Taurine Neuroprotection and Neurogenesis Effect in Chronic Ethanol-Induced Rats.

Taurine (2-aminoethanesulfonic acid) is a non-protein ß-amino acid essential for cellular homeostasis, with antioxidant, anti-inflammatory, and cytoprotective properties that are crucial for life maintenance. This study aimed to evaluate the effects of taurine administration on hippocampal neurogenesis, neuronal preservation, or reverse damage in rats exposed to forced ethanol consumption in an animal model. Wistar rats were treated with ethanol (EtOH) for a 28-day period (5% in the 1st week, 10% in the 2nd week, and 20% in the 3rd and 4th weeks). Two taurine treatment protocols (300 mg/kg i.p.) were implemented: one during ethanol consumption to analyze neuroprotection, and another after ethanol consumption to assess the reversal of ethanol-induced damage. Overall, the results demonstrated that taurine treatment was effective in protecting against deficits induced by ethanol consumption in the dentate gyrus. The EtOH+TAU group showed a significant increase in cell proliferation (145.8%) and cell survival (54.0%) compared to the EtOH+Sal group. The results also indicated similar effects regarding the reversal of ethanol-induced damage 28 days after the cessation of ethanol consumption. The EtOH+TAU group exhibited a significant increase (41.3%) in the number of DCX-immunoreactive cells compared to the EtOH+Sal group. However, this amino acid did not induce neurogenesis in the tissues of healthy rats, implying that its activity may be contingent upon post-injury stimuli.

Ketamine's Amelioration of Fear Extinction in Adolescent Male Mice Is Associated with the Activation of the Hippocampal Akt-mTOR-GluA1 Pathway.

Fear-related disorders, including post-traumatic stress disorder (PTSD), and anxiety disorders are pervasive psychiatric conditions marked by persistent fear, stemming from its dysregulated acquisition and extinction. The primary treatment for these disorders, exposure therapy (ET), relies heavily on fear extinction (FE) principles. Adolescence, a vulnerable period for developing psychiatric disorders, is characterized by neurobiological changes in the fear circuitry, leading to impaired FE and increased susceptibility to relapse following ET. Ketamine, known for relieving anxiety and reducing PTSD symptoms, influences fear-related learning processes and synaptic plasticity across the fear circuitry. Our study aimed to investigate the effects of ketamine (10 mg/kg) on FE in adolescent male C57 BL/6 mice at the behavioral and molecular levels. We analyzed the protein and gene expression of synaptic plasticity markers in the hippocampus (HPC) and prefrontal cortex (PFC) and sought to identify neural correlates associated with ketamine's effects on adolescent extinction learning. Ketamine ameliorated FE in the adolescent males, likely affecting the consolidation and/or recall of extinction memory. Ketamine also increased the Akt and mTOR activity and the GluA1 and GluN2A levels in the HPC and upregulated BDNF exon IV mRNA expression in the HPC and PFC of the fear-extinguished mice. Furthermore, ketamine increased the c-Fos expression in specific brain regions, including the ventral HPC (vHPC) and the left infralimbic ventromedial PFC (IL vmPFC). Providing a comprehensive exploration of ketamine's mechanisms in adolescent FE, our study suggests that ketamine's effects on FE in adolescent males are associated with the activation of hippocampal Akt-mTOR-GluA1 signaling, with the vHPC and the left IL vmPFC as the proposed neural correlates.

Alimentary Treatment with Trehalose in a Pharmacological Model of Alzheimer's Disease in Mice: Effects of Different Dosages and Treatment Regimens.

