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The hippocampus is a brain region that is critical for spatial learning, context-dependent memory, and episodic memory. It receives major inputs from the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC). MEC neurons show much greater spatial firing than LEC neurons in a recording chamber with a single, salient landmark. The MEC cells are thought to derive their spatial tuning through path integration, which permits spatially selective firing in such a cue-deprived environment. In accordance with theories that postulate two spatial mapping systems that provide input to the hippocampus—an internal, path-integration system and an external, landmark-based system—it was possible that LEC neurons can also convey a spatial signal, but that the signal requires multiple landmarks to define locations, rather than movement integration. To test this hypothesis, neurons from the MEC and LEC were recorded as rats foraged for food in cue-rich environments. In both environments, LEC neurons showed little spatial specificity, whereas many MEC neurons showed a robust spatial signal. These data strongly support the notion that the MEC and LEC convey fundamentally different types of information to the hippocampus, in terms of their spatial firing characteristics, under various environmental and behavioral conditions.

Memories are thought to be encoded as a distributed representation in the neocortex. The medial prefrontal cortex (mPFC) has been shown to support the expression of memories that initially depend on the hippocampus (HPC), yet the mechanisms by which the HPC and mPFC access the distributed representations in the neocortex are unknown. By measuring phase synchronization of local field potential (LFP) oscillations, we found that learning initiated changes in neuronal communication of the HPC and mPFC with the lateral entorhinal cortex (LEC), an area that is connected with many other neocortical regions. LFPs were recorded simultaneously from the three brain regions while rats formed an association between an auditory stimulus (CS) and eyelid stimulation (US) in a trace eyeblink conditioning paradigm, as well as during retention 1 month following learning. Over the course of learning, theta oscillations in the LEC and mPFC became strongly synchronized following presentation of the CS on trials in which rats exhibited a conditioned response (CR), and this strengthened synchronization was also observed during remote retention. In contrast, CS-evoked theta synchronization between the LEC and HPC decreased with learning. Our results suggest that communication between the LEC and mPFC are strengthened with learning whereas the communication between the LEC and HPC are concomitantly weakened, suggesting that enhanced LEC–mPFC communication may be a neuronal correlate for theoretically proposed neocortical reorganization accompanying encoding and consolidation of a memory.

Using functional magnetic resonance imaging, the current study explored the differential mnemonic contributions of the hippocampus and surrounding medial temporal lobe (MTL) cortices to explicit recognition memory and configural learning. Using a task that required processing of repeated and novel visuospatial contexts across multiple trials, we examined MTL activation in relation to 3 forms of learning in a single paradigm: 1) context-independent procedural learning, 2) context-dependent configural learning, and 3) explicit recognition memory. Activations in hippocampus and parahippocampal cortex were associated with explicit memory, differentiating between subsequently remembered and forgotten repeated contexts, but were unrelated to context-dependent configural learning. Activations in regions of perirhinal and entorhinal cortex were associated with configural learning of repeated contexts independent from explicit memory for those contexts. Procedural learning was unrelated to activation in any MTL region. The time course of activation across learning further differed in MTL subregions with MTL cortex demonstrating repetition-related decreases and hippocampus repetition-related increases. These repetition effects were differentially sensitive to recognition with only activation in hippocampus and parahippocampal cortex tracking recognized items. These imaging findings converge with studies of amnesia and indicate dissociable roles for hippocampus in learning that supports explicit recognition and for anterior MTL cortex in configural learning.

Recording the activity of neurons is a mainstay of animal memory research, while human recordings are generally limited to the activity of large ensembles of cells. The relationship between ensemble activity and neural firing rate during declarative memory processes, however, remains unclear. We recorded neurons and local field potentials (LFPs) simultaneously from the same sites in the human hippocampus and entorhinal cortex (ERC) in patients with implanted intracranial electrodes during a virtual taxi-driver task that also included a memory retrieval component. Neurons increased their firing rate in response to specific passengers or landmarks both during navigation and retrieval. Although we did not find item specificity in the broadband LFP, both θ- and γ-band LFPs increased power to specific items on a small but significant percent of channels. These responses, however, did not correlate with item-specific neural responses. To contrast item-specific responses with process-specific responses during memory, we compared neural and LFP responses during encoding (navigation) and retrieval (associative and item-specific recognition). A subset of neurons also altered firing rates nonspecifically while subjects viewed items during encoding. Interestingly, LFPs in the hippocampus and ERC increased in power nonspecifically while subjects viewed items during retrieval, more often during associative than item-recognition. Furthermore, we found no correlation between neural firing rate and broadband, θ-band, and γ-band LFPs during process-specific responses. Our findings suggest that neuronal firing and ensemble activity can be dissociated during encoding, item-maintenance, and retrieval in the human hippocampal area, likely relating to functional properties unique to this region.

