Hippocampal Lesions Research Articles

Cognitive flexibility impairment in temporal lobe epilepsy: The impact of epileptic foci lateralization on executive functions

IntroductionTemporal Lobe Epilepsy (TLE) has been associated with memory impairments, which are typically linked to hippocampal and mesial temporal cortex lesions. Considering the presence of extensive bidirectional frontotemporal connections, it can be hypothesized that executive dysfunction in TLE is modulated by the lateralization of the epileptic foci. Material and MethodsA comprehensive neuropsychological executive functions protocol was administered to 63 participants, including 42 individuals with temporal lobe epilepsy (20 with right-TLE and 22 with left-TLE) and 21 healthy controls aged 20–49. ResultsThe results indicate that TLE patients exhibit poorer executive performance compared to healthy controls in working memory (F(2,60) = 4.18, p <.01), planning (F(2,60) = 4.71, p <.05), set shifting (F(2,60) = 10.1, p <.001), phonetic verbal fluency (F(2,60) = 11.71, p <.01) and semantic verbal fluency (F(2,60) = 9.61, p <.001. No significant differences were found in cognitive inhibition. Furthermore, right-TLE patients showed lower performance than left-TLE in set shifting (F(1,61) = 6.45, p <.05), while no significant differences were observed in working memory, planning, inhibition, and verbal fluency. ConclusionsThis research emphasize the importance of considering the lateralization of the temporal lobe focus to achieve a more accurate neuropsychological characterization. The cognitive differences between left and right TLE patients highlight the need for individualized approaches in their treatment and care.

Differential Effects of Neonatal Ventral Hippocampus Lesion on Behavior and Corticolimbic Plasticity in Wistar-Kyoto and Spontaneously Hypertensive Rats.

Dysfunction of the corticolimbic system, particularly at the dendritic spine level, is a recognized core mechanism in neurodevelopmental disorders such as schizophrenia. Neonatal ventral hippocampus lesion (NVHL) in Sprague-Dawley rats induces both a schizophrenia-related behavioral phenotype and dendritic spine pathology (reduced total number and mature spines) in corticolimbic areas, which is mitigated by antipsychotics. However, there is limited information on the impact of rat strain on NVHL outcomes and antipsychotic effects. We compared the behavioral performance in the open field, novel object recognition (NORT), and social interaction tests, as well as structural neuroplasticity with the Golgi-Cox stain in Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) male rats with and without NVHL. Additionally, we explored the effect of the atypical antipsychotic risperidone (RISP). WKY rats with NVHL displayed motor hyperactivity without impairments in memory and social behavior, accompanied by dendritic spine pathology in the neurons of the prefrontal cortex (PFC) layer 3 and basolateral amygdala. RISP treatment reduced motor activity and had subtle and selective effects on the neuroplasticity alterations. In SH rats, NVHL increased the time spent in the border area during the open field test, impaired the short-term performance in NORT, and reduced social interaction time, deficits that were corrected after RISP administration. The NVHL caused dendritic spine pathology in the PFC layers 3 and 5 of SH rats, which RISP treatment ameliorated. Our results support the utility of the NVHL model for exploring neuroplasticity mechanisms in schizophrenia and understanding pharmacotherapy.

Analysis of hippocampus in rats with acute brain ischemia-reperfusion injury treated with leuprolide acetate, an agonist of GnRH.

The hippocampus is highly vulnerable to damage in the brain ischemia-reperfusion injury model. Leuprolide acetate has been shown to promote neurological recovery after injury in various regions of the central nervous system. The objective of this study was to assess the histology of the hippocampus and the expression of neuronal recovery markers, specifically the 200 kDa neurofilaments and the myelin basic protein, in rats with brain ischemia-reperfusion injury treated with leuprolide acetate. The rats were divided into three groups: Sham, ischemia-reperfusion with saline solution, and ischemia-reperfusion treated with leuprolide acetate. Coronal brain slices were obtained and stained with hematoxylin-eosin. The histological analysis involved quantifying the number of neurons in the hippocampal regions CA1, CA3 and DG. The myelin basic protein and neurofilaments were quantified using western blot. The number of neurons in CA1 and DG was significantly higher in the leuprolide acetate group compared to the untreated group. Additionally, the expression of neurofilament and myelin basic protein markers was significantly increased in rats treated with leuprolide acetate compared to the untreated rats. Leuprolide acetate promotes the recovery of hippocampal neurons in an acute brain ischemia-reperfusion injury model. These findings suggest that leuprolide acetate could be a potential therapeutic intervention for reversing damage in hippocampal ischemic lesions.

