Heterosynaptic NMDA Receptor Plasticity in Hippocampal Dentate Granule Cells

The dentate gyrus is a key relay station that controls information transfer from the entorhinal cortex to the hippocampus proper. This process heavily relies on dendritic integration by dentate granule cells (GCs) of excitatory synaptic inputs from medial and lateral entorhinal cortex via medial and lateral perforant paths (MPP and LPP, respectively). N-methyl-D-aspartate receptors (NMDARs) can contribute significantly to the integrative properties of neurons. While early studies reported that excitatory inputs from entorhinal cortex onto GCs can undergo activity-dependent long-term plasticity of NMDAR-mediated transmission, the input-specificity of this plasticity along the dendritic axis remains unknown. Here, we examined the NMDAR plasticity rules at MPP-GC and LPP-GC synapses using physiologically relevant patterns of stimulation in acute rat hippocampal slices. We found that MPP-GC, but not LPP-GC synapses, expressed homosynaptic NMDAR-LTP. In addition, induction of NMDAR-LTP at MPP-GC synapses heterosynaptically potentiated distal LPP-GC NMDAR plasticity. The same stimulation protocol induced homosynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-LTP at MPP-GC but heterosynaptic AMPAR-LTD at distal LPP synapses, demonstrating that NMDAR and AMPAR are governed by different plasticity rules. Remarkably, heterosynaptic but not homosynaptic NMDAR-LTP required Ca2+ release from intracellular, ryanodine-dependent Ca2+ stores. Lastly, the induction and maintenance of both homo- and heterosynaptic NMDAR-LTP were blocked by GluN2D antagonism, suggesting the recruitment of GluN2D-containing receptors to the synapse. Our findings uncover a mechanism by which distinct inputs to the dentate gyrus may interact functionally and contribute to hippocampal-dependent memory formation.

Effect of Berberine Isolated from Barberry Species by Centrifugal Partition Chromatography on Memory and the Expression of Parvalbumin in the Mouse Hippocampus Proper

Neurodegenerative diseases associated with memory disturbances are important health issues occurring due to a prolonged life span. This article presents the results of a study targeting the emergence of a drug candidate with antiamnesic properties. The effect of berberine (BBR), an isoquinoline alkaloid isolated from the overground parts of Berberis sibirica Pall., on memory and expression of parvalbumin in the mouse hippocampus proper were determined. High-purity BBR was isolated by centrifugal partition chromatography from a methanolic extract from B. sibirica by using a methyl-tert-butyl ether and water (1:1 v/v) solvent system with 10 mmol/L of triethylamine and hydrochloric acid. In an in vivo study, we assessed the influence of the chronic administration of BBR on different stages of memory-related responses in mice. Our results indicated that the chronic administration of BBR in a higher dose (5 mg/kg) improves long-term memory acquisition in mice, as determined in the passive avoidance test. The hippocampal CA1–CA3 fields showed an increased number of parvalbumin-immunoreactive neurons (PV-IR) and nerve fibers as compared to the control. No significant changes in the dentate gyrus were observed between the groups. The HPLC-ESI-QTOF-MS/MS analysis of the biological material revealed the content of BBR as 363.4 ± 15.0 ng (4.11% of RSD) per brain, 15.06 ± 0.89 ng (5.91% of RSD) per hippocampus, and 54.45 ± 1.40 (4.05% of RSD) ng in 100 µL plasma. The study showed that BBR could be a factor influencing the expression of PV in hippocampal neurons. We speculate that BBR may modulate the level of Ca2+ in neurons and thus potentially act as a neuroprotective factor against neuronal damages.

Synchronous activity patterns in the dentate gyrus during immobility

The hippocampal dentate gyrus is an important relay conveying sensory information from the entorhinal cortex to the hippocampus proper. During exploration, the dentate gyrus has been proposed to act as a pattern separator. However, the dentate gyrus also shows structured activity during immobility and sleep. The properties of these activity patterns at cellular resolution, and their role in hippocampal-dependent memory processes have remained unclear. Using dual-color in-vivo two-photon Ca2+ imaging, we show that in immobile mice dentate granule cells generate sparse, synchronized activity patterns associated with entorhinal cortex activation. These population events are structured and modified by changes in the environment; and they incorporate place- and speed cells. Importantly, they are more similar than expected by chance to population patterns evoked during self-motion. Using optogenetic inhibition, we show that granule cell activity is not only required during exploration, but also during immobility in order to form dentate gyrus-dependent spatial memories.