Since the time of Aristotle it has been thought that memories can be divided into two basic types; conscious recollections and familiarity-based judgments. Neuropsychological studies have provided indirect support for this distinction by suggesting that different regions within the human medial temporal lobe (MTL) are involved in these two forms of memory, but none of these studies have demonstrated that these brain regions can be fully dissociated. In a group of nondemented elderly subjects, we found that performance on recall and recognition tests was predicted preferentially by hippocampal and entorhinal volumes, respectively. Structural equation modeling revealed a double dissociation, whereby age-related reductions in hippocampal volume resulted in decreases in recollection, but not familiarity, whereas entorhinal volume was preferentially related to familiarity. The results demonstrate that the forms of episodic memory supported by the human hippocampus and entorhinal cortex can be fully dissociated, and indicate that recollection and familiarity reflect neuroanatomically distinct memory processes.

Summary

Purpose

To study whether induction of prolonged (>30-min duration) in vitro electrographic seizure discharges resembling status epilepticus (SE) is graded or all-or-none, and to determine the critical factors mediating SE induction.

Methods

Prolonged electrographic seizure discharges were induced in combined hippocampal–entorhinal cortical (HEC) brain slices by electrical stimulation of the Schaeffer collaterals. Discharges were recorded by using field-potential electrodes in the dentate gyrus, CA3, CA1, and entorhinal cortex. Slices were prepared from rats that were (a) 21- to 30-day-old naive, (b) 60- to 120-day old naive, (c) epileptic, and (d) status post a prior traumatic brain injury.

Results

Induction of SE discharges was dependent on the duration, but not amplitude of the preceding stimulus train–induced afterdischarge in HEC slices from 21- to 30-day-old control, brain-injured, and epileptic animals, but not from 60- to 120-day-old animals. In slices from 21- to 30-day-old control animals, once afterdischarges exceeded 4 min in duration, SE was induced in 50% of slices, and after ≥6 min 37 s seizure activity; SE was induced in 95% of slices. A defined SE threshold also was evident in brain-damaged rats, including rats in which an epileptic condition was induced by pilocarpine injection 4–16 weeks before recording, and rats subjected to a fluid percussive head trauma 1–8 weeks before recording. However, in these brain-damaged animals, mean SE threshold was considerably lower (24 and 44 s, respectively). HEC slices from 60- to 120-day-old controls for the brain-injured and epileptic animals did not develop SE even after 20 stimulations, demonstrating the pronounced effect of brain injury and epilepsy on the development of SE in the HEC slice preparation compared with that in age-matched controls.

Conclusions

In vitro, SE discharges have a defined temporal threshold for initiation. Once a seizure exceeds 6–7 min in duration in control animals, and 30–55 s in brain-damaged animals, the probability of SE induction is greatly increased. This demonstrates that brain injury lowers the afterdischarge duration required to produce SE and suggests that brains injured from trauma or SE are more susceptible to develop status epilepticus.