Proteomic analysis by 4D label-free MS-PRM identified that Nptx1, Ptpmt1, Slc25a11, and Cpt1c are involved in diabetes-associated cognitive dysfunction

Background Diabetes-associated cognitive dysfunction (DACD) is a chronic ailment that exerts a substantial influence on the overall well-being of individuals. The hippocampus assumes a pivotal role in the progression and sustenance of cognitive impairment. The identification of differentially expressed proteins (DEPs) in the hippocampus is crucial for understanding the mechanisms of DACD. Methods A rat model of DACD was established by a high-fat diet combined with streptozotocin intraperitoneal injection. The Morris water maze (MWM), hematoxylin and eosin (H&E) staining, Nissl staining, and transmission electron microscope (TEM) were performed on the rats. The proteins expressed in the hippocampus were detected using 4D label-free quantitative proteomics. Four DEPs, namely Nptx1, Ptpmt1, Slc25a11, and Cpt1c, were validated using parallel reaction monitoring (PRM). Result Our study found that hippocampal lesions were present in the DACD rat models. There were 59 up-regulated and 98 down-regulated DEPs in the Model group compared to the Control group. We found that the levels of Nptx1, Ptpmt1, Slc25a11, and Cpt1c were elevated in the Model group, which are important for cell mitochondrial function. It should be noted that in our study, we only used PRM to validate the expression of these proteins. However, more evidence is needed to establish the relationship between these protein changes and DACD. Conclusion Our research results may provide further insight into the molecular pathology of hippocampal injury in DACD. In addition, further studies and clinical trials are required to confirm our findings and establish a more conclusive molecular mechanism for DACD.

Absence of higher order association based mnemonic percepts in Alzheimer’s disease

AbstractBackgroundEveryday learning involves higher order associations (HOA) across new and old experiences when a response is encoded without reinforcement. However, the neural and behavioral mechanisms of HOA‐based learning during remote memory retrieval are unknown.MethodWe implement novel behavior to test the neural and behavioral mechanisms of HOA during remote memory retrieval. We train the animals in context A and sequentially test these animals for remote retrieval in same (A), similar(B), or novel (C) context, while invoking HOA‐based learning to investigate the neural correlates of HOA using hippocampal lesions, chemo genetics, and 2‐photon in vivo imaging.ResultCohorts of AD mice show overall differences in freezing vs. controls (1‐w ANOVA, P&gt;F = 1.48E‐11, n = 5). Subgroups of AD (n = 12) and control (n = 14) mice during remote retrieval in BAC show overall difference (1‐w ANOVA, P&gt;F = 4.59E‐6), with AD mice showing similar freezing in B and A (t = ‐0.70). Freezing in C is different for control mice in ABC vs. BAC order (P&gt;F = 1.84E‐8, n = 5,14) whereas, interestingly, AD mice show similar increase in C freezing on Day3 of remote testing for ABC vs. BAC testing orders (P&gt;F = n.s, n = 5, 12). AD (n = 3) and WT (n = 4) mice were trained with tone and tested after 70 days. Freezing before and during the tone was significantly different for WT mice (1‐t Paired‐sample‐t‐test, P&lt;t = 0.015). Discrimination‐index indicates better discrimination ability for WT as compared to AD mice (1‐t two‐sample‐t‐test, P&lt;t = 0.026). We further evaluate the neural correlates of such behavior in WT mice by timed‐hippocampus lesions, chemogenetic inhibition of PVcre interneurons in dorsal CA1, and longitudinal 2p‐in vivo imaging.ConclusionWe find that PVcre neurons are necessary for HOA during remote learning in WT mice and there is a loss of specificity in HOA‐based new learning during remote memory retrieval with AD mice. Our novel findings establish a basis for early behavioral and neural markers for predicting AD diagnosis to assist with early medical interventions.

