.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

Interruptions of early cortical development affect limbic association areas and social behaviour in rats; possible relevance for neurodevelopmental disorders.

Deficits in social behaviour are found in several neuropsychiatric disorders with a presumed developmental origin. Adequate social behaviour may rely importantly on the associative integration of new stimuli with previously stored, related information. The limbic allocortex, in particular the entorhinal region, is thought to support this kind of processing. Therefore, in the present study, gestating dams were treated with methylazoxymethanol acetate (MAM) on one of gestational days nine to twelve, to interrupt neuronal proliferation in the entorhinal region of the developing foetuses. Effects of prenatal MAM administration on social behaviour were evaluated in adult animals. As the entorhinal cortex has been implicated by some studies in spatial memory, effects on this function were also investigated. Following the behavioural studies, brain morphology was screened for effects of MAM. Our results show moderate to severe social impairment in MAM-treated animals, depending on the exact timing of prenatal exposure. By contrast, spatial reference and working memory were not importantly affected in any group. Analysis of brain morphology in the MAM-treated offspring supported maldevelopment of the entorhinal cortex and revealed mild abnormalities also in some connected limbic and limbic affiliated structures, such as the perirhinal and ectorhinal cortex, the anterior cingulate cortex and the medial septum-diagonal band region. Findings are discussed with respect to entorhinal cortex function, and with regard to their relevance for psychiatric disorders with a putatively neurodevelopmental pathogenesis, such as schizophrenia.

Animals↗

Intracellular correlates of hippocampal theta rhythm in identified pyramidal cells, granule cells, and basket cells.

The cellular-synaptic generation of rhythmic slow activity (RSA or theta) in the hippocampus has been investigated by intracellular recording from principal cells and basket cells in anesthetized rats. In addition, the voltage-, coherence-, and phase versus depth profiles were examined by simultaneously recording field activity at 16 sites in the intact rat, during urethane anesthesia, and after bilateral entorhinal cortex lesion. In the extracellular experiments the large peak of theta at the hippocampal fissure was attenuated by urethane anesthesia and abolished by entorhinal cortex lesion. The phase versus depth profiles were similar during urethane anesthesia and following entorhinal cortex lesion but distinctly different in the intact, awake rat. These observations suggest that dendritic currents underlying theta in the awake rat may not be revealed under urethane anesthesia. The frequency of theta-related membrane potential oscillation was voltage-independent in pyramidal neurons, granule cells, and basket cells. On the other hand, the phase and amplitude of intracellular theta were voltage-dependent in all three cell types with an almost complete phase reversal at chloride equilibrium potential in pyramidal cells and basket cells. At strong depolarization levels (less than 30 mV) pyramidal cells emitted calcium spike oscillations, phase-locked to theta. Basket cells possessed the most regular membrane oscillations of the three cell types. All neurons of this study were verified by intracellular injection of biocytin. The observations provide direct evidence that theta-related rhythmic hyper-polarization of principal cells is brought about by the rhythmically discharging basket neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗

bFGF promotes the survival of entorhinal layer II neurons after perforant path axotomy.

Infusion of basic fibroblast growth factor (bFGF) prevents the loss of cholinergic neurons in the septum/diagonal band of broca following fimbria-fornix transection. However, an in vivo test of whether bFGF will also rescue injured non-cholinergic or cortical neurons has not been carried out. Previous studies have shown that the majority of layer II stellate neurons utilize an excitatory amino acid as their neurotransmitter. In order to determine if bFGF acts on non-cholinergic cortical neurons, a paradigm was developed to examine whether or not bFGF could spare layer II entorhinal stellate cells from axotomy induced death or atrophy. Axotomy of the medial entorhinal cortex fibers projecting to the dentate gyrus of the hippocampal formation via the perforant path lead to retrograde cell loss in entorhinal cortex. Fourteen or thirty days after a unilateral knife cut axotomy of the perforant path, layer II of medical entorhinal cortex showed a 28% decrease in large stellate neurons as well as many weakly stained, hollow cells compared to the non-lesioned side or naive controls. Layer IV neurons, however, which do not project via the perforant path, showed little detectable change in the number of cells ipsilateral to the knife-cut as compared to the contralateral side. Intraventricular infusion of bFGF over a period of 14 days reduced the 28% cell loss to less than 6%. Thus, bFGF is capable of preventing cortical neuronal loss and/or atrophy associated with retrograde degeneration of non-cholinergic neurons following axotomy.

Animals↗

Postnatal development of the serotonin innervation of the hippocampus and dentate gyrus following raphe implants.