Caloric restriction by fasting has been implicated to facilitate synaptic plasticity and promote contextual learning. However, cellular and molecular mechanisms underlying the effect of fasting on memory consolidation are not completely understood. We hypothesized that fasting-induced enhancement of synaptic plasticity was mediated by the increased signaling mediated by CREB (cAMP response element binding protein), an important nuclear protein and the transcription factor that is involved in the consolidation of memories in the hippocampus. In the in vivo rat model of 18 h fasting, the expression of phosphorylated CREB (pCREB) was examined using anti-phospho-CREB (Ser133) in cardially-perfused and cryo-sectioned rat brain specimens. When compared with control animals, the hippocampus exhibited up to a twofold of increase in pCREB expression in fasted animals. The piriform cortex, the entorhinal cortex, and the cortico-amygdala transitional zone also significantly increased immunoreactivities to pCREB. In contrast, the amygdala did not show any change in the magnitude of pCREB expression in response to fasting. The arcuate nucleus in the medial hypothalamus, which was previously reported to up-regulate CREB phosphorylation during fasting of up to 48 h, was also strongly immunoreactive and provided a positive control in the present study. Our findings demonstrate a metabolic demand not only stimulates cAMP-dependent signaling cascades in the hypothalamus, but also signals to various limbic brain regions including the hippocampus by activating the CREB signaling mechanism. The hippocampus is a primary brain structure for learning and memory. It receives hypothalamic and arcuate projections directly from the fornix. The hippocampus is also situated centrally for functional interactions with other limbic cortexes by establishing reciprocal synaptic connections. We suggest that hippocampal neurons and those in the surrounding limbic cortexes are intimately involved in the metabolism-dependent plasticity, which may be essential and necessary for successful achievement of adaptive appetitive behavior.

Spike-timing-dependent synaptic plasticity (STDP) is a simple and effective learning rule for sequence learning. However, synapses being subject to STDP rules are readily influenced in noisy circumstances because synaptic conductances are modified by pre- and postsynaptic spikes elicited within a few tens of milliseconds, regardless of whether those spikes convey information or not. Noisy firing existing everywhere in the brain may induce irrelevant enhancement of synaptic connections through STDP rules and would result in uncertain memory encoding and obscure memory patterns. We will here show that the LTD windows of the STDP rules enable robust sequence learning amid background noise in cooperation with a large signal transmission delay between neurons and a theta rhythm, using a network model of the entorhinal cortex layer II with entorhinal-hippocampal loop connections. The important element of the present model for robust sequence learning amid background noise is the symmetric STDP rule having LTD windows on both sides of the LTP window, in addition to the loop connections having a large signal transmission delay and the theta rhythm pacing activities of stellate cells. Above all, the LTD window in the range of positive spike-timing is important to prevent influences of noise with the progress of sequence learning.

Long-term potentiation (LTP) which has long been considered a cellular model for learning and memory is defined as a lasting enhancement in synaptic transmission efficacy. This cellular mechanism has been demonstrated reliably in the hippocampus and the amygdala—two limbic structures implicated in learning and memory. Earlier studies reported on the ability of cortical stimulation of the entorhinal cortex to induce LTP simultaneously in the two sites. However, to retain a stable baseline of comparison with the majority of the LTP literature, it is important to investigate the ability of fiber stimulation such as perforant path activation to induce LTP concurrently in both structures. Therefore, in this paper we report on concurrent LTP in the basolateral amygdala (BLA) and the dentate gyrus (DG) subfield of the hippocampus induced by theta burst stimulation of perforant path fibers in freely behaving Sprague-Dawley rats. Our results indicate that while perforant path-evoked potentials in both sites exhibit similar triphasic waveforms, the latency and amplitude of BLA responses were significantly shorter and smaller than those of DG. In addition, we observed no significant differences in either the peak level or the duration of LTP between DG and BLA.

Entorhinal cortex lesions induce significant reorganization of several homotypic and heterotypic inputs to the hippocampus. This investigation determined whether surviving heterotypic inputs after bilateral entorhinal lesions would support the acquisition of a learned alternation task. Rats with entorhinal lesions or sham operations were trained to acquire a spatial alternation task. Although the sham-operated rats acquired the task within about three weeks postsurgery, rats with bilateral entorhinal lesions failed to learn the task after 12 consecutive weeks of training despite heterotypic sprouting of the cholinergic septodentate pathway and the expansion of the commissural/associational fiber plexus within the dentate gyrus. Thus, heterotypic sprouting failed to ameliorate significantly the effects of bilateral entorhinal lesions. Rather, entorhinal lesions produce a persistent impairment of spatial memory, characterized by a mixture of random error production and perseverative responding.

