Hippocampal Subregions Research Articles

Neuropathology of trisomy 21 mosaicism in a case with early-onset dementia.

This study investigated the impact of trisomy 21 mosaicism (mT21) on Alzheimer's disease (AD) neuropathology in a well-characterized clinical case described by Ringman etal. We describe AD neuropathology in mT21 including amyloid beta, phosphorylated tau, astrogliosis, microgliosis, α-synuclein, and TAR DNA-binding protein 43 (TDP-43) in cerebral cortex, hippocampal subregions, and amygdala using immunohistochemistry. We observed high AD neuropathologic change with a score of A3B3C3. In addition, there was widespread astrogliosis, cerebral amyloid angiopathy, and perivascular space widening throughout the brain. Lewy bodies and neurites were noted in the amygdala only and no TDP-43 was observed. The findings in this case report highlight that mT21 is sufficient to induce AD neuropathology and early-onset dementia. Trisomy 21 mosaicism (mT21) occurs when three copies of chromosome 21 are present in some but not all somatic cells in an individual. mT21 accounts for ≈ 2% of people diagnosed with Down syndrome (DS). Immunohistochemical identification of amyloid beta, tau, astrocytes, microglia, α-synuclein, and TAR DNA-binding protein 43 show that Alzheimer's disease (AD) pathology in mT21 is similar to full trisomy 21. The findings in this case report highlight that mT21 is sufficient to induce AD neuropathology and early-onset dementia.

MorphoGlia, an interactive method to identify and map microglia morphologies, demonstrates differences in hippocampal subregions of an Alzheimer’s disease mouse model

Microglia are dynamic central nervous system cells crucial for maintaining homeostasis and responding to neuroinflammation, as evidenced by their varied morphologies. Existing morphology analysis often fails to detect subtle variations within the full spectrum of microglial morphologies due to their reliance on predefined categories. Here, we present MorphoGlia, an interactive, user-friendly pipeline that objectively characterizes microglial morphologies. MorphoGlia employs a machine learning ensemble to select relevant morphological features of microglia cells, perform dimensionality reduction, cluster these features, and subsequently map the clustered cells back onto the tissue, providing a spatial context for the identified microglial morphologies. We applied this pipeline to compare the responses between saline solution (SS) and scopolamine (SCOP) groups in a SCOP-induced mouse model of Alzheimer’s disease, with a specific focus on the hippocampal subregions CA1 and Hilus. Next, we assessed microglial morphologies across four groups: SS-CA1, SCOP-CA1, SS-Hilus, and SCOP-Hilus. The results demonstrated that MorphoGlia effectively differentiated between SS and SCOP-treated groups, identifying distinct clusters of microglial morphologies commonly associated with pro-inflammatory states in the SCOP groups. Additionally, MorphoGlia enabled spatial mapping of these clusters, identifying the most affected hippocampal layers. This study highlights MorphoGlia’s capability to provide unbiased analysis and clustering of microglial morphological states, making it a valuable tool for exploring microglial heterogeneity and its implications for central nervous system pathologies.

Intranasal oxytocin alleviates postsurgical pain and comorbid anxiety in mice: Participation of BK(Ca) channels in the hippocampus

The affective dimension in postsurgical pain is still poorly understood. Since neuropeptide oxytocin (OXT) has been implicated in a broad spectrum of pain and negative emotion, we investigated the potential therapeutic effect of intranasal OXT on postsurgical pain and associated anxiety in a mice model of plantar incision. The role of large conductance Ca(2+)-activated K(+) (BK(Ca)) channels was explored by using behavioral pharmacology experiments. We reported that plantar incision in mice induced anxiety-like behaviors and mechanical pain hypersensitivity, with a concurrent decrease of the oxytocin receptor (OTR) in the hippocampus. The immunofluorescence staining showed that the OTR were enriched in pyramidal neurons in CA3 subregion of hippocampus and which were highly co-expressed with the BK(Ca) channels in CA3 subregion. Intranasal OXT significantly ameliorated this postsurgical pain and associated anxiety in a dose-dependent manner, while Intra-CA3 microinjection of OTR antagonist atosiban or the BK(Ca) channel blocker paxilline reduced the effect of OXT in incisional mice. Moreover, intra-CA3 microinjection of BK(Ca) channel opener NS1619 produced a similar effect on postsurgical pain and associated anxiety-like behaviors as those observed following intranasal OXT administration. Conversely, intra-CA3 microinjection of BK(Ca) channel blocker paxilline in normal mice was sufficient to evoke mechanical pain hypersensitivity. Taken together, our data suggested that intranasal OXT administration exerted analgesic and anxiolytic effects in incisional mice by opening BK(Ca) channels in the CA3 subregion of hippocampus.