Serotoninergic (5-HT) neurons derived from the embryonic raphe nuclear area (brainstem, embryonic days (E 16-18) were implanted into the entorhinal cortex of 6-day-old (P6) neonatal rat recipients which had received a fimbria lesion and entorhinal cortex ablation on P3. The hippocampus, dentate gyrus, and the raphe implant area were examined with 5-HT immunohistochemistry 7, 14, 21, 30, and 60 days after implantation. The pattern of 5-HT reinnervation was compared to that of normal and lesioned animals, and to previous studies in which rats received septal or striatal implants. In the hippocampus adjacent to the implant 5-HT-immunoreactive fibers were first observed by 7 days postimplantation and increased in density and in their septotemporal and dorsoventral extent with increasing time postimplantation. Moderately dense fiber networks were diffusely distributed in the hippocampus and dentate gyrus at 30 and 60 days postimplant. Little, if any, indication of lamination was present. Retrogradely labeled neurons (the majority of which contained 5-HT immunoreactivity) were observed in the raphe implant following injections of Fast Blue into the hippocampal formation. A few retrogradely labeled cells did not contain 5-HT, methionine-enkephalin (ME), or substance P (SP) immunoreactivity, although ME- and SP- immunoreactive neurons were observed in the implants. The lamination patterns and the increased density of 5-HT-immunoreactive fibers following a raphe implant into the entorhinal cortex clearly differ from the normal 5-HT pattern and from the patterns of lamination following a striatal or septal implant.

Aging↗

The effects of lesions to the rat hippocampus or rhinal cortex on olfactory and spatial memory: retrograde and anterograde findings.

The role of the hippocampal system in retrograde and anterograde amnesia was investigated by using a novel olfactory-guided paradigm and a traditional test of spatial learning. In the retrograde study, rats were trained on a sequence of two-choice olfactory discriminations in the weeks prior to receiving neurotoxic lesions of the hippocampus or aspiration lesions of the perirhinal-entorhinal cortex. Memory tests for preoperatively learned discriminations revealed no statistical impairment for subjects with damage to the hippocampus on a problem learned remote in time from surgery (i.e., 4 weeks +) or on the two recently learned discriminations (i.e., 1-3 weeks prior to surgery). The performance of subjects with perirhinal-entorhinal damage provided an important comparison for subjects with specific hippocampal lesions. Despite showing intact memory for the remotely learned problem, perirhinal-entorhinal damage resulted in numerically (although not significantly) weaker performance on postoperative tests of retention for the discriminations learned in the 3 weeks prior to surgery. In the anterograde portion of the study, long-term memory for newly acquired discriminations was spared in subjects with damage to the hippocampus, whereas subjects in the perirhinal-entorhinal lesion group again showed the weakest memory performance on these tests of 5-day retention. Postoperative water maze learning was uniformly impaired in subjects with damage to the hippocampus and perirhinal-entorhinal cortex, thus confirming the effect of these lesions and supporting the involvement of these brain areas in spatial processes. These findings further dissociate the specific involvement of the hippocampus in tasks of a spatial-relational nature versus nonrelational tasks, such as discrimination learning and recognition memory (e.g., Duva et al., 1997; Eichenbaum, 1997; Eichenbaum, Schoenbaum, Young, & Bunsey, 1996). Moreover, the results suggest that damage to the hippocampus itself does not contribute to retrograde or anterograde memory impairments for all types of information, whereas the data suggest a more important role for the perirhinal-entorhinal cortex in recognition memory, irrespective of modality.

Animals↗

Electrolytic entorhinal lesions cause seizures.

The entorhinal cortex is a key site of interneuronal communication between a variety of cortical and subcortical areas and hippocampal formation. Lesioning the entorhinal cortex is commonly used in studies of the hippocampal formation, animal behavior and neuronal plasticity. We have found that electrolytic destruction of the entorhinal cortex consistently produces limbic seizure activity in rats. The propensity of lesions in this area for producing seizure activity may facilitate insights into the normal function of this network of neural connections. This unexpected phenomenon represents a potential confounding variable for all researchers using this method for making brain lesions.

Animals↗

A subset of calretinin-positive neurons are abnormal in Alzheimer's disease.

