Lateral entorhinal cortex inputs modulate hippocampal dendritic excitability by recruiting a local disinhibitory microcircuit

The lateral entorhinal cortex (LEC) provides information about multi-sensory environmental cues to the hippocampus through direct inputs to the distal dendrites of CA1 pyramidal neurons. A growing body of work suggests that LEC neurons perform important functions for episodic memory processing, coding for contextually-salient elements of an environment or the experience within it. However, we know little about the functional circuit interactions between LEC and the hippocampus. In this study, we combine functional circuit mapping and computational modeling to examine how long-range glutamatergic LEC projections modulate compartment-specific excitation-inhibition dynamics in hippocampal area CA1. We demonstrate that glutamatergic LEC inputs can drive local dendritic spikes in CA1 pyramidal neurons, aided by the recruitment of a disinhibitory vasoactive intestinal peptide (VIP)-expressing inhibitory neuron microcircuit. Our circuit mapping further reveals that, in parallel, LEC also recruits cholecystokinin (CCK)-expressing inhibitory neurons, which our model predicts act as a strong suppressor of dendritic spikes. These results provide new insight into a cortically-driven GABAergic microcircuit mechanism that gates non-linear dendritic computations, which may support compartment-specific coding of multi-sensory contextual features within the hippocampus.

A neural network model of hippocampal contributions to category learning

In addition to its critical role in encoding individual episodes, the hippocampus is capable of extracting regularities across experiences. This ability is central to category learning, and a growing literature indicates that the hippocampus indeed makes important contributions to this kind of learning. Using a neural network model that mirrors the anatomy of the hippocampus, we investigated the mechanisms by which the hippocampus may support novel category learning. We simulated three category learning paradigms and evaluated the network's ability to categorize and to recognize specific exemplars in each. We found that the trisynaptic pathway within the hippocampus-connecting entorhinal cortex to dentate gyrus, CA3, and CA1-was critical for remembering individual exemplars, reflecting the rapid binding and pattern separation functions of this circuit. The monosynaptic pathway from entorhinal cortex to CA1, in contrast, was responsible for detecting the regularities that define category structure, made possible by the use of distributed representations and a slower learning rate. Together, the simulations provide an account of how the hippocampus and its constituent pathways support novel category learning.

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.

Histological Changes of Wistar Rats' Hippocampus and Entorhinal Cortex After Prenatal Exposure to Mosquito Coil Smoke

Background: The structural integrity of the hippocampus and the entorhinal cortex appears to be a prerequisite for normal acquisition of information about relational and contextual representation. Increased exposures to pyrethroids by pregnant women and children have raised concerns over their potentials as developmental neurotoxicants. Objectives: We studied the histological changes on the hippocampus and entorhinal cortex of adolescent Wistar rats prenatally exposed to mosquito coil smoke (MCS). Methods: 30 adult Wistar rats (20 females, 10 males) were used for the study. Mating was induced, and pregnancy was confirmed. Pregnant animals were grouped into four, 3 animals per group. Group I was exposed to fresh air. Groups II, III, and IV were exposed to mosquito coil smoke for 4, 6 and 8 hours daily respectively throughout gestation period. On Post-natal day (PND) 29, experimental animals were humanely sacrificed and regions of the hippocampus and entorhinal cortex were processed for histological studies using H & E stain. Results and Conclusion: Our results showed that prenatal exposure to mosquito coil smoke caused neuronal degeneration, distortion in cytoarchitecture of cellular layers and vacuolations in the hippocampus and entorhinal cortex of prenatally exposed groups.

Evaluation of Memory Impairment Following Prenatal Exposure to Mosquito Coil Smoke