In the treatment of experimental neurodegeneration with disaccharide trehalose, various regimens are used, predominantly a 2% solution, drunk for several weeks. We studied the effects of different regimens of dietary trehalose treatment in an amyloid-ß (Aß) 25-35-induced murine model of Alzheimer's disease (AD). Aß-treated mice received 2% trehalose solution daily, 4% trehalose solution daily (continuous mode) or every other day (intermittent mode), to drink for two weeks. We revealed the dose-dependent effects on autophagy activation in the frontal cortex and hippocampus, and the restoration of behavioral disturbances. A continuous intake of 4% trehalose solution caused the greatest activation of autophagy and the complete recovery of step-through latency in the passive avoidance test that corresponds to associative long-term memory and learning. This regimen also produced an anxiolytic effect in the open field. The effects of all the regimens studied were similar in Aß load, neuroinflammatory response, and neuronal density in the frontal cortex and hippocampus. Trehalose successfully restored these parameters to the levels of the control group. Thus, high doses of trehalose had increased efficacy towards cognitive impairment in a model of early AD-like pathology. These findings could be taken into account for translational studies and the development of clinical approaches for AD therapy using trehalose.

Fecal microbiota transplantation ameliorates high-fat diet-induced memory impairment in mice.

Gut dysbiosis is linked to metabolic and neurodegenerative diseases and comprises a plausible link between high-fat diet (HFD) and brain dysfunction. Here we show that gut microbiota modulation by either antibiotic treatment for 5 weeks or a brief 3-day fecal microbiota transplantation (FMT) regimen from low-fat (control) diet-fed mice decreased weight gain, adipose tissue hypertrophy, and glucose intolerance induced by HFD in C57BL/6 male mice. Notably, gut microbiota modulation by FMT completely reversed impaired recognition memory induced by HFD, whereas modulation by antibiotics had less pronounced effect. Improvement in recognition memory by FMT was accompanied by decreased HFD-induced astrogliosis in the hippocampal cornu ammonis region. Gut microbiome composition analysis indicated that HFD diminished microbiota diversity compared to control diet, whereas FMT partially restored the phyla diversity. Our findings reinforce the role of the gut microbiota on HFD-induced cognitive impairment and suggest that modulating the gut microbiota may be an effective strategy to prevent metabolic and cognitive dysfunction associated with unfavorable dietary patterns.

SKArred 2 death: neuroinflammatory breakdown of the hippocampus.

A multitude of cellular responses to intrinsic and extrinsic signals converge on macroautophagy/autophagy, a conserved catabolic process that degrades cytoplasmic constituents and organelles in the lysosome, particularly during starvation or stress. In addition to protein degradation, autophagy is deeply interconnected with unconventional protein secretion and polarized sorting at multiple levels within eukaryotic cells. Secretory autophagy (SA) has been recognized as a novel mechanism in which autophagosomes fuse with the plasma membrane and actively participate in the secretion of a series of cytosolic proteins, ranging from tissue remodeling factors to inflammatory molecules of the IL1 family. SA is partially controlled by the glucocorticoid-responsive, HSP90 co-chaperone FKBP5 and members of the SNARE proteins, SEC22B, SNAP23, SNAP29, STX3 and STX4. SA deregulation is implicated in several inflammatory pathologies, including cancer, cell death and degeneration. However, the key molecular mechanisms governing SA and its regulation remain elusive, as does its role in neuroinflammation and neurodegeneration. To further characterize SA and pinpoint its involvement in neuroinflammatory processes, we studied SA-relevant protein interaction networks in mouse brain, microglia and human postmortem brain tissue from control subjects and Alzheimer disease cases. We demonstrate that SA regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling.

Sleep deprivation in adolescent mice impairs long-term memory till early adulthood via suppression of hippocampal astrocytes.