The distribution of the calcium-binding protein calretinin was investigated by immunohistochemistry in the hippocampus, the subicular areas, and the entorhinal cortex in patients with Alzheimer's disease and in control subjects. By double immunolabelling, the calretinin immunoreactivity was compared to the immunoreactivity for beta/A4 amyloid or for tau proteins. Calretinin-positive neurons were mainly observed in the molecular layer of the gyrus dentatus, the stratum radiatum of the Ammon's horn, and in layers II and III of the entorhinal cortex. The general pattern of calretinin immunoreactivity was conserved in Alzheimer's disease. Calretinin-positive neurons appeared normal in the hippocampus but had a reduced dendritic tree in the entorhinal cortex. Dystrophic calretinin immunoreactive fibres were often observed in the outer molecular layer of the gyrus dentatus and in the CA4 sector in Alzheimer's disease. Most neurons containing neurofibrillary tangles were not calretinin immunoreactive and most senile plaques were not associated with calretinin positive fibres. These results show that entorhinal calretinin-positive neurons are affected in Alzheimer's disease in spite of an absence of systematic association with neurofibrillary tangles and senile plaques.

Aged↗

Differences in lesion-induced hippocampal plasticity between mice and rats.

We studied the differences between mice and rats in lesion-induced sprouting in the hippocampus. The entorhinal cortex was unilaterally lesioned with ibotenic acid in adult, female mice and rats. Four weeks later the subsequent axonal sprouting in the dentate gyrus was analysed, by measuring the density of the synaptophysin immunohistochemical and acetylcholinesterase histochemical staining in the termination area of the entorhinal cortex axons. The data demonstrate that both mice and rats display a significantly increased density of staining for synaptophysin and acetylcholinesterase in the molecular layer of the dentate gyrus, indicative of axonal sprouting. Both species also show an upregulation in the density of staining for acetylcholinesterase in the molecular layer of the dentate gyrus. Further, rats, but not mice, show a significant upregulation of synaptophysin staining in stratum lacunosum moleculare of CA1 following the lesions. However, whereas rats show significant shrinkage of the molecular layer of the dentate gyrus, mice do not show any shrinkage of that layer following entorhinal cortex lesions. Taken together, these data indicate that whereas the process of reinnervation in the hippocampus is similar between the mouse and the rat, the hippocampal response to denervation shows clear differences between these two species.

Acetylcholinesterase↗

Tau protein aggregation in the frontal and entorhinal cortices as a function of aging.

OBJECTIVES: The abnormal accumulation of tau protein is increasingly recognized as the neuropathological hallmark of a number of dementing illness in which frontotemporal lobar degeneration occurs. In this paper we examined the age-dependant deposition of tau protein in the frontal and entorhinal neocortices. METHODS: We examined autopsy records from 1997 to 2002 and selected 87 cases (10 in each decade from 0 to 79 years of age, 7 in 80-89 decade) with no history of dementia or other neurodegenerative diseases, and for which neurodegenerative diseases were excluded neuropathologically. Archival paraffin-embedded frontal and entorhinal cortices were examined by both Gallyas-Braak silver staining and a panel of antibodies recognizing tau protein accumulation. RESULTS: Tau neuronal aggregates were observed in both frontal and entorhinal cortices in the third decade. While the frontal neuronal tau aggregates remained infrequent in the remaining decades, the number and extent ofneuronal tau aggregates in the entorhinal cortex increased such that by the 7th decade the majority of cases showed extensive tau aggregate formation. The most consistent morphological observation was of dense, perikaryal neuronal tau-immunoreactive aggregates, similar to the total tau distribution, firstly presenting in cortical layers II and III and subsequently involving in layers IV-VI. Neuropil threads became maximal in the 9th decade in both frontal and entorhinal cortices. Astrocytic tau accumulation was first observed in both frontal and entorhinal cortices in the 6th decade, predominantly in layer I and subcortical white matter, and increased in number with aging. Extraneuronal tau reactive aggregates and coiled bodies were rarely observed in the entorhinal cortex, and when present, were scattered through layer II to VI. CONCLUSIONS: We have observed an age-dependant pattern of neuronal, extraneuronal and glial tau protein accumulation in the entorhinal cortex in individuals without neurodegenerative diseases. In contrast, tau protein aggregation is infrequently observed in the frontal cortex as a function of aging.

Adolescent↗

Autoradiographic analysis of [35S]TBPS binding in entorhinal cortex-kindled rat brains.

A quantitative autoradiographic analysis of [35S]t-butylbicyclophosphorothionate (TBPS) binding to the gamma-aminobutyric acid (GABA)-mediated chloride ionophore was carried out in 104 brain areas of entorhinal cortex-kindled and control rats. Subjects were sacrificed either 24 h or 28 days after the last kindled seizure. Kindled subjects in the 24 h group showed reductions in mean [35S]TBPS binding in the lateral nucleus of the amygdala (-31%), the infralimbic cortex (-14%), and the paracentral nucleus of the thalamus (-22%). At 28 days, reductions in binding were observed in the infralimbic cortex (-15%) and the paracentral nucleus of the thalamus (-18%). These data suggest that repeated seizures (kindling) modify the GABA-mediated chloride ionophore, and that in some brain areas related to seizure generalization the modifications are very long lasting.