The value of hippocampal sub-region imaging features for the diagnosis and severity grading of ASD in children

BackgroundHippocampal structural changes in Autism Spectrum Disorder (ASD) are inconsistent. This study investigates hippocampal subregion changes in ASD patients to reveal intrinsic hippocampal anomalies. MethodsA retrospective study from Hainan Children’s Hospital database (2020–2023) included ASD patients and matched controls. We classified ASD participants based on severity, dividing all subjects into four groups: normal, mild, moderate, and severe. High-resolution T1-weighted MRI images were analyzed for hippocampal subregion segmentation and volume calculations using Freesurfer. Texture features were extracted via the Gray-Level Co-occurrence Matrix. The Receiver Operating Characteristic curve was used to evaluate seven random forest predictive models constructed from volume, subregion, and texture features, as well as their combinations following feature selection. ResultsThe study included 114 ASD patients (98 boys, 2–8 years; 16 girls, 2–6 years; 17 mild, 57 moderate, 40 severe) and 111 healthy controls (HCs). No significant differences in volumes were found between ASD patients and HCs (adjusted P-value >0.05). The seven random forest models showed that single volume and texture features performed poorly for ASD classification; however, integrating various feature types improved AUC values. Further selection of texture, subregion, and volume features enhanced AUC performance across normal and varying severity categories, demonstrating the potential value of specific subregions and integrated features in ASD diagnosis. ConclusionRandom forest models revealed that hippocampal volume, texture features, and subregion characteristics are crucial for diagnosing and assessing the severity of ASD. Integrating selected texture and subregion features optimized diagnostic efficacy, while combining texture, subregion, and volume features further improved severity grading effectiveness.

Recurrent Connectivity Shapes Spatial Coding in Hippocampal CA3 Subregions.

Stable and flexible neural representations of space in the hippocampus are crucial for navigating complex environments. However, how these distinct representations emerge from the underlying local circuit architecture remains unknown. Using two-photon imaging of CA3 subareas during active behavior, we reveal opposing coding strategies within specific CA3 subregions, with proximal neurons demonstrating stable and generalized representations and distal neurons showing dynamic and context-specific activity. We show in artificial neural network models that varying the recurrence level causes these differences in coding properties to emerge. We confirmed the contribution of recurrent connectivity to functional heterogeneity by characterizing the representational geometry of neural recordings and comparing it with theoretical predictions of neural manifold dimensionality. Our results indicate that local circuit organization, particularly recurrent connectivity among excitatory neurons, plays a key role in shaping complementary spatial representations within the hippocampus.

Enlarged choroid plexus related to atrophy of hippocampal subfield volumes and glymphatic dysfunction in benzodiazepine use disorder.

The aim of this study was to explore the relationship of choroid plexus (CP) volume with hippocampal subregion volume and glymphatic system in patients with benzodiazepine use disorders (BUD). Eighty-four participants were recruited including 23 patients with BUD, 29 patients with chronic insomnia (CI) and 32 healthy controls (HC). The morphological alterations in CP, hippocampal subfield volumes and diffusion tensor image analysis along the perivascular space (DTI-ALPS) index were compared between the three groups and the relationships between CP volume and hippocampal subfield volumes and the glymphatic system were further investigated. Compared with the HC individuals, the CP volumes augmented and hippocampal subfield volumes reduced in patients with BUD (P < .05) but not in patients with CI (P > .05). In patients with BUD, there were extensive relationships between augmented CP volume and decreased hippocampal subfield volumes (P < .05, r = -0.421--0.513). CP volume was negatively related with the DTI-ALPS index (r = -0.582, P = .004) within the BUD group. In patients with BUD, the volume of bilateral cornu ammonis (CA)1 body, molecular layer (ML) body, hippocampal tail, left CA1 head volumes, right dentate gyrus body volumes, and right CA4 body volumes were positively related with the Montreal Cognitive Assessment scores (P < .05, r = 0.422-0.683). Right CA1 and ML body volumes positively related with the Mini-Mental State Examination scores (P < .05, r = 0.503-0.575). The enlarged CP related to atrophy of hippocampal subfield volumes and the glymphatic system dysfunction were shown in BUD patients.