Background: Developmental Neurotoxicity can lead to the buildup of reactive oxygen species which is an indicator to oxidative stress in the prenatally exposed offspring. Neuronal oxidative stress induces neuroinflammation, precedes tangle formation, and disrupts synaptic plasticity. The result of such changes may be expressed into adulthood as behavioral deficits. All together, these mechanisms are implicated in memory disorders. Objectives: To investigate the histochemical changes in the hippocampus and entorhinal cortex of Wistar rats' offspring after prenatal exposure to mosquito coil smoke and its effect on memory. . Methods: 12 pregnant Wistar rats were grouped into four, 3 animals per group. Group I was exposed to fresh air. Groups II, III, and IV were exposed to mosquito coil smoke for 4, 6 and 8 hours daily respectively throughout gestation period. On Post-natal day (PND) 28 and 29, shortterm spatial and recognition memory of adolescent wistar rats were assessed using water licking task and novel object recognition test respectively. For each animal group (I-IV), a total of 8 animals were randomly selected from the litters for neurobehavioral studies. Experimental animals were humanely sacrificed and sections from the hippocampus and entorhinal cortex were processed for histochemical studies using Bielschowsky stain. Data were presented as mean ± SEM; analysed using One-way analysis of variance and Tukey's Multiple Comparison Test (p<0.05). Results and Conclusion: Our results showed significant impairment in short-term recognition and spatial memory of group III and IV adolescent wistar rats when compared with the control (p<0.05) and the formation of neurofibrillary tangle-like structures in neurons of the studied regions. .

Visit-to-Visit Blood Pressure Variability and Longitudinal Tau Accumulation in Older Adults

Background: Elevated blood pressure variability (BPV) is predictive of dementia, independent of average blood pressure levels, but neuropathological mechanisms remain unclear. We examined whether BPV in older adults is related to tau accumulation in brain regions vulnerable to Alzheimer disease and whether relationships are modified by apoϵ4 carrier status. Methods: Two hundred eighty-six Alzheimer’s Disease Neuroimaging Initiative participants without history of dementia underwent 3 to 4 blood pressure measurements over 12 months and ≥1 tau positron emission tomography thereafter. BPV was calculated as variability independent of mean. Each scan determined tau burden (standardized uptake value ratio) for a temporal meta–region of interest, including burden from entorhinal cortex, amygdala, parahippocampus, fusiform, inferior temporal, and middle temporal. Bayesian linear growth modeling examined the role of BPV, apolipoprotein ϵ4 carrier status, and time on regional tau accumulation after controlling for several variables, including baseline hypertension. Results: Elevated BPV was related to tau accumulation at follow-up in a temporal meta-region, independent of average blood pressure levels (ß, 0.89 [95% credible interval, 0.86–0.92]) and especially in entorhinal cortex (ß, 2.57 [95% credible interval, 2.15–2.99]). Apoϵ4 carriers with elevated BPV had the fastest tau accumulation at follow-up (ß, 1.73 [95% credible interval, 0.47–3.03]). Conclusions: BPV is related to tau accumulation in brain regions vulnerable to Alzheimer disease, independent of average blood pressure. APOEϵ4 modified this relationship. Bidirectionality of findings is possible. BPV may represent a marker of vascular dysfunction related to early-stage tau pathology contributing to Alzheimer disease.

Differential Effects of Lateral and Medial Entorhinal Cortex Lesions on Trace, Delay and Contextual Fear Memories

The entorhinal cortex (EC), with connections to the hippocampus, amygdala, and neocortex, is a critical, yet still underexplored, contributor to fear memory. Previous research suggests possible heterogeneity of function among its lateral (LEC) and medial (MEC) subregions. However, it is not well established what unique roles these subregions serve as the literature has shown mixed results depending on target of manipulation and type of conditioning used. Few studies have manipulated both the LEC and MEC within the same experiment. The present experiment systematically manipulated LEC and MEC function to examine their potential roles in fear memory expression. Long-Evans rats were trained using either trace or delay fear conditioning. The following day, rats received an N-methyl-D-aspartate (NMDA)-induced lesion to the LEC or MEC or received a sham surgery. Following recovery, rats were given an 8-min context test in the original context. The next day, rats were tested for tone freezing in a novel context with three discrete tone presentations. Further, rats were tested for hyperactivity in an open field under both dark and bright light gradient conditions. Results: Following either LEC or MEC lesion, freezing to context was significantly reduced in both trace and delay conditioned rats. LEC-lesioned rats consistently showed significantly less freezing following tone-offset (trace interval, or equivalent, and intertrial interval) in both trace and delay fear conditioned rats. Conclusions: These data suggest that the LEC may play a role in the expression of a conjunctive representation between the tone and context that mediates the maintenance of post-tone freezing.