Animals↗

Comparison of the effects of losigamone and its isomers on maximal electroshock induced convulsions in mice and on three different patterns of low magnesium induced epileptiform activity in slices of the rat temporal cortex.

Losigamone (AO-33) is a recemate of a tetronic acid derivative. The effects of losigamone and its three isomers (AO-242, AO-294 and AO-23) were compared on maximal electroshock (MES) induced convulsions in mice and on different patterns of extracellularly recorded, low Mg2+ induced epileptiform activity in slices of the rat temporal cortex. Lowering Mg2+ induced recurrent short discharges in areas CA3 and CA1 while ictaform events that lasted for many seconds were induced in the entorhinal cortex. In the hippocampus the activity stayed stable over a number of hours. In contrast, the ictaform events in the entorhinal cortex changed their characteristics after one to two hours to recurrent discharges of 0.8 to 10 s. Afterdischarges and interictal events were absent. 50 microM AO-242 showed a similar efficacy to 50 microM AO-33 in reducing and blocking epileptiform discharges in areas CA1 and CA3 while 50 microM AO-294 and 50 microM AO-23 had weaker effects than 50 microM AO-33. Concentrations of 50 microM and 100 microM AO-242 showed a similar efficacy to AO-33 on ictaform events in the entorhinal cortex. Late recurrent discharges were also blocked by AO-33 and AO-242 although at higher concentrations (300 microM). The in vitro observations are with respect to order of efficacy in accordance with the in vivo data obtained in the maximal electroshock test in mice. The order of potency in the MES test was AO-242 greater than AO-33 much greater than AO-294 much greater than AO-23.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Neuropathological criteria for the diagnosis of Alzheimer's disease.

The definitive diagnosis of Alzheimer's disease (AD) is made at autopsy by the presence of abundant neuritic plaques (NP) and neurofibrillary tangles (NFT) in the neocortex, entorhinal cortex, and hippocampus. The two criteria most frequently used by neuropathologists for the diagnosis of AD over the past 12 years are those described by Khachaturian and the Consortium to Establish a Registry for Alzheimer's Disease. Though both have been useful, they have weaknesses and lack validation. The majority of recent studies has shown that NFT in the entorhinal cortex, hippocampus, and neocortex and NP in the neocortex correlate best with severity of dementia in AD. The criteria recommended by the Workshop on Diagnostic Criteria for the Neuropathological Assessment of AD uses semiquantitation of NFT and NP in the neocortex, adds evaluation of the hippocampus and entorhinal cortex, places emphasis on coexisting lesions such as vascular lesions and Lewy bodies, and establishes criteria for general pathologists and more rigorous criteria for the AD research setting. These criteria will require further refinement and validation.

Aged↗

Pathways through cingulate, neo- and entorhinal cortices mediate atropine-resistant hippocampal rhythmical slow activity.

Rats prepared with a lesion separating the entorhinal cortex from the neocortex and cingulate cortex displayed apparently normal hippocampal rhythmical slow activity (RSA) with a frequency of 6-12 Hz in both CA1 and dentate gyrus during Type 1 behavior (locomotion, head movements, changes in posture). Variations in the commissural average evoked potential (AEP) and increased power in the 30-100 Hz range (fast waves) also correlated with Type 1 behavior. Urethane did not abolish the RSA. However, systemic administration of atropinic drugs eliminated all RSA and eliminated or attenuated the Type 1 behavior-related variations in the AEP and fast waves. Thus, the normally present atropine-resistant RSA was eliminated by the cortical lesion while atropine-sensitive RSA remained intact. Removal of cingulate cortex alone was partially effective in suppressing atropine-resistant RSA but a lesion of the neocortex only, sparing cingulate cortex, had a minimal effect on it. Lesions of the amygdala, the anterior or medial thalamus or the cerebellum had little or no effect on atropine-resistant RSA. Previous work has shown that lesions of the entorhinal cortex or lateral hypothalamus eliminate atropine-resistant RSA. We suggest that atropine-resistant RSA is mediated by a somewhat diffuse pathway which traverses the hypothalamus, cingulate cortex, and neocortex before reaching the hippocampus via the entorhinal cortex.

Animals↗