Plasma neurofilament light and brain volumetric outcomes among middle‐aged urban adults

AbstractBackgroundElevated plasma neurofilament light chain (NfL) is associated with dementia, but the specific underlying mechanisms are largely unknown. We examined cross‐sectional and longitudinal relationships of plasma NfL with selected brain structural magnetic resonance imaging (sMRI) prognostic markers of dementia, namely global and cortical brain, hippocampal and white matter lesion volumes (WMLV).MethodData were extracted from three prospective visits within the Healthy Aging in Neighborhoods of Diversity Across the Life Span (HANDLS) study, selecting participants with complete v1 (2004‐2009) and v2 (2009‐2013) plasma NfL exposure and ancillary sMRI data at vscan (2011‐2015, n = 179, mean v1 to vscan time: 5.4y). Multivariable‐adjusted linear regression models were conducted, overall, by sex, and by race, correcting for multiple testing with q‐values.ResultNfL(v1) (Loge transformed) had a moderately strong association with larger WMLV at follow‐up vscan visit, after a period of 5‐6 years of follow‐up, overall (β = +2.131±0.660, b = +0.29, p = 0.001, q = 0.0029). Moreover, a 1 unit increase in NfLv2 was linked to a left hippocampal volume that was lower by 125 mm3 (p = 0.004, q = 0.015), using minimally adjusted models and mainly among males. Associations were largely unaltered by further adjustment for downstream health‐related factors.ConclusionIn summary, plasma NfL may be an independent medium‐term (within 5 years) marker for increase in WMLV, and a short term (within 1 year) marker for smaller hippocampal volumes normalized to the intracranial volume, independently of other confounding factors. Therefore, plasma NfL holds promise as a blood‐based marker to predict future subclinical brain pathologies in middle‐aged adults.

Cortical reactivation of spatial and non-spatial features coordinates with hippocampus to form a memory dialogue

Episodic memories comprise diverse attributes of experience distributed across neocortical areas. The hippocampus is integral to rapidly binding these diffuse representations, as they occur, to be later reinstated. However, the nature of the information exchanged during this hippocampal-cortical dialogue remains poorly understood. A recent study has shown that the secondary motor cortex carries two types of representations: place cell-like activity, which were impaired by hippocampal lesions, and responses tied to visuo-tactile cues, which became more pronounced following hippocampal lesions. Using two-photon Ca2+ imaging to record neuronal activities in the secondary motor cortex of male Thy1-GCaMP6s mice, we assessed the cortical retrieval of spatial and non-spatial attributes from previous explorations in a virtual environment. We show that, following navigation, spontaneous resting state reactivations convey varying degrees of spatial (trajectory sequences) and non-spatial (visuo-tactile attributes) information, while reactivations of non-spatial attributes tend to precede reactivations of spatial representations surrounding hippocampal sharp-wave ripples.

Multisensory input modulates memory-guided spatial navigation in humans

Efficient navigation is supported by a cognitive map of space. The hippocampus plays a key role for this map by linking multimodal sensory information with spatial memory representations. However, in human navigation studies, the full range of sensory information is often unavailable due to the stationarity of experimental setups. We investigated the contribution of multisensory information to memory-guided spatial navigation by presenting a virtual version of the Morris water maze on a screen and in an immersive mobile virtual reality setup. Patients with hippocampal lesions and matched controls navigated to memorized object locations in relation to surrounding landmarks. Our results show that availability of multisensory input improves memory-guided spatial navigation in both groups. It has distinct effects on navigational behaviour, with greater improvement in spatial memory performance in patients. We conclude that congruent multisensory information shifts computations to extrahippocampal areas that support spatial navigation and compensates for spatial navigation deficits.

Microbiota-indole 3-propionic acid-brain axis mediates abnormal synaptic pruning of hippocampal microglia and susceptibility to ASD in IUGR offspring

BackgroundAutism spectrum disorder (ASD) has been associated with intrauterine growth restriction (IUGR), but the underlying mechanisms are unclear.ResultsWe found that the IUGR rat model induced by prenatal caffeine exposure (PCE) showed ASD-like symptoms, accompanied by altered gut microbiota and reduced production of indole 3-propionic acid (IPA), a microbiota-specific metabolite and a ligand of aryl hydrocarbon receptor (AHR). IUGR children also had a reduced serum IPA level consistent with the animal model. We demonstrated that the dysregulated IPA/AHR/NF-κB signaling caused by disturbed gut microbiota mediated the hippocampal microglia hyperactivation and neuronal synapse over-pruning in the PCE-induced IUGR rats. Moreover, postnatal IPA supplementation restored the ASD-like symptoms and the underlying hippocampal lesions in the IUGR rats.ConclusionsThis study suggests that the microbiota-IPA-brain axis regulates ASD susceptibility in PCE-induced IUGR offspring, and supplementation of microbiota-derived IPA might be a promising interventional strategy for ASD with a fetal origin.21xhjpDoyB4JmdH7kH-NGnVideo

Hippocampal and neocortical BRAF mutant non-expansive lesions in focal epilepsies.