Sleep deficiency is a rampant issue in modern society, serving as a pathogenic element contributing to learning and memory impairment, with heightened sensitivity observed in children. Clinical observations suggest that learning disabilities associated with insufficient sleep during adolescence can persist through adulthood, but experimental evidence for this is lacking. In this study, we examined the impact of early-life sleep deprivation on both short-term and long-term memory, tracking the effects sequentially into adulthood. We employed a modified multiple platform method (MMPM) mouse model to investigate these outcomes. Sleep deprivation induced over a 14-day period, beginning on postnatal day 28 (PND28) in mice, led to significant impairment in long-term memory (while short-term memory remained unaffected) at PND42. Notably, this dysfunction persisted into adulthood at PND85. The specific impairment observed in long-term memory was elucidated through histopathological alterations in hippocampal neurogenesis, as evidenced by bromodeoxyuridine (BrdU) signals, observed both at PND42 and PND85. Furthermore, the hippocampal region exhibited significantly diminished protein expressions of astrocyte, characterized by lowered levels of aquaporin 4 (AQP4), a representative molecule involved in brain clearance processes, and reduced protein expressions of brain-derived neurotrophic factor (BDNF). In conclusion, we have presented experimental evidence indicating that sleep deficiency-related impairment of long-term memory in adolescence can endure into adulthood. The corresponding mechanisms may indicate that the modification of astrocyte-related molecules has led to changes in hippocampal neurogenesis.

Obesogenic diet induces sex-specific alterations of contextual fear memory and associated hippocampal activity in mice.

In addition to metabolic and cardiovascular disorders, obesity is associated with cognitive deficits in humans and animal models. We have previously shown that obesogenic high-fat and sugar diet intake during adolescence (adoHFSD) impairs hippocampus (HPC)-dependent memory in rodents. These results were obtained in males only and it remains to evaluate whether adoHFSD has similar effect in females. Therefore, here, we investigated the effects of adoHFSD consumption on HPC-dependent contextual fear memory and associated brain activation in male and female mice. Exposure to adoHFSD increased fat mass accumulation and glucose levels in both males and females but impaired contextual fear memory only in males. Compared with females, contextual fear conditioning induced higher neuronal activation in the dorsal and ventral HPC (CA1 and CA3 subfields) as well as in the medial prefrontal cortex in males. Also, adoHFSD-fed males showed enhanced c-Fos expression in the dorsal HPC, particularly in the dentate gyrus, and in the basolateral amygdala compared with the other groups. Finally, chemogenetic inactivation of the dorsal HPC rescued adoHFSD-induced memory deficits in males. Our results suggest that males are more vulnerable to the effects of adoHFSD on HPC-dependent aversive memory than females, due to overactivation of the dorsal HPC.

Acrobatic training prevents learning impairments and astrocyte remodeling in the hippocampus of rats undergoing chronic cerebral hypoperfusion: sex-specific benefits.

Background: Chronic cerebral hypoperfusion (CCH) leads to memory and learning impairments associated with degeneration and gliosis in the hippocampus. Treatment with physical exercise carries different therapeutic benefits for each sex. We investigated the effects of acrobatic training on astrocyte remodeling in the CA1 and CA3 subfields of the hippocampus and spatial memory impairment in male and female rats at different stages of the two-vessel occlusion (2VO) model. Methods: Wistar rats were randomly allocated into four groups of males and females: 2VO acrobatic, 2VO sedentary, sham acrobatic, and sham sedentary. The acrobatic training was performed for 4 weeks prior to the 2VO procedure. Brain samples were collected for morphological and biochemical analysis at 3 and 7 days after 2VO. The dorsal hippocampi were removed and prepared for Western blot quantification of Akt, p-Akt, COX IV, cleaved caspase-3, PARP, and GFAP. GFAP immunofluorescence was performed on slices of the hippocampus to count astrocytes and apply the Sholl's circle technique. The Morris water maze was run after 45 days of 2VO. Results: Acutely, the trained female rats showed increased PARP expression, and the 2VO-trained rats of both sexes presented increased GFAP levels in Western blot. Training, mainly in males, induced an increase in the number of astrocytes in the CA1 subfield. The 2VO rats presented branched astrocytes, while acrobatic training prevented branching. However, the 2VO-induced spatial memory impairment was partially prevented by the acrobatic training. Conclusion: Acrobatic training restricted the astrocytic remodeling caused by 2VO in the CA1 and CA3 subfields of the hippocampus. The improvement in spatial memory was associated with more organized glial scarring in the trained rats and better cell viability observed in females.

Chronic Alcohol Exposure Alters the Levels and Assembly of the Actin Cytoskeleton and Microtubules in the Adult Mouse Hippocampus.

