Authors: Rafiad Islam, Jordon D White, Tanzil M Arefin...

BACKGROUND

Early life adversity impairs hippocampal development and function across diverse species. While initial evidence indicated potential variations between males and females, further research is required to validate these observations and better understand the underlying mechanisms contributing to these sex differences. Furthermore, most of the preclinical work in rodents was performed in adult males, with only few studies examining sex differences during adolescence when such differences appear more pronounced. To address these concerns, we investigated the impact of limited bedding (LB), a mouse model of early adversity, on hippocampal development in prepubescent and adolescent male and female mice.

METHODS

RNA sequencing, confocal microscopy, and electron microscopy were used to evaluate the impact of LB and sex on hippocampal development in prepubescent postnatal day 17 (P17) mice. Additional studies were conducted on adolescent mice aged P29-36, which included contextual fear conditioning, retrograde tracing, and ex vivo diffusion magnetic resonance imaging (dMRI).

RESULTS

More severe deficits in axonal innervation and myelination were found in the perforant pathway of prepubescent and adolescent LB males compared to LB female littermates. These sex differences were due to a failure of reelin-positive neurons located in the lateral entorhinal cortex (LEC) to innervate the dorsal hippocampus via the perforant pathway in males, but not LB females, and were strongly correlated with deficits in contextual fear conditioning.

CONCLUSIONS

LB impairs the capacity of reelin-positive cells located in the LEC to project and innervate the dorsal hippocampus in LB males but not female LB littermates. Given the critical role that these projections play in supporting normal hippocampal function, a failure to establish proper connectivity between the LEC and the dorsal hippocampus provides a compelling and novel mechanism to explain the more severe deficits in myelination and contextual freezing found in adolescent LB males.

Topics: Animals; Male; Female; Sex Characteristics; Reelin Protein; Memory; Mice, Inbred C57BL; Perforant Pathway; Hippocampus; Fear; Mice; Stress, Psychological

PubMed: 38715106
DOI: 10.1186/s13293-024-00616-0

Authors: Emmanuelle C Genin, Pauline Pozzo di Borgo, Thomas Lorivel...

CHCHD10-related disease causes a spectrum of clinical presentations including mitochondrial myopathy, cardiomyopathy, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We generated a knock-in mouse model bearing the p.Ser59Leu (S59L) CHCHD10 variant. Chchd10 mice have been shown to phenotypically replicate the disorders observed in patients: myopathy with mtDNA instability, cardiomyopathy and typical ALS features (protein aggregation, neuromuscular junction degeneration and spinal motor neuron loss). Here, we conducted a comprehensive behavioral, electrophysiological and neuropathological assessment of Chchd10 mice. These animals show impaired learning and memory capacities with reduced long-term potentiation (LTP) measured at the Perforant Pathway-Dentate Gyrus (PP-DG) synapses. In the hippocampus of Chchd10 mice, neuropathological studies show the involvement of protein aggregates, activation of the integrated stress response (ISR) and neuroinflammation in the degenerative process. These findings contribute to decipher mechanisms associated with CHCHD10 variants linking mitochondrial dysfunction and neuronal death. They also validate the Chchd10 mice as a relevant model for FTD, which can be used for preclinical studies to test new therapeutic strategies for this devastating disease.

Topics: Animals; Frontotemporal Dementia; Disease Models, Animal; Mice; Mitochondrial Proteins; Mice, Transgenic; Behavior, Animal; Male; Long-Term Potentiation; Mice, Inbred C57BL; Hippocampus

PubMed: 38583639
DOI: 10.1016/j.nbd.2024.106498

Authors: Pierre Wibawa, Mark Walterfang, Charles B Malpas...

INTRODUCTION

While individuals with Huntington disease (HD) show memory impairment that indicates hippocampal dysfunction, the available literature does not consistently identify structural evidence for involvement of the whole hippocampus but rather suggests that hippocampal atrophy may be confined to certain hippocampal subregions.