Dynamin-1 is a potential mediator in cancer-related cognitive impairment

Dynamin-1 (DNM1) is crucial for synaptic activity, neurotransmission, and associative memory, positioning it as a potential biomarker of cancer-related cognitive impairment (CRCI), a neurological consequence of cancer treatment characterized by memory loss, poor concentration, and impaired executive function. Through a stepwise approach, this study investigated the role of DNM1 in CRCI pathogenesis, incorporating both human data and animal models. The human study recruited newly diagnosed, chemotherapy-naïve adolescent and young adult cancer and non-cancer controls to complete a cognitive instrument (FACT-Cog) and blood draws for up to three time points. Following that, a syngeneic young-adult WT (C57BL/6) female mouse model of breast cancer chemobrain was developed to study DNM1 expression in the hippocampus. Samples from eighty-six participants with 30 adolescent and young adult (AYA) cancer and 56 non-cancer participants were analyzed. DNM1 levels were 32 ​% lower (P ​= ​0.041) among cancer participants compared to non-cancer prior to treatment. After receiving cytotoxic treatment, cognitively impaired cancer patients were found to have 46 ​% lower DNM1 levels than those without impairment (P ​= ​0.049). In murine breast cancer-bearing mice receiving chemotherapy, we found a greater than 40 ​% decline (P ​< ​0.0001) in DNM1 immunoreactivity in the hippocampal CA1 and CA3 subregions concurrent with a deterioration in spatial recognition memory (P ​< ​0.02), compared to control mice without exposure to cancer and chemotherapy. Consistently observed in both human and animal studies, the downregulation of DNM1 is linked with the onset of CRCI. DNM1 might be a biomarker and therapeutic target for CRCI.

Spatially resolved transcriptomic signatures of hippocampal subregions and Arc-expressing ensembles in active place avoidance memory.

The rodent hippocampus is a spatially organized neuronal network that supports the formation of spatial and episodic memories. We conducted bulk RNA sequencing and spatial transcriptomics experiments to measure gene expression changes in the dorsal hippocampus following the recall of active place avoidance (APA) memory. Through bulk RNA sequencing, we examined the gene expression changes following memory recall across the functionally distinct subregions of the dorsal hippocampus. We found that recall induced differentially expressed genes (DEGs) in the CA1 and CA3 hippocampal subregions were enriched with genes involved in synaptic transmission and synaptic plasticity, while DEGs in the dentate gyrus (DG) were enriched with genes involved in energy balance and ribosomal function. Through spatial transcriptomics, we examined gene expression changes following memory recall across an array of spots encompassing putative memory-associated neuronal ensembles marked by the expression of the IEGs Arc, Egr1, and c-Jun. Within samples from both trained and untrained mice, the subpopulations of spatial transcriptomic spots marked by these IEGs were transcriptomically and spatially distinct from one another. DEGs detected between Arc + and Arc- spots exclusively in the trained mouse were enriched in several memory-related gene ontology terms, including "regulation of synaptic plasticity" and "memory." Our results suggest that APA memory recall is supported by regionalized transcriptomic profiles separating the CA1 and CA3 from the DG, transcriptionally and spatially distinct IEG expressing spatial transcriptomic spots, and biological processes related to synaptic plasticity as a defining the difference between Arc + and Arc- spatial transcriptomic spots.

Elevated circulating levels of GFAP associated with reduced volumes in hippocampal subregions linked to mild cognitive impairment among community-dwelling elderly individuals.