The hippocampus of the mammalian brain is important for the formation of long term memories. Hippocampal-dependent learning can be affected by a number of neurotransmitters including the activation of μ-opioid receptors (MOR). It has been shown that MOR activation can alter synaptic plasticity and network oscillations in the hippocampus, both of which are thought to be important for the encoding of information and formation of memories. One hippocampal oscillation that has been correlated with learning and memory formation is the 4-10 Hz theta rhythm. During theta rhythms, inputs to hippocampal CA1 from CA3 (Schaffer collaterals, SC) and the entorhinal cortex (perforant path) can integrate at different times within an individual theta cycle. Consequently, when excitatory inputs in the stratum lacunosum-moleculare (the temporo-ammonic pathway (TA), which includes the perforant path) are stimulated approximately one theta period before SC inputs, the TA can indirectly inhibit SC inputs. This inhibition is due to the activation of postsynaptic GABAB receptors on CA1 pyramidal neurons. Importantly, MOR activation has been shown to suppress GABAB inhibitory postsynaptic potentials in CA1 pyramidal neurons. Therefore, we examined how MOR activation affects the integration between TA inputs and SC inputs in hippocampal CA1. To do this we used voltage-sensitive dye imaging and whole cell patch clamping from acute hippocampal slices taken from young adult rats. Here we show that MOR activation has no effect on the integration between TA and SC inputs when activation of the TA precedes SC by less than one half of a theta cycle (< 75 ms). However, MOR activation completely blocked the inhibitory action of TA on SC inputs when TA stimulation occurred approximately one theta cycle before SC activation (> 150 ms). This MOR suppression of TA driven inhibition occurred in both the SC input layer of hippocampal CA1 (stratum radiatum) and the output layer of CA1 pyramidal neurons (stratum pyramidale). Thus MOR activation can have profound effects on the temporal integration between two primary excitatory pathways to hippocampal CA1 and subsequently the resultant output from CA1 pyramidal neurons. These data provide important information for understanding how acute or chronic MOR activation may affect the integration of activity within hippocampal CA1 during theta rhythm.

Profound neuronal dysfunction in the entorhinal cortex contributes to early loss of short-term memory in Alzheimer’s disease1–3. Here we show broad neuroprotective effects of entorhinal brain-derived neurotrophic factor (BDNF) administration in several animal models of Alzheimer’s disease, with extension of therapeutic benefits into the degenerating hippocampus. In amyloid-transgenic mice, BDNF gene delivery, when administered after disease onset, reverses synapse loss, partially normalizes aberrant gene expression, improves cell signaling and restores learning and memory. These outcomes occur independently of effects on amyloid plaque load. In aged rats, BDNF infusion reverses cognitive decline, improves age-related perturbations in gene expression and restores cell signaling. In adult rats and primates, BDNF prevents lesion-induced death of entorhinal cortical neurons. In aged primates, BDNF reverses neuronal atrophy and ameliorates age-related cognitive impairment. Collectively, these findings indicate that BDNF exerts substantial protective effects on crucial neuronal circuitry involved in Alzheimer’s disease, acting through amyloid-independent mechanisms. BDNF therapeutic delivery merits exploration as a potential therapy for Alzheimer’s disease.

Summary

Purpose

The adenosinergic system is known to exert an inhibitory affect in the brain and as such adenosine has been considered an endogenous anticonvulsant. Entorhinal cortex (EC) layer II neurons, which serve as the primary input to the hippocampus, are spared in temporal lobe epilepsy (TLE) and become hyperexcitable. Since these neurons also express adenosine receptors, the activity of these neurons may be controlled by adenosine, specifically during seizure activity when adenosine levels are thought to rise. In light of this, we determined if the actions of adenosine on medial EC (mEC) layer II stellate neurons are augmented in TLE and by which receptor subtype.

Methods

Horizontal brain slices were prepared from rats exhibiting spontaneous seizures (TLE) induced by electrical stimulation and compared with age matched control rats. mEC layer II stellate neurons were visually identified and action potentials (AP) evoked by either a series of depolarizing current injection steps or via presynaptic stimulation of mEC deep layers. The effects of adenosine were compared with actions of adenosine A1 and A2A receptor-specific agonists (CPA and CGS 21680) and antagonists (DPCPX and ZM241385) respectively. Immunohistochemical and qPCR techniques were also employed to assess relative adenosine A1 receptor message and expression.