METHODS

We processed T1-weighted MRI from IMAGE-HD study using FreeSurfer 7.0 and compared the volumes of the hippocampal subfields among 36 early motor symptomatic (symp-HD), 40 pre-symptomatic (pre-HD), and 36 healthy control individuals across three timepoints over 36 months.

RESULTS

Mixed-model analyses revealed significantly lower subfield volumes in symp-HD, compared with pre-HD and control groups, in the subicular regions of the perforant-pathway: presubiculum, subiculum, dentate gyrus, tail, and right molecular layer. These adjoining subfields aggregated into a single principal component, which demonstrated an accelerated rate of atrophy in the symp-HD. Volumes between pre-HD and controls did not show any significant difference. In the combined HD groups, CAG repeat length and disease burden score were associated with presubiculum, molecular layer, tail, and perforant-pathway subfield volumes. Hippocampal left tail and perforant-pathway subfields were associated with motor onset in the pre-HD group.

CONCLUSIONS

Hippocampal subfields atrophy in early symptomatic HD affects key regions of the perforant-pathway, which may implicate the distinctive memory impairment at this stage of illness. Their volumetric associations with genetic and clinical markers suggest the selective susceptibility of these subfields to mutant Huntingtin and disease progression.

Topics: Humans; Huntington Disease; Hippocampus; Magnetic Resonance Imaging; Temporal Lobe; Atrophy

PubMed: 37306313
DOI: 10.1111/ene.15918

Authors: Robert Siman, Ryan Cocca, Yina Dong...

The perforant pathway projection from layer II of the entorhinal cortex to the hippocampal dentate gyrus is especially important for long-term memory formation, and is preferentially vulnerable to developing a degenerative tauopathy early in Alzheimer's disease (AD) that may spread over time trans-synaptically. Despite the importance of the perforant pathway to the clinical onset and progression of AD, a therapeutic has not been identified yet that protects it from tau-mediated toxicity. Here, we used an adeno-associated viral vector-based mouse model of early-stage AD-type tauopathy to investigate effects of the mTOR inhibitor and autophagy stimulator rapamycin on the tau-driven loss of perforant pathway neurons and synapses. Focal expression of human tau carrying a P301L mutation but not eGFP as a control in layer II of the lateral entorhinal cortex triggered rapid degeneration of these neurons, loss of lateral perforant pathway synapses in the dentate gyrus outer molecular layer, and activation of neuroinflammatory microglia and astroglia in the two locations. Chronic systemic rapamycin treatment partially inhibited phosphorylation of a mechanistic target of rapamycin substrate in brain and stimulated LC3 cleavage, a marker of autophagic flux. Compared with vehicle-treated controls, rapamycin protected against the tau-induced neuronal loss, synaptotoxicity, reactive microgliosis and astrogliosis, and activation of innate neuroimmunity. It did not alter human tau mRNA or total protein levels. Finally, rapamycin inhibited trans-synaptic transfer of human tau expression to the dentate granule neuron targets for the perforant pathway, likely by preventing the synaptic spread of the AAV vector in response to pathway degeneration. These results identify systemic rapamycin as a treatment that protects the entorhinal cortex and perforant pathway projection from tau-mediated neurodegeneration, axonal and synapse loss, and neuroinflammatory reactive gliosis. The findings support the potential for slowing the progression of AD by abrogating tau-mediated neurotoxicity at its earliest neuropathological stages.

Topics: Alzheimer Disease; Animals; Axons; Dentate Gyrus; Disease Models, Animal; Entorhinal Cortex; Hippocampus; Humans; Male; Memory, Long-Term; Mice; Microglia; Neurodegenerative Diseases; Neurons; Perforant Pathway; Phosphorylation; Sirolimus; Synapses; TOR Serine-Threonine Kinases; Tauopathies; tau Proteins

PubMed: 26540269
DOI: 10.1371/journal.pone.0142340

Latent toxoplasmosis impairs learning and memory yet strengthens short-term and long-term hippocampal synaptic plasticity at perforant pathway-dentate gyrus, and Schaffer collatterals-CA1 synapses.