Cerebrospinal fluid biomarkers are challenging to use for diagnosing mild cognitive impairment (MCI) in large populations, and there is an urgent need for new blood biomarkers. The aim of this study is to investigate whether astrocyte activation is correlated with hippocampal atrophy, and to assess the potential of glial fibrillary acidic protein (GFAP) as a biomarker for diagnosing MCI among community-dwelling older individuals. This cross-sectional study included 107 older adults. The levels of GFAP in serum were measured, and the volumetric assessment of gray matter within hippocampal subregions was conducted using Voxel-Based Morphometry (VBM). The relationship between hippocampal subregion volume and blood biomarkers were analyzed using partial correlation. The effectiveness of blood biomarkers in differentiating MCI was assessed using a receiver operating characteristic (ROC) curve. We found that serum GFAP levels were significantly elevated in the MCI group compared to the cognitively normal (CN) group. Additionally, individuals with MCI exhibited a reduction gray matter volume in specific hippocampal subregions. Notably, the right dentate gyrus (DG) and right cornu ammonis (CA) subregions were found to be effective for distinguishing MCI patients from CN individuals. Serum levels of GFAP demonstrate a sensitivity of 65.9% and a specificity of 75.6% in differentiating patients with MCI from CN individuals. Specific atrophy within hippocampal subregions has been observed in the brains of community-dwelling elderly individuals. Elevated levels of circulating GFAP may serve as a sensitive peripheral biomarker indicative of hippocampal-specific cognitive alterations in patients with MCI.

Hippocampal fimbria atrophy and its mediating effect between cerebral small vessel disease and cognitive impairment

We aimed to investigate the relationship between the volume reduction in hippocampal (HP) subregions and cognitive impairment in patients with cerebral small vessel disease (CSVD). Clinical, cognitive, and magnetic resonance imaging data were obtained for 315 participants. The CSVD group included 146 participants with a total CSVD score of 1–4. 169 participants with a total CSVD score of zero were used as control group (CSVD-0). The volume differences of 19 HP subregions between CSVD and CSVD–0 groups were analyzed, and we investigated the hazard factors that might cause subregional volume reduction in HP. Mediation analysis was performed to detect the relationship among HP subregional volumes, CSVD burden, and cognitive function. In our results, significant differences can be found in the volumes of CA4 body, presubiculum–head, presubiculum–body, subiculum–body, GC–ML–DG–head, GC–ML–DG–body, fimbria, and HP tail between CSVD group and control group. Regression analysis showed that fimbria was the most impacted HP subregion by CSVD. And mediation analysis revealed fimbria volume was a mediator variable between total CSVD score and MoCA/SCWT score. These results suggest that the volumes of HP subregions, especially the fimbria, may be effective potential biomarkers for early detecting cognitive impairment in CSVD.

Structural and covariance network alterations of the hippocampus and amygdala in congenital hearing loss children

ObjectiveThe hippocampus and amygdala, as important components of the limbic system, play crucial roles in central remodeling in congenital hearing loss. This study aimed to investigate the morphological integrity and network properties of the subfields of hippocampus and amygdala in children with congenital hearing loss. MethodsA total of 24 children with congenital hearing loss and 17 age- and sex- matched healthy controls (HC) are included in the study. T1-weighted images are analyzed by segmenting the brain into cortical and subcortical regions. Intergroup difference of volumes were explored. Structural covariance networks for the whole brain and hippocampus-amygdala subregions were constructed. Between-group differences of network property are investigated by comparing area under a range of network sparsity. ResultsPatients with congenital hearing loss exhibited significantly larger volumes in the right dentate gyrus and CA3 of the hippocampus. However, there were no significant differences in total hippocampal or showed decreased global efficiency and increased characteristic path length, indicating reduced network integration. Lower betweenness centrality was observed in the left hippocampal fissure in the hearing loss group. The changes in volume and network topological properties are not affected by age and sex. ConclusionChildren with congenital hearing loss display specific volumetric increases in hippocampal subregions, suggesting compensatory adaptations to auditory deprivation. The hippocampus-amygdala network shows significant reorganization, potentially underpinning cognitive and behavioral development issues associated with congenital hearing loss. These findings highlight the importance of targeted neural substrates in understanding and addressing the developmental challenges faced by children with congenital hearing loss.

Intrinsic functional connectivity of right dorsolateral prefrontal cortex and hippocampus subregions relates to emotional and sensory-perceptual properties of intrusive trauma memories.