Mesial Temporal Lobe Epilepsy-associated Hippocampal Sclerosis (MTLE-HS) is a syndrome associated with various aetiologies. We previously identified CD34-positive extravascular stellate cells (CD34+ cells) possibly related to BRAFV600E oncogenic variant in a subset of MTLE-HS. We aimed to identify the BRAFV600E oncogenic variants and characterise the CD34+ cells. We analysed BRAFV600E oncogenic variant by digital droplet Polymerase Chain Reaction in 53 MTLE-HS samples (25 with CD34+ cells) and 9 non-expansive neocortical lesions resected during epilepsy surgery (5 with CD34+ cells). Ex vivo multi-electrode array recording, immunolabelling, methylation microarray and single nuclei RNAseq were performed on BRAFwildtype MTLE-HS and BRAFV600E mutant non-expansive lesion of hippocampus and/or neocortex. We identified a BRAFV600E oncogenic variant in 5 MTLE-HS samples with CD34+ cells (19%) and in 5 neocortical samples with CD34+ cells (100%). Single nuclei RNAseq of resected samples revealed two unique clusters of abnormal cells (including CD34+ cells) associated with senescence and oligodendrocyte development in both hippocampal and neocortical BRAFV600E mutant samples. The co-expression of the oncogene-induced senescence marker p16INK4A and the outer subventricular zone radial glia progenitor marker HOPX in CD34+ cells was confirmed by multiplex immunostaining. Pseudotime analysis showed that abnormal cells share a common lineage from progenitors to myelinating oligodendrocytes. Epilepsy surgery led to seizure freedom in 8 of the 10 patients with BRAF mutant lesions. BRAFV600E underlies a subset of MTLE-HS and epileptogenic non-expansive neocortical focal lesions. Detection of the oncogenic variant may help diagnosis and opens perspectives for targeted therapies.

Hippocampal damage causes retrograde amnesia for objects' visual, but not odour, properties in male rats.

Damage to the hippocampus produces profound retrograde amnesia, but odour and object discrimination memories can be spared in the retrograde direction. Prior lesion studies testing retrograde amnesia for object/odour discriminations are problematic due to sparing of large parts of the hippocampus, which may support memory recall, and/or the presence of uncontrolled, distinctive odours that may support object discrimination. To address these issues, we used a simple object discrimination test to assess memory in male rats. Two visually distinct objects, paired with distinct odour cues, were presented. One object was associated with a reward. Following training, neurotoxic hippocampal lesions were made using N-methyl-D-aspartate (NMDA). The rats were then tested on the preoperatively learned object discrimination problem, with and without the availability of odour or visual cues during testing. The rats were also postoperatively trained on a new object discrimination problem. Lesion sizes ranged from 67% to 97% of the hippocampus (average of 87%). On the preoperatively learned discrimination problem, the rats with hippocampal lesions showed preserved object discrimination memory when tested in the dark (i.e., without visual cues) but not when the explicit odour cues were removed from the objects. Hippocampal lesions increased the number of trials required to reach criterion but did not prevent rats from solving the postoperatively learned discrimination problem. Our results support the idea that long-term memories for odours, unlike recall of visual properties of objects, do not depend on the hippocampus in rats, consistent with previous observations that hippocampal damage does not cause retrograde amnesia for odour memories.