Key Findings

mEC layer II stellate neurons were hyper-excitable in TLE, evoking a higher frequency of AP's when depolarized and generating bursts of AP's when synaptically stimulated. Adenosine reduced AP frequency and synaptically evoked AP's in a dose dependent manner (500 nM – 100 μM); however, in TLE, the inhibitory actions of adenosine occurred at concentrations that were without affect in control neurons. In both cases, the inhibitory actions of adenosine were mediated via activation of the A1 and not the A2A receptor subtype. qPCR and immunohistochemical experiments revealed an up-regulation of the adenosine A1 mRNA and an increase in A1 receptor staining in TLE neurons compared to control.

Significance

Our data indicates the actions of adenosine on mEC layer II stellate neurons is accentuated in TLE due to an up-regulation of adenosine A1 receptors. Since adenosine levels are thought to rise during seizure activity, activation of adenosine A1 receptors could provide a possible endogenous mechanism to suppress seizure activity and spread within the temporal lobe.

Entorhinal neurons receive extensive intracortical projections, and form the primary input to the hippocampus via the perforant pathway. The glutamatergic cells of origin for the perforant pathway are distinguished by their expression of reelin, a glycoprotein involved in learning and synaptic plasticity. The functional significance of reelin signaling within the entorhinal cortex, however, remains unexplored. To determine whether interrupting entorhinal reelin signaling might have consequences for learning and memory, we administered recombinant receptor-associated protein (RAP) into the lateral entorhinal cortex (LEC) of young Long-Evans rats. RAP prevents reelin from binding to its receptors, and we verified the knockdown of reelin signaling by quantifying the phosphorylation state of reelin’s intracellular signaling target, disabled-1 (DAB1). Effective knockdown of reelin signaling was associated with impaired performance in the hippocampus-dependent version of the water maze. Moreover, inhibition of reelin signaling induced a localized loss of synaptic marker expression in the LEC. These observations support a role for entorhinal reelin signaling in spatial learning, and suggest that an intact reelin signaling pathway is essential for synaptic integrity in the adult entorhinal cortex.

The subiculum is the major output area of the hippocampus. It is closely interconnected with the entorhinal cortex and other parahippocampal areas. In animal models of temporal lobe epilepsy (TLE) and in TLE patients it exerts increased network excitability and may crucially contribute to the propagation of limbic seizures. Using immunohistochemistry and in situ-hybridization we now investigated neuropathological changes affecting parvalbumin and calretinin containing neurons in the subiculum and other parahippocampal areas after kainic acid-induced status epilepticus. We observed prominent losses in parvalbumin containing interneurons in the subiculum and entorhinal cortex, and in the principal cell layers of the pre- and parasubiculum. Degeneration of parvalbumin-positive neurons was associated with significant precipitation of parvalbumin-immunoreactive debris 24 h after kainic acid injection. In the subiculum the superficial portion of the pyramidal cell layer was more severely affected than its deep part. In the entorhinal cortex, the deep layers were more severely affected than the superficial ones. The decrease in number of parvalbumin-positive neurons in the subiculum and entorhinal cortex correlated with the number of spontaneous seizures subsequently experienced by the rats. The loss of parvalbumin neurons thus may contribute to the development of spontaneous seizures. On the other hand, surviving parvalbumin neurons revealed markedly increased expression of parvalbumin mRNA notably in the pyramidal cell layer of the subiculum and in all layers of the entorhinal cortex. This indicates increased activity of these neurons aiming to compensate for the partial loss of this functionally important neuron population. Furthermore, calretinin-positive fibers terminating in the molecular layer of the subiculum, in sector CA1 of the hippocampus proper and in the entorhinal cortex degenerated together with their presumed perikarya in the thalamic nucleus reuniens. In addition, a significant loss of calretinin containing interneurons was observed in the subiculum. Notably, the loss in parvalbumin positive neurons in the subiculum equaled that in human TLE. It may result in marked impairment of feed-forward inhibition of the temporo-ammonic pathway and may significantly contribute to epileptogenesis. Similarly, the loss of calretinin-positive fiber tracts originating from the nucleus reuniens thalami significantly contributes to the rearrangement of neuronal circuitries in the subiculum and entorhinal cortex during epileptogenesis.