Trauma-related intrusive memories (TR-IMs), unwanted and vivid, are core symptoms of posttraumatic stress disorder (PTSD). Prior research links voluntary TR-IM suppression to inhibitory control of the right dorsolateral prefrontal cortex (dlPFC) over the hippocampus (HPC). However, the potential relevance of tonic resting-state inhibition has not been examined, nor has the functional differentiation of the anterior and posterior hippocampus (aHPC/HPC). This study examined relationships of TR-IM frequency and properties with resting-state negative coupling between the right dlPFC and right aHPC/pHPC in trauma-exposed individuals with PTSD symptoms. Participants (N=109; 88 female) completed two weeks of ecological momentary assessments capturing TR-IM frequency and properties (intrusiveness, emotional intensity, vividness, visual properties, and reliving). Using 3T resting-state magnetic resonance imaging, participant-specific 4-mm spheres were placed at the right dlPFC voxel most anticorrelated with the right aHPC and pHPC. Quasi-Poisson and linear mixed-effects models assessed relationships of TR-IM frequency and properties with right dlPFC-right aHPC and pHPC anticorrelation. TR-IM emotional intensity was positively associated with right dlPFC-aHPC connectivity, while vividness and visual properties were linked to right dlPFC-pHPC connectivity. No significant associations were found between TR-IM frequency, intrusiveness, or reliving, and anticorrelation with either HPC subregion. This study provides novel insights into the neural correlates of TR-IMs, highlighting the relevance of intrinsic negative coupling between the right dlPFC and aHPC/pHPC to their emotional impact and perceptual properties. Further research on inhibitory mechanisms in this circuit could improve understanding of component processes of intrusive reexperiencing, a severe and treatment-refractory PTSD symptom.

Distinct Disruptions in CA1 and CA3 Place Cell Function in Alzheimer's Disease Mice.

The hippocampus, a critical brain structure for spatial learning and memory, is susceptible to neurodegenerative disorders such as Alzheimer's disease (AD). The APPswe/PSEN1dE9 (APP/PS1) transgenic mouse model is widely used to study the pathology of AD. Although previous research has established AD-associated impairments in hippocampal-dependent learning and memory, the neurophysiological mechanisms underlying these cognitive dysfunctions remain less understood. To address this gap, we investigated the activities of place cells in both CA1 and CA3 hippocampal subregions, which have distinct yet complementary computational roles. Behaviorally, APP/PS1 mice demonstrated impaired spatial recognition memory compared to wild-type (WT) mice in the object location test. Physiologically, place cells in APP/PS1 mice showed deterioration in spatial representation compared to WT. Specifically, CA1 place cells exhibited significant reductions in coherence and spatial information, while CA3 place cells displayed a significant reduction in place field size. Both CA1 and CA3 place cells in APP/PS1 mice also showed significant disruptions in their ability to stably encode the same environment. Furthermore, the burst firing properties of these cells were altered to forms correlated with reduced cognition. Additionally, the theta rhythm was significantly attenuated in CA1 place cells of APP/PS1 mice compared to WT. Our results suggest that distinct alteration in the physiological properties of CA1 and CA3 place cells, coupled with disrupted hippocampal theta rhythm in CA1, may collectively contribute to impaired hippocampal-dependent spatial learning and memory in AD.

Abnormal resting-state functional connectivity of hippocampal subregions in type 2 diabetes mellitus-associated cognitive decline.