BACKGROUND: Alcohol abuse, a prevalent global health issue, is associated with the onset of cognitive impairment and neurodegeneration. Actin filaments (F-actin) and microtubules (MTs) polymerized from monomeric globular actin (G-actin) and tubulin form the structural basis of the neuronal cytoskeleton. Precise regulation of the assembly and disassembly of these cytoskeletal proteins, and their dynamic balance, play a pivotal role in regulating neuronal morphology and function. Nevertheless, the effect of prolonged alcohol exposure on cytoskeleton dynamics is not fully understood. This study investigates the chronic effects of alcohol on cognitive ability, neuronal morphology and cytoskeleton dynamics in the mouse hippocampus. METHODS: Mice were provided ad libitum access to 5% (v/v) alcohol in drinking water and were intragastrically administered 30% (v/v, 6.0 g/kg/day) alcohol for six weeks during adulthood. Cognitive functions were then evaluated using the Y maze, novel object recognition and Morris water maze tests. Hippocampal histomorphology was assessed through hematoxylin-eosin (HE) and Nissl staining. The polymerized and depolymerized states of actin cytoskeleton and microtubules were separated using two commercial assay kits and quantified by Western blot analysis. RESULTS: Mice chronically exposed to alcohol exhibited significant deficits in spatial and recognition memory as evidenced by behavioral tests. Histological analysis revealed notable hippocampal damage and neuronal loss. Decreased ratios of F-actin/G-actin and MT/tubulin, along with reduced levels of polymerized F-actin and MTs, were found in the hippocampus of alcohol-treated mice. CONCLUSIONS: Our findings suggest that chronic alcohol consumption disrupted the assembly of the actin cytoskeleton and MTs in the hippocampus, potentially contributing to the cognitive deficits and pathological injury induced by chronic alcohol intoxication.

Apoptosis of hippocampus and cerebellum induced with brain ischemia reperfusion prevented by 3',4'-dihydroxyflavonol (DiOHF).

The present study aimed to determine the effect of 3',4'-dihydroxyflavonol (DiOHF) on apoptosis in the cerebellum and hippocampus in rats with ischemia-reperfusion. A total of 38 Wistar albino male rats were used. Experimental groups were designed as Group 1-Sham; Group 2-Ischemia-reperfusion (IR), in which animals were anesthetized and carotid arteries ligated for 30 minutes (ischemia) and reperfused 30 minutes; Group 3- IR + DiOHF (10 mg/kg); Group 4- Ischemia + DiOHF (10 mg/kg) + reperfusion; Group 5-DiOHF + IR. DiOHF was supplemented as 10 mg/kg by intraperitoneal injection 30 minutes before IR. Following application, the animals were sacrificed under general anesthetic by cervical dislocation, and the cerebellum and hippocampus tissues were analyzed for apoptosis. IR significantly increased hippocampus and cerebellum apoptosis activity, confirmed by Hematoxylin-Eosin, TUNEL labeling, and Caspase-8 activity. However, these values were significantly suppressed by the administration of DiOHF, especially when used before the ischemia and reperfusion. The results of the study show that increased apoptosis in the cerebellum and hippocampus tissue was inhibited by intraperitoneal DiOHF supplementation.

Involvement of dysregulated hippocampal histone H3K9 methylation at the promoter of the BDNF gene in impaired memory extinction.