Graphical Abstract

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Highlights

▶A subpopulation of PV neurons degenerates in subiculum and entorhinal cortex after KA seizures. ▶Surviving PV neurons exhibit increased PV mRNA expression. ▶The loss in PV neurons in subiculum and entorhinal cortex correlates to spontaneous seizures. ▶Degeneration of PV neurons in the subiculum may be related to seizure-induced loss of feed-forward inhibition. ▶CR-ir neurons in the N. reuniens thalami and their projections to the subiculum degenerate.

The entorhinal cortex is a part of the hippocampal complex that is essential to learning and memory, and nicotine affects memory by activating nicotinic acetylcholine receptors (nAChRs) in the hippocampal complex. However, it is not clear what types of neurons in the entorhinal cortex are sensitive to nicotine, and whether they play a role in nicotine-induced memory functions. Here we have used voltage sensitive dye imaging (VSDI) methods to locate the neuronal populations responsive to nicotine in entorhino-hippocampal slices, and to clarify which nAChR subtypes are involved. In combination with patch-clamp methods, we found that a concentration of nicotine comparable to exposure during smoking depolarized neurons in layer VI of the EC (ECVI) by acting through the non-α7 subtype of nAChRs. Neurons in the subiculum (Sb; close to the deep EC layers) also contain nicotine-sensitive neurons, and it is known that Sb neurons project to the ECVI. When we recorded evoked EPSCs (eEPSCs) from ECVI neurons while stimulating the Sb near the CA1 region, a low dose of nicotine not only enhanced synaptic transmission (by increasing eEPSC amplitude), but also enhanced plasticity by converting tetanus stimulation-induced short-term potentiation (STP) to long-term potentiation (LTP); nicotine enhanced synaptic transmission and plasticity of ECVI synapses by acting on both the α7 and non-α7 subtypes of nAChRs. Our data suggest that ECVI neurons are important regulators of hippocampal function and plasticity during smoking.

Spatial mapping and navigation are figured prominently in the extant literature that describes hippocampal function. The medial entorhinal cortex is likewise attracting increasing interest, insofar as evidence accumulates that this area also contributes to spatial information processing. Here, we discuss recent electrophysiological findings that offer an alternate view of hippocampal and medial entorhinal function. These findings suggest complementary contributions of the hippocampus and medial entorhinal cortex in support of episodic memory, wherein hippocampal networks encode sequences of events that compose temporally and spatially extended episodes, whereas medial entorhinal networks disambiguate overlapping episodes by binding sequential events into distinct memories.

Brain regions and neural circuits differ in their vulnerability to changes that occur during aging and in age-related neurodegenerative diseases. Among the areas that comprise the medial temporal lobe memory system, the layer II neurons of the entorhinal cortex, which form the perforant path input to the hippocampal formation, exhibit early alterations over the course of aging Reelin, a glycoprotein implicated in synaptic plasticity, is expressed by entorhinal cortical layer II neurons. Here, we report that an age-related reduction in reelin expression in the entorhinal cortex is associated with cognitive decline. Using immunohistochemistry and in situ hybridization, we observed decreases in the number of Reelin-immunoreactive cells and reelin messenger RNA expression in the lateral entorhinal cortex of aged rats that are cognitively impaired relative to young adults and aged rats with preserved cognitive abilities. The lateral entorhinal cortex of aged rats with cognitive impairment also exhibited changes in other molecular markers, including increased accumulation of phosphorylated tau and decreased synaptophysin immunoreactivity. Taken together, these findings suggest that reduced reelin expression, emanating from layer II entorhinal neurons, may contribute to network dysfunction that occurs during memory loss in aging.

Some theories of memory propose that the hippocampus integrates the individual items and events of experience within a contextual or spatial framework. The hippocampus receives cortical input from two major pathways: the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC). During exploration in an open field, the firing fields of MEC grid cells form a periodically repeating, triangular array. In contrast, LEC neurons show little spatial selectivity, and it has been proposed that the LEC may provide non-spatial input to the hippocampus. Here, we recorded MEC and LEC neurons while rats explored an open field that contained discrete objects. LEC cells fired selectively at locations relative to the objects, whereas MEC cells were weakly influenced by the objects. These results provide the first direct demonstration of a double dissociation between LEC and MEC inputs to the hippocampus under conditions of exploration typically used to study hippocampal place cells.