Type 2 diabetes mellitus (T2DM) over time predisposes to inflammatory responses and abnormalities in functional brain networks that damage learning, memory, or executive function. The hippocampus is a key region often reporting connectivity abnormalities in memory disorders. Here, we investigated peripheral inflammatory responses and resting-state functional connectivity (RSFC) changes characterized of hippocampal subregions in type 2 diabetes-associated cognitive decline (T2DACD). The study included 16 patients with T2DM, 16 patients with T2DACD and 25 healthy controls (HCs). Subjects were assessed for cognitive performance, tested for the expression of inflammatory factors IL-6, IL-10 and TNF-α in peripheral serum, underwent resting-state functional magnetic resonance imaging scans, and analyzed for RSFC using the hippocampal subregions as seeds. We also calculated the correlation between cognitive performance and RSFC of hippocampal subregion, and analyzed the significantly altered RSFC values of T2DACD for Receiver Operating Characteristic (ROC) analysis. T2DACD patients showed a decline in their ability to complete cognitive assessment scales and experimental paradigms, and T2DM did not show abnormal cognitive performance. IL-6 expression was increased in peripheral serum in both T2DACD and T2DM. Compared with HCs, T2DACD showed abnormalities RSFC of the left anterior hippocampus with left precentral gyrus and left angular gyrus. T2DM showed abnormalities RSFC of the left middle hippocampus with right medial frontal gyrus, right anterior and middle hippocampus with left precuneus, left anterior hippocampus with right precuneus and right posterior middle temporal gyrus. Compared with T2DM, T2DACD showed abnormalities RSFC of the left posterior hippocampus and right middle hippocampus with left precuneus. In addition, RSFC in the left posterior hippocampus with left precuneus of T2DACD was positively correlated with Flanker conflict response time (r=0.766, P=0.001). In the ROC analysis, the significantly altered RSFC values of T2DACD achieved significant performance. T2DACD showed a significant decrease in attentional inhibition and working memory, peripheral pro-inflammatory response increased, and abnormalities RSFC of the hippocampal subregions with default mode network and sensory-motor network. T2DM did not show a significant cognitive decline, but peripheral pro-inflammatory response increased and abnormalities RSFC of the hippocampus subregions occurred in the brain. In addition, the left precuneus may be a key brain region in the conversion of T2DM to T2DACD. The results of this study may provide a basis for the preliminary diagnosis of T2DACD.

Anatomo-functional changes in neural substrates of cognitive memory in developmental amnesia: Insights from automated and manual Magnetic Resonance Imaging examinations.

Despite bilateral hippocampal damage dating to the perinatal or early childhood period and severely impaired episodic memory, patients with developmental amnesia continue to exhibit well-developed semantic memory across the developmental trajectory. Detailed information on the extent and focality of brain damage in these patients is needed to hypothesize about the neural substrate that supports their remarkable capacity for encoding and retrieval of semantic memory. In particular, we need to assess whether the residual hippocampal tissue is involved in this preservation, or whether the surrounding cortical areas reorganize to rescue aspects of these critical cognitive memory processes after early injury. We used voxel-based morphometry (VBM) analysis, automatic (FreeSurfer) and manual segmentation to characterize structural changes in the brain of an exceptionally large cohort of 23 patients with developmental amnesia in comparison with 32 control subjects. Both the VBM and the FreeSurfer analyses revealed severe structural alterations in the hippocampus and thalamus of patients with developmental amnesia. Milder damage was found in the amygdala, caudate, and parahippocampal gyrus. Manual segmentation demonstrated differences in the degree of atrophy of the hippocampal subregions in patients. The level of atrophy in CA-DG subregions and subicular complex was more than 40%, while the atrophy of the uncus was moderate (-24%). Anatomo-functional correlations were observed between the volumes of residual hippocampal subregions in patients and selective aspects of their cognitive performance, viz, intelligence, working memory, and verbal and visuospatial recall. Our findings suggest that in patients with developmental amnesia, cognitive processing is compromised as a function of the extent of atrophy in hippocampal subregions. More severe hippocampal damage may be more likely to promote structural and/or functional reorganization in areas connected to the hippocampus. In this hypothesis, different levels of hippocampal function may be rescued following this variable reorganization. Our findings document not only the extent, but also the limits of circuit reorganization occurring in the young brain after early bilateral hippocampal damage.

Detection of sex-specific glutamate changes in subregions of hippocampus in an early-stage Alzheimer's disease mouse model using GluCEST MRI.