The non-conventional edible plant foroba (Parkia biglobosa) has anti-obesity effect, improves lipid peroxidation and reverses colon and hippocampal lesions in healthy and obese rats

We evaluated the Parkia biglobosa pulp (PB) effects on food intake, body composition and oxidative and inflammatory parameters related to gut and brain of rats. A total of 32 male Wistar rats were randomised into four groups: healthy (HG), obese (OG); and healthy (HPB) and obese (OPB) groups with PB (400 mg/kg body weight). The rats consumed a control or cafeteria diet for 16 weeks. Body weight, food intake, bacteria count, organic acids in faeces were quantified. NF-κB and oxidative parameters were evaluated in the colon and hippocampus. PB contains fibres, 3,4-dihydroxybenzoic acid, catechin, and myricetin. PB treatment decreased fat mass and energy intake; increased the count of lactic acid bacteria and faecal organic acids, improved lipid peroxidation and reversed colon and hippocampal lesions, with reduction the NF-κB in OPB colon. PB has anti-obesity effect with potential to modulation gut-brain axis, mainly via blocking the activation of NF-κB.

Aripiprazole attenuates the medial prefrontal cortex morphological and biochemical alterations in rats with neonatal ventral hippocampus lesion

Schizophrenia is a neurodevelopmental disorder characterized by a loss of dendritic spines in the medial prefrontal cortex (mPFC). Multiple subclinical and clinical studies have evidenced the ability of antipsychotics to improve neuroplasticity. In this study, it was evaluated the effect of the atypical antipsychotic aripiprazole (ARI) on the behavioral and mPFC neuronal disturbances of rats with neonatal ventral hippocampus lesion (nVHL), which is a heuristic developmental model relevant to the study of schizophrenia. ARI attenuated open field hyperlocomotion in the rats with nVHL. Also, ARI ameliorated structural neuroplasticity disturbances of the mPFC layer 3 pyramidal cells, but not in the layer 5 neurons. These effects can be associated with the ARI capability of increasing brain-derived neurotrophic factor (BDNF) levels. Moreover, in the animals with nVHL, ARI attenuated the immunoreactivity for some oxidative stress-related molecules such as the nitric oxide synthase 2 (NOS-2), 3-nitrotyrosine (3-NT), and cyclooxygenase 2 (COX-2), as well as the reactive astrogliosis in the mPFC. These results contribute to current knowledge about the neurotrophic, anti-inflammatory, and antioxidant properties of antipsychotics which may be contributing to their clinical effects and envision promising therapeutic targets for the treatment of schizophrenia.

The Hippocampus Contributes to Temporal Discounting When Delays and Rewards Are Experienced in the Moment.

Temporal discounting (TD) represents the mental devaluation of rewards that are available after a delay. Whether the hippocampus is critical for TD remains unclear, with marked discrepancies between animal and human studies: although animals with discrete hippocampal lesions display impaired TD, human participants with similar lesions show intact performance on classic intertemporal choice tasks. A candidate explanation for this discrepancy is that delays and rewards are experienced in the moment in animal studies but tend to be hypothetical in human studies. We tested this hypothesis by examining the performance of amnesic participants with hippocampal lesions (one female, six males) on a novel experiential intertemporal choice task that used interesting photographs occluded by thick lines as rewards (Patt et al., 2021). Using a logistic function to model indifference points data, we compared performance to that on a classic intertemporal choice task with hypothetical outcomes. Participants with hippocampal lesions displayed impaired patterns of choices in the experiential task but not in the hypothetical task. Specifically, hippocampal lesions were associated with decreased amplitude of the delay-reward trade-off, with persistent choice of the delayed option despite delay increase. These results help explain previous discrepancies across animal and human studies, indicating that the hippocampus plays a critical role in temporal discounting when the outcomes of decisions are experienced in the moment, but not necessarily when they are hypothetical.SIGNIFICANCE STATEMENT Impaired temporal discounting (TD) has been related to maladaptive behaviors, including substance dependence and nonadherence to medical treatment. There is consensus that TD recruits the brain valuation network but whether the hippocampal memory system is additionally recruited remains unclear. This study examined TD in hippocampal amnesia, providing a unique opportunity to explore the role of the hippocampus in cognition. Whereas most human studies have used hypothetical outcomes, this study used a novel experiential task with real-time delays and rewards. Results demonstrated hippocampal involvement in the experiential task, but not in a classic hypothetical task administered for comparison. These findings elucidate previous discrepancies between animal and human TD studies. This reconciliation is critical as animals serve as models of human neurocognition.