Authors: Samira Choopani, Bahereh Kiani, Shayan Aliakbari...

Investigating long-term potentiation (LTP) in disease models provides essential mechanistic insight into synaptic dysfunction and relevant behavioral changes in many neuropsychiatric and neurological diseases. Toxoplasma (T) gondii is an intracellular parasite causing bizarre changes in host's mind including losing inherent fear of life-threatening situations. We examined hippocampal-dependent behavior as well as in vivo short- and long-term synaptic plasticity (STP and LTP) in rats with latent toxoplasmosis. Rats were infected by T. gondii cysts. Existence of REP-529 genomic sequence of the parasite in the brain was detected by RT-qPCR. Four and eight weeks after infection, spatial, and inhibitory memories of rats were assessed by Morris water maze and shuttle box tests, respectively. Eight weeks after infection, STP was assessed in dentate gyrus (DG) and CA1 by double pulse stimulation of perforant pathway and Shaffer collaterals, respectively. High frequency stimulation (HFS) was applied to induce LTP in entorhinal cortex-DG (400 Hz), and CA3-CA1 (200 Hz) synapses. T. gondii infection retarded spatial learning and memory performance at eight weeks post-infection period, whereas inhibitory memory was not changed. Unlike uninfected rats that normally showed paired-pulse depression, the infected rats developed paired-pulse facilitation, indicating an inhibitory synaptic network disruption. T. gondii-infected rats displayed strengthened LTP of both CA1-pyramidal and DG-granule cell population spikes. These data indicate that T. gondii disrupts inhibition/excitation balance and causes bizarre changes to the post-synaptic neuronal excitability, which may ultimately contribute to the abnormal behavior of the infected host.

Topics: Rats; Animals; Perforant Pathway; Hippocampus; Neuronal Plasticity; Long-Term Potentiation; Synapses; Dentate Gyrus; Toxoplasmosis

PubMed: 37268701
DOI: 10.1038/s41598-023-35971-2

Review

Authors: Jean C Augustinack, André J W van der Kouwe, Bruce Fischl...

This review focuses on the ex vivo magnetic resonance imaging (MRI) modeling of medial temporal cortices and associated structures, the entorhinal verrucae and the perforant pathway. Typical in vivo MRI has limited resolution due to constraints on scan times and does not show laminae in the medial temporal lobe. Recent studies using ex vivo MRI have demonstrated lamina in the entorhinal, perirhinal, and hippocampal cortices. These studies have enabled probabilistic brain mapping that is based on the ex vivo MRI contrast, validated to histology, and subsequently mapped onto an in vivo spherically warped surface model. Probabilistic maps are applicable to other in vivo studies.

Topics: Animals; Brain Mapping; Humans; Magnetic Resonance Imaging; Temporal Lobe

PubMed: 23881818
DOI: 10.1002/cne.23432

Authors: Samaneh Safari, Nesa Ahmadi, Reihaneh Mohammadkhani...

BACKGROUND

Recent studies show that gender may have a significant impact on brain functions. However, the reports of sex effects on spatial ability and synaptic plasticity in rodents are divergent and controversial. Here spatial learning and memory was measured in male and female rats by using Morris water maze (MWM) task. Moreover, to assess sex difference in hippocampal synaptic plasticity we examined hippocampal long-term potentiation (LTP) at perforant pathway-dentate gyrus (PP-DG) synapses.

RESULTS

In MWM task, male rats outperformed female rats, as they had significantly shorter swim distance and escape latency to find the hidden platform during training days. During spatial reference memory test, female rats spent less time and traveled less distance in the target zone. Male rats also had larger LTP at PP-DG synapses, which was evident in the high magnitude of population spike (PS) potentiation and the field excitatory post synaptic potentials (fEPSP) slope.

CONCLUSIONS

Taken together, our results suggest that sex differences in the LTP at PP-DG synapses, possibly contribute to the observed sex difference in spatial learning and memory.