Regional glucose hypometabolism resulting in glutamate loss has been shown as one of the characteristics of Alzheimer's disease (AD). Because the impact of AD varies between the sexes, we utilized glutamate-weighted chemical exchange saturation transfer (GluCEST) magnetic resonance imaging (MRI) for high-resolution spatial mapping of cerebral glutamate and investigated subregional changes in a sex-specific manner. Eight-month-old male and female AD mice harboring mutant amyloid precursor protein (APPNL-F/NL-F: n = 36) and wild-type (WT: n = 39) mice underwent GluCEST MRI, followed by proton magnetic resonance spectroscopy (1H-MRS) in hippocampus and thalamus/hypothalamus using 9.4T preclinical MR scanner. GluCEST measurements revealed significant (p≤0.02) glutamate loss in the entorhinal cortex (% change ± standard error: 8.73±2.12%), hippocampus (11.29±2.41%), and hippocampal fimbriae (19.15±2.95%) of male AD mice. A similar loss of hippocampal glutamate in male AD mice (11.22±2.33%; p = 0.01) was also observed in 1H-MRS. GluCEST MRI detected glutamate reductions in the fimbria and entorhinal cortex of male AD mice, which was not reported previously. Resilience in female AD mice against these changes indicates an intact status of cerebral energy metabolism. Glutamate levels were monitored in different brain regions of early-stage Alzheimer's disease (AD) and wild-type male and female mice using glutamate-weighted chemical exchange saturation transfer (GluCEST) magnetic resonance imaging (MRI). Male AD mice exhibited significant glutamate loss in the hippocampus, entorhinal cortex, and the fimbriae of the hippocampus. Interestingly, female AD mice did not have any glutamate loss in any brain region and should be investigated further to find the probable cause. These findings demonstrate previously unreported sex-specific glutamate changes in hippocampal sub-regions using high-resolution GluCEST MRI.

Neuron collinearity differentiates human hippocampal subregions: a validated deep learning approach.

The hippocampus is heterogeneous in its architecture. It contributes to cognitive processes such as memory and spatial navigation and is susceptible to neurodegenerative disease. Cytoarchitectural features such as neuron size and neuronal collinearity have been used to parcellate the hippocampal subregions. Moreover, pyramidal neuron orientation (orientation of one individual neuron) and collinearity (how neurons align) have been investigated as a measure of disease in schizophrenia. However, a comprehensive quantitative study of pyramidal neuron orientation and collinearity within the hippocampal subregions has not yet been conducted. In this study, we present a high-throughput deep learning approach for the automated extraction of pyramidal neuron orientation in the hippocampal subregions. Based on the pretrained Cellpose algorithm for cellular segmentation, we measured 479 873 pyramidal neurons in 168 hippocampal partitions. We corrected the neuron orientation estimates to account for the curvature of the hippocampus and generated collinearity measures suitable for inter- and intra-individual comparisons. Our deep learning results were validated with manual orientation assessment. This study presents a quantitative metric of pyramidal neuron collinearity within the hippocampus. It reveals significant differences among the individual hippocampal subregions (P < 0.001), with cornu ammonis 3 being the most collinear, followed by cornu ammonis 2, cornu ammonis 1, the medial/uncal subregions and subiculum. Our data establishes pyramidal neuron collinearity as a quantitative parameter for hippocampal subregion segmentation, including the differentiation of cornu ammonis 2 and cornu ammonis 3. This novel deep learning approach could facilitate large-scale multicentric analyses in subregion parcellation and lays groundwork for the investigation of mental illnesses at the cellular level.

Reduced Number of Oligodendrocytes in the Cingulum in Schizophrenia: A Design-Based Stereology Study

Schizophrenia is a severe mental disorder with a neurodevelopmental origin whose pathophysiological processes are poorly understood. Magnetic resonance imaging studies have shown structural alterations, such as volume loss in the temporal lobe, including the hippocampus and amygdala, thalamus, and frontal and temporal cortex, while other studies have found reduced oligodendrocyte numbers in the hippocampal CA4 subregion and dorsolateral prefrontal cortex. The decreased number of oligodendrocytes in CA4 was reported to be related to cognitive deficits. The hippocampus and other parts of the limbic system are connected to the white matter of the cingulum bundle, but it had remained unknown whether schizophrenia affects the number of oligodendrocytes also in the cingulum. In a post mortem study, we applied a design-based stereological approach to investigate the number and density of oligodendrocytes in gallocyanin-stained serial sections in the cingulum of the left and right hemispheres in 12 brains from male donors with schizophrenia and 11 brains from age- and sex-matched controls without mental illness. In addition, we evaluated whether oligodendrocyte numbers and densities in the cingulum correlated with the corresponding data in the hippocampal CA4 subregion of the same brains. In schizophrenia, both the mean volume of the left cingulum (difference, -12.7%) and the mean total oligodendrocyte number in the left cingulum (difference, -19.9%) were statistically significantly lower than in healthy controls (p = 0.049 and p = 0.037). No correlations were found for covariates (age, post mortem interval, fixation time). The individual oligodendrocyte numbers in the right cingulum correlated with those in the right hippocampal CA4, and the individual oligodendrocyte densities in the left cingulum correlated with that in the left hippocampal CA4. This post mortem study shows, for the first time, a statistically significant reduction in the mean volume of and the mean oligodendrocyte number in the left cingulum of patients with schizophrenia. Our results support findings of a reduction of oligodendrocytes in limbic regions in schizophrenia, reinforcing the hypothesis that deficits in myelination and trophic support of long projecting axons play a role in the functional disconnectivity of the hippocampus and prefrontal cortex in schizophrenia.