A fully automated home cage for long-term continuous phenotyping of mouse cognition and behavior

Automated home-cage monitoring systems present a valuable tool for comprehensive phenotyping of natural behaviors. However, current systems often involve complex training routines, water or food restriction, and probe a limited range of behaviors. Here, we present a fully automated home-cage monitoring system for cognitive and behavioral phenotyping in mice. The system incorporates T-maze alternation, novel object recognition, and object-in-place recognition tests combined with monitoring of locomotion, drinking, and quiescence patterns, all carried out over long periods. Mice learn the tasks rapidly without any need for water or food restrictions. Behavioral characterization employs a deep convolutional neural network image analysis. We show that combined statistical properties of multiple behaviors can be used to discriminate between mice with hippocampal, medial entorhinal, and sham lesions and predict the genotype of an Alzheimer's disease mouse model with high accuracy. This technology may enable large-scale behavioral screening for genes and neural circuits underlying spatial memory and other cognitive processes.

Structural plasticity in the entorhinal and perirhinal cortices following hippocampal lesions in rhesus monkeys.

Immature neurons expressing the Bcl2 protein are present in various regions of the mammalian brain, including the amygdala and the entorhinal and perirhinal cortices. Their functional role is unknown but we have previously shown that neonatal and adult hippocampal lesions increase their differentiation in the monkey amygdala. Here, we assessed whether hippocampal lesions similarly affect immature neurons in the entorhinal and perirhinal cortices. Since Bcl2-positive cells were found mainly in areas Eo, Er, and Elr of the entorhinal cortex and in layer II of the perirhinal cortex, we also used Nissl-stained sections to determine the number and soma size of immature and mature neurons in layer III of area Er and layer II of area 36 of the perirhinal cortex. We found different structural changes in these regions following hippocampal lesions, which were influenced by the time of the lesion. In neonate-lesioned monkeys, the number of immature neurons in the entorhinal and perirhinal cortices was generally higher than in controls. The number of mature neurons was also higher in layer III of area Er of neonate-lesioned monkeys but no differences were found in layer II of area 36. In adult-lesioned monkeys, the number of immature neurons in the entorhinal cortex was lower than in controls but did not differ from controls in the perirhinal cortex. The number of mature neurons in layer III of area Er did not differ from controls, but the number of small, mature neurons in layer II of area 36 was lower than in controls. In sum, hippocampal lesions impacted populations of mature and immature neurons in discrete regions and layers of the entorhinal and perirhinal cortices, which are interconnected with the amygdala and provide major cortical inputs to the hippocampus. These structural changes may contribute to some functional recovery following hippocampal injury in an age-dependent manner.

Prednisolone improves hippocampal regeneration after trimethyltin-induced neurodegeneration in association with prevention of T lymphocyte infiltration.

The endogenous regenerative capacity of the brain is quite weak; however, a regenerative reaction, the production of new neurons (neurogenesis), has been reported to occur in brain lesions. In addition, leukocytes are well known to infiltrate brain lesions. Therefore, leukocytes would also have a link with regenerative neurogenesis; however, their role has not been fully elucidated. In this study, we investigated leukocyte infiltration and its influence on brain tissue regeneration in a trimethyltin (TMT)-injected mouse model of hippocampal regeneration. Immunohistochemically, CD3-positive T lymphocytes were found in the hippocampal lesion of TMT-injected mice. Prednisolone (PSL) treatment inhibited T lymphocyte infiltration and increased neuronal nuclei (NeuN)-positive mature neurons and doublecortin (DCX)-positive immature neurons in the hippocampus. Investigation of bromodeoxyuridine (BrdU)-labeled newborn cells revealed the percentage of BrdU/NeuN- and BrdU/DCX-positive cells increased by PSL treatment. These results indicate that infiltrated T lymphocytes prevent brain tissue regeneration by inhibiting hippocampal neurogenesis.

Transcriptome Profiling of Hippocampus After Cerebral Hypoperfusion in Mice.