Topics: Animals; Dentate Gyrus; Female; Hippocampus; Long-Term Potentiation; Male; Perforant Pathway; Rats; Rats, Wistar; Sex Characteristics; Spatial Learning; Synapses

PubMed: 34724971
DOI: 10.1186/s12993-021-00184-y

Authors: Yuto Uchida, Kengo Onda, Zhipeng Hou...

BACKGROUND

Conventional neuroimaging biomarkers for the neurodegeneration of Alzheimer's disease (AD) are not sensitive enough to detect neurodegenerative alterations during the preclinical stage of AD individuals.

OBJECTIVE

We examined whether neurodegeneration of the entorhinal-hippocampal pathway could be detected along the AD continuum using ultra-high-field diffusion tensor imaging and tractography for ex vivo brain tissues.

METHODS

Postmortem brain specimens from a cognitively unimpaired individual without AD pathological changes (non-AD), a cognitively unimpaired individual with AD pathological changes (preclinical AD), and a demented individual with AD pathological changes (AD dementia) were scanned with an 11.7T diffusion magnetic resonance imaging. Fractional anisotropy (FA) values of the entorhinal layer II and number of perforant path fibers counted by tractography were compared among the AD continuum. Following the imaging analyses, the status of myelinated fibers and neuronal cells were verified by subsequent serial histological examinations.

RESULTS

At 250μm (zipped to 125μm) isotropic resolution, the entorhinal layer II islands and the perforant path fibers could be identified in non-AD and preclinical AD, but not in AD dementia, followed by histological verification. The FA value of the entorhinal layer II was the highest among the entorhinal laminae in non-AD and preclinical AD, whereas the FA values in the entorhinal laminae were homogeneously low in AD dementia. The FA values and number of perforant path fibers decreased along the AD continuum (non-AD>preclinical AD > AD dementia).

CONCLUSION

We successfully detected neurodegenerative alterations of the entorhinal-hippocampal pathway at the preclinical stage of the AD continuum.

Topics: Humans; Alzheimer Disease; Diffusion Tensor Imaging; Hippocampus; Brain; Diffusion Magnetic Resonance Imaging

PubMed: 37638442
DOI: 10.3233/JAD-230452

Impairment in social interaction and hippocampal long-term potentiation at perforant pathway-dentate gyrus synapses in a prenatal valproic acid-induced rat model of autism.

Authors: Reihaneh Mohammadkhani, Reza Ghahremani, Iraj Salehi...

It is well established that prenatal valproic acid exposure in rats leads to autism-like behaviours and social deficits. Long-term potentiation changes in the brain have been proposed as a potential mechanism in the development of autistic behaviour. However, there are controversies regarding the effect of valproic acid exposure on long-term potentiation. This study examined the social interaction and long-term potentiation induction in perforant pathway-dentate gyrus synapses in male offspring of a rat model of autism induced by prenatal exposure to valproic acid. On Embryonic Day 12.5, the pregnant dams received an injection of 500 mg/kg valproic acid (intraperitoneal) to produce the autism model. The sociability test was performed between Postnatal Days 37 and 40. The offsprings were urethane-anaesthetized and placed into a stereotaxic apparatus for surgery, electrode implantation and field potential recording on Postnatal Days 45-55. In the dentate gyrus region, excitatory postsynaptic potential slope and population spike amplitude were measured. Valproic acid-exposed offspring showed significantly impaired social interaction. The birth weight in valproic acid-exposed rats was significantly lower than in control rats. The ability of dentate gyrus synapses to induce long-term potentiation was hampered by valproic acid exposure. The decreasing excitatory postsynaptic potential slope and population spike amplitude of long-term potentiation provide evidence in favour of this notion. It is widely supposed that the hippocampus plays a central role in the process of learning and memory as well as social interaction and social memory. Therefore, deficiencies in hippocampal synaptic plasticity may be responsible, at least in part, for the social interaction deficits in valproic acid-exposed rats.

PubMed: 36092302
DOI: 10.1093/braincomms/fcac221