NS-Pten knockout mice exhibit sex and hippocampal subregion-specific increases in microglia/macrophage density

Seizures induce hippocampal subregion dependent enhancements in microglia/macrophage phagocytosis and cytokine release that may contribute to the development of epilepsy. As a model of hyperactive mTOR induced epilepsy, neuronal subset specific phosphatase and tensin homolog (NS-Pten) knockout (KO) mice exhibit hyperactive mTOR signaling in the hippocampus, seizures that progress with age, and enhanced hippocampal microglia/macrophage activation. However, it is unknown where microglia/macrophages are most active within the hippocampus of NS-Pten KO mice. We quantified the density of IBA1 positive microglia/macrophages in the CA1, CA2/3, and dentate gyrus of NS-Pten KO and wildtype (WT) male and female mice at 4, 10, and 15 weeks of age. NS-Pten KO mice exhibited an overall increase in the number of IBA1 positive microglia/macrophages in each subregion and in the entire hippocampus. After accounting for differences in size, the whole hippocampus of NS-Pten KO mice still exhibited an increased density of IBA1 positive microglia/macrophages. Subregion analyses showed that this increase was restricted to the dentate gyrus of both male and female NS-Pten KO mice and to the CA1 of male NS-Pten KO mice. These data suggest enhanced microglia/macrophage activity may occur in the NS-Pten KO mice in a hippocampal subregion and sex-dependent manner. Future work should seek to determine whether these region-specific increases in microgliosis play a role in the progression of epilepsy in this model.

Objective Sleep Function is Associated with Hippocampal Subfield Volumes in Community-Dwelling Adults.

Sleep patterns often shift as people age, a phenomenon frequently associated with the onset of neurodegenerative conditions. Additionally, distinct alterations occur in brain structure as individuals grow older, particularly within the hippocampus, a region known for its role in cognition and sleep regulation. Yet, how exactly do changes in sleep relate to specific subfields within the hippocampus is still unclear. We conducted a study involving non-demented healthy adults from the Aiginition Longitudinal Biomarker Investigation Of Neurodegeneration (ALBION) cohort. Participants underwent objective sleep measurements using wrist Actiwatch and WatchPAT devices. Further, all participants underwent the same Magnetic Resonance Imaging (MRI) protocol, including a 3D high resolution T1-weighted sequence, on the same 3.0 Tesla MRI scanner using an eight-channel head coil. The study aimed to examine the relationship between objectively measured sleep metrics and the morphology of twenty-two distinct hippocampal subregions. In total, 75 non-demented participants with 63 mean years of age were included in the study. Results indicated that a higher frequency of awakenings during sleep was associated with increased volume in the right presubiculum body (beta = 0.630, p False Discovery Rate (FDR) <0.036). Longer sleep duration showed a tendency to be associated with smaller volumes of the right presubiculum body, hinting at a possible negative impact of prolonged sleep on this brain region. Similar trends were observed regarding sleep apnea and the presubiculum body volume. Further analysis based on age stratification revealed that in younger participants, longer sleep duration was linked to decreased volume of the presubiculum body, while a greater number of awakenings was correlated with increased volume of the same region. Among older participants, higher frequencies of awakenings were associated with larger volumes in various hippocampal subfields. These findings shed light on the complex relationship between sleep characteristics and brain structure, highlighting potential age-related differences. The study provides valuable insights into how sleep disruptions may impact hippocampal morphology and cognitive function of cognitively healthy adults. Further research is warranted to elucidate the underlying mechanisms and implications for neurodegenerative diseases.