CD200 Change Is Involved in Neuronal Death in Gerbil Hippocampal CA1 Field Following Transient Forebrain Ischemia and Postischemic Treatment with Risperidone Displays Neuroprotection without CD200 Change

It has been reported that CD200 (Cluster of Differentiation 200), expressed in neurons, regulates microglial activation in the central nervous system, and a decrease in CD200 expression causes an increase in microglial activation and neuronal loss. The aim of this study was to investigate time-dependent changes in CD200 expression in the hippocampus proper (CA1, 2, and 3 fields) after transient forebrain ischemia for 5 min in gerbils. In this study, 5-min ischemia evoked neuronal death (loss) of pyramidal neurons in the CA1 field, but not in the CA2/3 fields, at 5 days postischemia. In the sham group, CD200 expression was found in pyramidal neurons of the CA1 field, and the immunoreactivity in the group with ischemia was decreased at 6 h postischemia, dramatically increased at 12 h postischemia, decreased (to level found at 6 h postischemia) at 1 and 2 days postischemia, and significantly increased again at 5 days postischemia. At 5 days postischemia, CD200 immunoreactivity was strongly expressed in microglia and GABAergic neurons. However, in the CA3 field, the change in CD200 immunoreactivity in pyramidal neurons was markedly weaker than that in the CA1 field, showing there was no expression of CD 200 in microglia and GABAergic neurons. In addition, treatment of 10 mg/kg risperidone (an atypical antipsychotic drug) after the ischemia hardly changed CD200 immunoreactivity in the CA1 field, showing that CA1 pyramidal neurons were protected from the ischemic injury. These results indicate that the transient ischemia-induced change in CD200 expression may be associated with specific and selective neuronal death in the hippocampal CA1 field following transient forebrain ischemia.

Anatomy and Function of the Primate Entorhinal Cortex

The entorhinal cortex (EC) is a critical element of the hippocampal formation located within the medial temporal lobe (MTL) in primates. The EC has historically received attention for being the primary mediator of cortical information going into and coming from the hippocampus proper. In this review, we highlight the significance of the EC as a major player in memory processing, along with other associated structures in the primate MTL. The complex, convergent topographies of cortical and subcortical input to the EC, combined with short-range intrinsic connectivity and the selective targeting of EC efferents to the hippocampus, provide evidence for subregional specialization and integration of information beyond what would be expected if this structure were a simple conduit of information for the hippocampus. Lesion studies of the EC provide evidence implicating this region as critical for memory and the flexible use of complex relational associations between experienced events. The physiology of this structure's constituent principal cells mirrors the complexity of its anatomy. EC neurons respond preferentially to aspects of memory-dependent paradigms including object, place, and time. EC neurons also show striking spatial representations as primates explore visual space, similar to those identified in rodents navigating physical space. In this review, we highlight the great strides that have been made toward furthering our understanding of the primate EC, and we identify paths forward for future experiments to provide additional insight into the role of this structure in learning and memory.

Preserved visual memory and relational cognition performance in monkeys with selective hippocampal lesions

The theory that the hippocampus is critical for visual memory and relational cognition has been challenged by discovery of more spared hippocampal tissue than previously reported in H.M., previously unreported extra-hippocampal damage in developmental amnesiacs, and findings that the hippocampus is unnecessary for object-in-context memory in monkeys. These challenges highlight the need for causal tests of hippocampal function in nonhuman primate models. Here, we tested rhesus monkeys on a battery of cognitive tasks including transitive inference, temporal order memory, shape recall, source memory, and image recognition. Contrary to predictions, we observed no robust impairments in memory or relational cognition either within- or between-groups following hippocampal damage. These results caution against over-generalizing from human correlational studies or rodent experimental studies, compel a new generation of nonhuman primate studies, and indicate that we should reassess the relative contributions of the hippocampus proper compared to other regions in visual memory and relational cognition.

Dentate gyrus population activity during immobility supports formation of precise memories

The hippocampal dentate gyrus is an important relay conveying sensory information from the entorhinal cortex to the hippocampus proper. During exploration, the dentate gyrus has been proposed to act as a pattern separator. However, the dentate gyrus also shows structured activity during immobility and sleep. The properties of these activity patterns at cellular resolution, and their role in hippocampal-dependent memory processes have remained unclear. Using dual-color in-vivo two-photon Ca2+ imaging, we show that in immobile mice dentate granule cells generate sparse, synchronized activity patterns associated with entorhinal cortex activation. These population events are structured and modified by changes in the environment; and they incorporate place- and speed cells. Importantly, they recapitulate population patterns evoked during self-motion. Using optogenetic inhibition during immobility, we show that granule cell activity during immobility is required to form dentate gyrus-dependent spatial memories. These data suggest that memory formation is supported by dentate gyrus replay of population codes of the current environment.