The entorhinal cortex (EC) is considered as the gate to control the flow of information into and out of the hippocampus. The EC is important for numerous physiological functions such as emotional control, learning and memory and pathological disorders including Alzheimer’s disease, schizophrenia and temporal lobe epilepsy. Serotonin is a classical neurotransmitter which may modify these physiological functions and pathology of neurological diseases. The EC receives profuse serotonergic innervations from the raphe nuclei in the brainstem and expresses high density of serotonergic receptors including 5-HT1A, 5-HT1D, 5-HT1E, 5-HT2A, 5-HT3 and 5-HT6. The prominent innervation by serotonergic neurons and the dense expression of serotonergic receptors in the EC suggest that serotonin is a major modulator in this brain region. Serotonin exerts inhibitory effects in the EC. Serotonin hyperpolarizes entorhinal neurons and inhibits the excitatory synaptic transmission via activation of 5-HT1A receptors but facilitates GABA release via activation of 5-HT2A receptors. Both 5-HT1A and 5-HT2A receptors are required for serotonin-induced inhibition of epileptiform activity although 5-HT3 receptors may be involved in serotonin-mediated inhibition of acetylcholine release in the EC. Furthermore, the functions of serotonin in the EC may be implicated in Parkinson’s disease, Alzheimer’s disease and depression. Thus, understanding the roles of serotonergic modulation in the EC is of major clinical importance. Here, I review recent findings concerning the effects of serotonin on neural circuitry activity in the EC.

Objective

Hippocampal atrophy and reductions in basal cerebral blood volume (CBV), a hemodynamic correlate of brain function, occur with cognitive impairment in Alzheimer's disease but whether these are early or late changes remains unclear. Magnetic resonance imaging (MRI) assesses structure and function in the hippocampal formation. The objective of the present study was to estimate differences in the associations of hippocampus and entorhinal cortex volumes and CBV with memory function in early and late stages of cognitive impairment by relating these measures with memory function in demented and nondemented persons with detailed brain imaging and neuropsychological assessment.

Design and Setting

Multivariate regression analyses were used to relate entorhinal cortex volume, entorhinal cortex CBV, hippocampus volume and hippocampus-CBV with measures of memory performance in 231 elderly persons from a community-based cohort. The same measures were related with language function as a reference cognitive domain.

Results

There was no association between entorhinal cortex volume or hippocampus-CBV and memory. Decreased hippocampus volume was strongly associated with worse performance in total recall, while lower entorhinal cortex CBV was significantly associated with lower performance in delayed recall. Excluding persons with Alzheimer's disease (AD), the associations of entorhinal cortex CBV with memory measures was stronger, while the association between hippocampus volume and total recall became non-significant.

Conclusions

These finding suggest that in the early stages of AD or in nondemented persons with worse memory ability functional/metabolic hippocampal hypofunction contribute to memory impairment, while in the later stages both functional and structural changes play a role.

The entorhinal cortex is perhaps the area of the brain in which neurofibrillary tangles and amyloid plaques are first detectable in old age with or without mild cognitive impairment, and very particularly in Alzheimer's disease. It plays a key role in memory formation, retrieval, and extinction, as part of circuits that include the hippocampus, the amygdaloid nucleus, and several regions of the neocortex, in particular of the prefrontal cortex. Lesions or biochemical impairments of the entorhinal cortex hinder extinction. Microinfusion experiments have shown that glutamate NMDA receptors, calcium and calmodulin-dependent protein kinase II, and protein synthesis in the entorhinal cortex are involved in and required for extinction. Aging also hinders extinction; it is possible that its effect may be in part mediated by the entorhinal cortex.