RATIONALE: Since the precise mechanisms of posttraumatic stress disorder (PTSD) remain unknown, effective treatment interventions have not yet been established. Impaired extinction of fear memory (EFM) is one of the core symptoms of PTSD and is associated with stress-induced epigenetic change in gene expression. OBJECTIVES: In this study, we examined whether the involvement of histone H3 lysine 9 dimethylation (H3K9me2) in EFM is mediated through brain-derived neurotrophic factor (BDNF) expression in the hippocampus, and whether BIX01294, a selective G9a and GLP histone methyltransferase inhibitor, could be treatment for impaired EFM in an animal model of PTSD. METHODS: The single prolonged stress (SPS) paradigm was used to model PTSD. We measured BDNF mRNA levels by RT-PCR, and H3K9me2 levels in the BDNF gene promoters by chromatin immunoprecipitation-qPCR. After undergoing contextual fear conditioning and hippocampal injection of BIX01294, male rats were subjected to extinction training and extinction testing and their freezing times and BDNF mRNA levels were measured. RESULTS: Compared to sham rats, SPS rats showed decreased BDNF mRNA levels 2 h after extinction training, no significant changes in levels of global H3K9me2 prior to extinction training, and increased levels of H3K9me2 in BDNF gene promoter IV, but not in BDNF gene promoter I. Administration of BIX01294 ameliorated the decrease in BDNF mRNA levels 2 h after extinction training and subsequently alleviated impaired EFM in extinction tests in SPS rats. CONCLUSION: We conclude that reduced hippocampal levels of BDNF mRNA due to increase in H3K9me2 levels may play a role in PTSD-associated EFM impairment, and BIX01294 could be a PTSD treatment option.

An Improved Dyna-Q Algorithm Inspired by the Forward Prediction Mechanism in the Rat Brain for Mobile Robot Path Planning.

The traditional Model-Based Reinforcement Learning (MBRL) algorithm has high computational cost, poor convergence, and poor performance in robot spatial cognition and navigation tasks, and it cannot fully explain the ability of animals to quickly adapt to environmental changes and learn a variety of complex tasks. Studies have shown that vicarious trial and error (VTE) and the hippocampus forward prediction mechanism in rats and other mammals can be used as key components of action selection in MBRL to support "goal-oriented" behavior. Therefore, we propose an improved Dyna-Q algorithm inspired by the forward prediction mechanism of the hippocampus to solve the above problems and tackle the exploration-exploitation dilemma of Reinforcement Learning (RL). This algorithm alternately presents the potential path in the future for mobile robots and dynamically adjusts the sweep length according to the decision certainty, so as to determine action selection. We test the performance of the algorithm in a two-dimensional maze environment with static and dynamic obstacles, respectively. Compared with classic RL algorithms like State-Action-Reward-State-Action (SARSA) and Dyna-Q, the algorithm can speed up spatial cognition and improve the global search ability of path planning. In addition, our method reflects key features of how the brain organizes MBRL to effectively solve difficult tasks such as navigation, and it provides a new idea for spatial cognitive tasks from a biological perspective.

Aerobic exercise training improves memory function through modulation of brain-derived neurotrophic factor and synaptic proteins in the hippocampus and prefrontal cortex of type 2 diabetic rats.

Aims/Introduction: Defective insulin signaling in the brain may disrupt hippocampal neuroplasticity resulting in learning and memory impairments. Thus, this study investigated the effect of aerobic exercise training on cognitive function and synaptic protein markers in diabetic rats. Materials and methods: Twenty male Wistar rats (200-250 g), were fed on high-fat diet and received a low dose of streptozotocin (35 mg/kg, i.p) to induce type 2 diabetes. Then diabetic animals were randomly divided into sedentary and training groups. The exercise training program was treadmill running at 27 m/min for 60 min/day for 8 weeks. One day after the last training session, Morris Water Maze (MWM) task was performed to evaluate spatial learning and memory. Then, the hippocamp and prefrontal cortex tissues were instantly dissected for immunoblotting assay of BDNF, GSK-3ß, p-GSK-3ß, P38, p-P38, ERK1/2, p-ERK1/2, heat shock protein-27 (HSP27), SNAP-25, synaptophysin, and PSD-95. Independent t-test analysis and two-way ANOVA was used to determine the differences under significance level of 0.05 using the 26th version of IBM SPSS statistical software. Results: The results showed that aerobic exercise improved memory as assessed in the MWM task. Moreover, aerobic exercise up-regulated HSP27 and BDNF protein levels in the prefrontal cortex, and hippocampus coincided with robust elevations in SNAP25 and PSD-95 levels. Moreover, exercise reduced phosphorylated P38, while increased p-ERK1/2 and p-GSK-3ß (p). Conclusion: Our findings suggest that aerobic exercise may debilitate the harmful effects of diabetes on the cognitive function possibly through enhancing synaptic protein markers.