Chronic cerebral hypoperfusion (CCH) is considered to be one of the major mechanism in the pathogenesis of vascular cognitive impairment (VCI). Increased inflammatory cells, particularly microglia, often parallel hypoperfusion-induced gray matter damage such as hippocampal lesions, but the exact mechanism remains largely unknown. To understand the pathological mechanisms, we analyzed hippocampus-specific transcriptome profiles after cerebral hypoperfusion. The mouse hypoperfusion model was induced by employing the 0.16/0.18mm bilateral common carotid artery stenosis (BCAS) procedure. Cerebral blood flow (CBF) was assessed after 3-week hypoperfusion. Pathological changes were evaluated via hematoxylin staining and immunofluorescence staining. RNA-sequencing (RNA-seq) was performed using RNA samples of sham- or BCAS-operated mice, followed by quantitative real-time PCR (qRT-PCR) validation. We found that the 0.16/0.18mm BCAS induced decreased CBF, hippocampal neuronal loss, and microglial activation. Furthermore, GSEA between sham and BCAS mice showed activation of interferon-beta signaling along with inflammatory immune responses. In addition, integrative analysis with published single-cell RNA-seq revealed that up-regulated differentially expressed genes (DEGs) were enriched in a distinct cell type of "microglia," and down-regulated DEGs were enriched in "CA1 pyramidal," not in "interneurons" or "S1 pyramidal." This database of transcriptomic profiles of BCAS-hypoperfusion will be useful for future studies to explore potential targets for vascular cognitive dysfunction.

Liver-expressed antimicrobial peptide 2 elevation contributes to age-associated cognitive decline.

Elderly individuals frequently report cognitive decline, while various studies indicate hippocampal functional declines with advancing age. Hippocampal function is influenced by ghrelin through hippocampus-expressed growth hormone secretagogue receptor (GHSR). Liver-expressed antimicrobial peptide 2 (LEAP2) is an endogenous GHSR antagonist that attenuates ghrelin signaling. Here, we measured plasma ghrelin and LEAP2 levels in a cohort of cognitively normal individuals older than 60 and found that LEAP2 increased with age while ghrelin (also referred to in literature as "acyl-ghrelin") marginally declined. In this cohort, plasma LEAP2/ghrelin molar ratios were inversely associated with Mini-Mental State Examination scores. Studies in mice showed an age-dependent inverse relationship between plasma LEAP2/ghrelin molar ratio and hippocampal lesions. In aged mice, restoration of the LEAP2/ghrelin balance to youth-associated levels with lentiviral shRNA Leap2 downregulation improved cognitive performance and mitigated various age-related hippocampal deficiencies such as CA1 region synaptic loss, declines in neurogenesis, and neuroinflammation. Our data collectively suggest that LEAP2/ghrelin molar ratio elevation may adversely affect hippocampal function and, consequently, cognitive performance; thus, it may serve as a biomarker of age-related cognitive decline. Moreover, targeting LEAP2 and ghrelin in a manner that lowers the plasma LEAP2/ghrelin molar ratio could benefit cognitive performance in elderly individuals for rejuvenation of memory.

Contactin-associated protein-2 and anti-aquaporin-4 antibody positive autoimmune encephalitis secondary to herpes simplex encephalitis: A case report.

Recurrent herpes simplex encephalitis (HSE) can easily induce autoimmune encephalitis (AE). However, there are few reports of anti-contactin-associated protein-2 (CASPR2)-related encephalitis, especially with positive anti-aquaporin 4 (AQP4) antibodies. A 14-year-old boy was admitted to the Department of Neurology of the First Affiliated Hospital of Kunming Medical University for "headache, dizziness, and fever for four days" with positive anti-CASPR2 and anti-AQP4 antibodies in the cerebrospinal fluid. Cranial MRI showed lesions in the right hippocampus, amygdala, and insular lobe, with local sulcus enhancement in the right insular, temporal, and frontal lobes. The fluid-attenuated inversion recovery was significantly enhanced. Human herpes virus type I was detected by cerebrospinal fluid metagenomic testing. The patient was diagnosed with AE secondary to HSE, with positive anti-CASPR2 and anti-AQP4 antibodies. After 2 weeks of immunoglobulin and methylprednisolone immunomodulatory therapy, acyclovir antivirus, mannitol dehydration, reducing intracranial pressure, and other symptomatic support therapy. The patient's symptoms significantly improved, with no complaints of discomfort, and he was discharged for observation. The patient was followed up a month after discharge and had no complaints of discomfort. CASPR2 and anti-aquaporin-4 antibody-positive AE have not been reported to be positive. This case will raise awareness of CASPR2 and anti-aquaporin-4 antibody-positive AE secondary to HSE, strengthen diagnostic capacities, and provide advice to treat it.