Postnatal Development of the Hippocampus in Male Albino Rats: A Histomorphometric Study

Introduction In recent year deterioration in cognitive, learning, and memory become one of the significant problems in human life. Hippocampus is a pivotal part of the brain’s limbic system which serves a critical role in memory, learning process and regulating the emotions. In most regions of the brain, neurons are generated only at specific periods of early development, and not born in the adulthood. In contrast, hippocampal neurons are generated throughout development and adult life. The hippocampal dentate gyrus was reported to be one of the few regions of the mammalian brain where neurogenesis continue to occur throughout adulthood. The neurogenesis in the dentate gyrus was thought to play an important role in hippocampus-dependent learning and memory. The hippocampal formation is composed of the hippocampus proper, the dentate gyrus and the subiculum. The hippocampus proper is the largest part and is subdivided into fields designated as Cornu Ammonis or Ammon’s horn (CA) from CA1 to CA4. Ammon's horn is continuous with the subiculum, which acts as the main output source of the hippocampal formation. Aim of the Study To study the postnatal development of the hippocampal formation. Materials and Methods Five male albino rats from the following postnatal ages day 1, week 1, week 2, week3 and week 4 were studied by histological, immunohistochemical, and morphometric methods. Results The general architecture of the hippocampus proper with its polymorphic, pyramidal, and molecular layers was present at day1, whereas the details of the adult structure appeared at week 2. In the dentate gyrus, distinct lamination appeared at week 1 and its maturation continued with the production of neurons at the interhilar zone that peaked at week 2. The number and density of pyramidal axons and dendrites increase by age. Astrocytes increased in size and staining affinity for glial filaments, and acquired a stellate shape with age. Furthermore, the number of granule cell layers increased concomitantly with the increase in thickness of the molecular and polymorphic layers of both the hippocampus proper and the dentate gyrus. Conclusion The important sequences of events in the growth and maturation of the hippocampal formation in male albino rat occurred in the first 2 postnatal weeks.

The Regional Specific Alterations in BBB Permeability are Relevant to the Differential Responses of 67-kDa LR Expression in Endothelial Cells and Astrocytes Following Status Epilepticus

Status epilepticus (a prolonged seizure activity, SE) differently affects vasogenic edema formation and dystrophin-aquaporin 4 (AQP4) expressions between the rat hippocampus and the piriform cortex (PC). In the present study, we explored whether the 67-kDa laminin receptor (LR) expression was relevant to the regional specific susceptibility of vasogenic edema at 3 days after SE. In spite of no difference in expression levels of 67-kDa LR, dystrophin, and AQP4 under physiological conditions, SE-induced serum extravasation was more severe in the PC than the hippocampus. Western blots demonstrated that SE reduced expression levels of 67-kDa LR, dystrophin, and AQP4 in the PC, but not in the hippocampus proper. Immunofluorescent studies revealed that SE increased 67-kDa LR expression in reactive CA1 astrocyte, but reduced it in the PC and the molecular layer of the dentate gyrus due to massive astroglial loss. Furthermore, SE decreased expressions of endothelial 67-kDa LR and SMI-71 (endothelial brain barrier antigen) in these regions. The 67-kDa LR neutralization evoked serum extravasation in these regions of normal animals without astroglial loss. Similar to SE, 67-kDa LR neutralization also reduced dystrophin-AQP4 expressions in the PC more than the total hippocampus. Furthermore, 67-kDa LR IgG infusion increased phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), but not c-Jun N-terminal kinase, independent of phosphoprotein enriched in astrocytes of 15 kDa (PEA15) activity. Co-treatment of U0126 (an ERK1/2 inhibitor) alleviated vasogenic edema formation and the reduced dystrophin-AQP4 expressions induced by 67-kDa LR neutralization. The 67-kDa LR IgG infusion also increased the susceptibility to SE induction. Therefore, our findings suggested that the cellular specific alterations in 67-kDa LR expression might be involved in the severity of SE-induced vasogenic edema formation in regional specific manners, which might affect the susceptibility to SE induction.

Pattern separation and pattern completion: Behaviorally separable processes?

Episodic memory capacity requires several processes, including mnemonic discrimination of similar experiences, termed pattern separation, and holistic retrieval of multidimensional experiences given a cue, termed pattern completion. Both computations seem to rely on the hippocampus proper, but they also seem to be instantiated by distinct hippocampal subfields. Thus, we investigated whether individual differences in behavioral expressions of pattern separation and pattern completion were correlatedafter accounting for general mnemonic ability. Young adult participants learned events comprised of a scene-animal-object triad. In the pattern separation task, we estimated mnemonic discrimination using lure classification for events that contained a similar lure element. In the pattern completion task, we estimated holistic recollection using dependency in retrieval success for different associations from the same event. Although overall accuracies for the two tasks correlated as expected, specific measures of individual variation in holistic retrieval and mnemonic discrimination did not correlate, suggesting that these two processes involve distinguishable properties of episodic memory.