To successfully navigate their habitats, many mammals use a combination of two mechanisms, path integration and calibration using landmarks, which together enable them to estimate their location and orientation, or pose. In large natural environments, both these mechanisms are characterized by uncertainty: the path integration process is subject to the accumulation of error, while landmark calibration is limited by perceptual ambiguity. It remains unclear how animals form coherent spatial representations in the presence of such uncertainty. Navigation research using robots has determined that uncertainty can be effectively addressed by maintaining multiple probabilistic estimates of a robot's pose. Here we show how conjunctive grid cells in dorsocaudal medial entorhinal cortex (dMEC) may maintain multiple estimates of pose using a brain-based robot navigation system known as RatSLAM. Based both on rodent spatially-responsive cells and functional engineering principles, the cells at the core of the RatSLAM computational model have similar characteristics to rodent grid cells, which we demonstrate by replicating the seminal Moser experiments. We apply the RatSLAM model to a new experimental paradigm designed to examine the responses of a robot or animal in the presence of perceptual ambiguity. Our computational approach enables us to observe short-term population coding of multiple location hypotheses, a phenomenon which would not be easily observable in rodent recordings. We present behavioral and neural evidence demonstrating that the conjunctive grid cells maintain and propagate multiple estimates of pose, enabling the correct pose estimate to be resolved over time even without uniquely identifying cues. While recent research has focused on the grid-like firing characteristics, accuracy and representational capacity of grid cells, our results identify a possible critical and unique role for conjunctive grid cells in filtering sensory uncertainty. We anticipate our study to be a starting point for animal experiments that test navigation in perceptually ambiguous environments.

Author Summary

Navigating robots face similar challenges to wild rodents in creating useable maps of their environments. Both must learn about their environments through experience, and in doing so face similar problems dealing with ambiguous and noisy information from their sensory inputs. Navigation research using robots has determined that uncertainty can be effectively addressed by maintaining multiple probabilistic estimates of a robot's pose. Neural recordings from navigating rats have revealed cells with grid-like spatial firing properties in the entorhinal cortex region of the rodent brain. Here we show how a robot equipped with conjunctive grid-cell-like cells can maintain multiple estimates of pose and solve a navigation task in an environment with no uniquely identifying cues. We propose that grid cells in the entorhinal cortex provide a similar ability for rodents. Robotics has learned much from biological systems. In a complementary way, in this study our understanding of neural systems is enhanced by insights from engineered solutions to a common problem faced by mobile robots and navigating animals.

Dentate granule cells play a critical role in the function of the entorhinal-hippocampal circuitry in health and disease. Dentate granule cells are situated to regulate the flow of information into the hippocampus, a structure required for normal learning and memory. Correspondingly, impaired granule cell function leads to memory deficits, and, interestingly, altered granule cell connectivity may contribute to the hyperexcitability of limbic epilepsy. It is important, therefore, to understand the molecular determinants of synaptic connectivity of these neurons. Brain-derived neurotrophic factor and its receptor TrkB are expressed at high levels in the dentate gyrus (DG) of the hippocampus, and are implicated in regulating neuronal development, neuronal plasticity, learning, and the development of epilepsy. Whether and how TrkB regulates granule cell structure, however, is incompletely understood. To begin to elucidate the role of TrkB in regulating granule cell morphology, here we examine conditional TrkB knockout mice crossed to mice expressing green fluorescent protein in subsets of dentate granule cells. In stratum lucidum, where granule cell mossy fiber axons project, the density of giant mossy fiber boutons was unchanged, suggesting similar output to CA3 pyramidal cell targets. However, filopodial extensions of giant boutons, which contact inhibitory interneurons, were increased in number in TrkB knockout mice relative to wildtype controls, predicting enhanced feedforward inhibition of CA3 pyramidal cells. In knockout animals, dentate granule cells possessed fewer primary dendrites and enlarged dendritic spines, indicative of disrupted excitatory synaptic input to the granule cells. Together, these findings demonstrate that TrkB is required for development and/or maintenance of normal synaptic connectivity of the granule cells, thereby implying an important role for TrkB in the function of the granule cells and hippocampal circuitry.

This review is focused on specific circuits of the medial temporal lobe that have become better understood in recent years for their computational properties contributing to episodic memory and to memory impairment associated with aging and other risk for AD. The layer II neurons in the entorhinal cortex and their targets in the dentate gyrus and CA3 region of hippocampus comprise a system that rapidly encodes representations that are distinct from prior memories. Frank neuron loss in the entorhinal cortex is specific for AD, and related structural and functional changes across the network comprised of the entorhinal cortex and the dentate/CA3 regions hold promise for predicting progression on the path to AD.