Transfer of preclinical study data on the influence of cimicifuga racemosaon functional changes in the hippocampus during menopause.

Menopausal transition in women involves complex neurobiochemical changes linked to ovarian dysfunction, resulting in symptoms like vasomotor symptoms (VMS), sleep disturbances, anxiety, and cognitive impairments. Hormone replacement therapy is the first-line treatment. However, many women are reluctant to use HRT or have contraindications toward HRT and seek for alternatives. Non-hormonal therapies with extracts of Cimicifuga racemosa rhizomes like the isopropanolic extract (iCR, black cohosh) offer a promising alternative. A preclinical pilot study exploring iCR's effects on gene expression in the hippocampus and hypothalamus of ovarectomized (OVX) rats mimicking menopausal conditions identified important signaling pathways and CNS-based contributions to the multitargeted modes of action of iCR. Especially in the hippocampus, iCR compensated effects of OVX on gene expression profiles. These changes are reflected by the genes AVPR1A, GAL, CALCA, HCRT, PNOC, ESR1, ESR2 and TAC3 contributing to the formation of hot flushes or thermoregulation as well as to secondary effects such as blood pressure, metabolism, hormonal regulation, homeostasis, mood regulation, neuroendocrine modulation, regulation of sleep and arousal, and in learning, memory and cognition. To understand the mechanisms in the brain of estrogen-depressed animals (OVX) and subsequent iCR treatment we combined the results of the pilot study with those of up-to-date literature and tried to transfer the current knowledge to humans during menopausal transition and adaptation. Focus was laid on changes in the hippocampal function, that is disturbed by hormonal fluctuations, but can also be brought back into balance by iCR.

Divergent effects of chronic continuous and intermittent social defeat stress on emotional behaviors: Impact on phosphorylated CREB and BDNF protein levels in the rat hippocampus.

Chronic psychosocial stress stands as a significant heterogeneous risk factor for psychiatric disorders. The brain's physiological response to such stress varies based on the frequency and intensity of stress episodes. However, whether stress episodes divergently could affect hippocampal cyclic AMP response element-binding protein (CREB)-brain-derived neurotrophic factor (BDNF) signaling remains unclear, a key regulator of psychiatric symptoms. We aimed to assess how two distinct patterns of social defeat stress exposure impact anxiety- and depression-like behaviors, fear, and hippocampal CREB-BDNF signaling in adult male rats. To explore this, adult male Sprague-Dawley rats were subjected to psychosocial stress using a Resident/Intruder paradigm for ten consecutive days (continuous social defeat stress: [CS]) or ten social defeat stress over the course of 21 days (intermittent social defeat stress [IS]). Behavioral tests (including novelty-suppressed feeding test, forced swimming test, and contextually conditioned fear) were conducted. Protein expression levels of phosphorylated CREB and BDNF in the dorsal and ventral hippocampi were examined. CS led to heightened anxiety-like behavior, fear, and increased levels of phosphorylated CREB in both the dorsal and ventral hippocampi. Conversely, IS resulted in increased anxiety-like behavior and behavioral despair alongside decreased levels of phosphorylated CREB and BDNF, particularly in the dorsal hippocampus. These findings indicate that chronic psychosocial stress divergently affects hippocampal CREB-BDNF signaling and emotional regulation depending on the stress episode. Such insights could enhance our understanding of the molecular basis of the heterogeneity of psychiatric disorders and facilitate the development of innovative treatment approaches to patients with psychiatric disorders.

Enhanced hippocampal LTP but normal NMDA receptor and AMPA receptor function in a rat model of CDKL5 deficiency disorder.

BACKGROUND: Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a Cdkl5-/y rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function and plasticity would be observed in the hippocampus of Cdkl5-/y rats. METHODS: To allow cross-species comparisons of phenotypes associated with the loss of CDKL5, we generated a loss of function mutation in exon 8 of the rat Cdkl5 gene and assessed the impact of the loss of CDLK5 using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology. RESULTS: Our results indicate that CA1 hippocampal long-term potentiation (LTP) is enhanced in slices prepared from juvenile, but not adult, Cdkl5-/y rats. Enhanced LTP does not result from changes in NMDA receptor function or subunit expression as these remain unaltered throughout development. Furthermore, Ca2+ permeable AMPA receptor mediated currents are unchanged in Cdkl5-/y rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability at Schaffer collateral to CA1 PC synapses. CONCLUSIONS: Our data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits contribute to the altered plasticity. LIMITATIONS: This study has focussed on the electrophysiological and anatomical properties of hippocampal CA1 PCs across early postnatal development. Studies involving other brain regions, older animals and behavioural phenotypes associated with the loss of CDKL5 are needed to understand the pathophysiology of CDD.

Regulation by Presynaptic NMDA Receptors of Non-Linear Postsynaptic Summation of the Cortical Input to CA1 Pyramidal Neurons.

Entorhinal cortex (EC) LIII and LII glutamatergic neurons make monosynaptic connections onto distal apical dendrites of hippocampal CA1 and CA2 pyramidal neurons (PNs), respectively, through perforant path (PP) projections. We previously reported that a brief train of PP stimuli evokes strong supralinear temporal summation of excitatory postsynaptic potentials (EPSPs) in CA1 PNs that requires NMDAR activation, with relatively little summation in CA2 PNs in mice of either sex. Here we provide evidence from combined immunogold electron microscopy, cell-type specific genetic deletion and pharmacology that the NMDARs required for supralinear temporal summation of the CA1 PP EPSP are presynaptic, located in the PP terminals. Moreover, we found that the number of NMDARs in PP terminals innervating CA1 PNs is significantly greater than that found in PP terminals innervating CA2 PNs, providing a potential explanation for the difference in temporal summation in these two classes of hippocampal PNs.

Exposing the latent phenotype of Gulf War Illness: examination of the mechanistic mediators of cognitive dysfunction.

Though it has been over 30 years since the 1990-1991 Gulf War (GW), the pathophysiology of Gulf War Illness (GWI), the complex, progressive illness affecting approximately 30% of GW Veterans, has not been fully characterized. While the symptomology of GWI is broad, many symptoms can be attributed to immune and endocrine dysfunction as these critical responses appear to be dysregulated in many GWI patients. Since such dysregulation emerges in response to immune threats or stressful situations, it is unsurprising that clinical studies suggest that GWI may present with a latent phenotype. This is most often observed in studies that include an exercise challenge during which many GWI patients experience an exacerbation of symptoms. Unfortunately, very few preclinical studies include such physiological stressors when assessing their experimental models of GWI, which creates variable results that hinder the elucidation of the mechanisms mediating GWI. Thus, the purpose of this review is to highlight the clinical and preclinical findings that investigate the inflammatory component of GWI and support the concept that GWI may be characterized as having a latent phenotype. We will mainly focus on studies assessing the progressive cognitive impairments associated with GWI and emphasize the need for physiological stressors in future work to create a more unified hypothesis that can identify potential therapeutics for this patient population.

Environmental enrichment: a systematic review on the effect of a changing spatial complexity on hippocampal neurogenesis and plasticity in rodents, with considerations for translation to urban and built environments for humans.

Introduction: Hippocampal neurogenesis is critical for improving learning, memory, and spatial navigation. Inhabiting and navigating spatial complexity is key to stimulating adult hippocampal neurogenesis (AHN) in rodents because they share similar hippocampal neuroplasticity characteristics with humans. AHN in humans has recently been found to persist until the tenth decade of life, but it declines with aging and is influenced by environmental enrichment. This systematic review investigated the impact of spatial complexity on neurogenesis and hippocampal plasticity in rodents, and discussed the translatability of these findings to human interventions. Methods: Comprehensive searches were conducted on three databases in English: PubMed, Web of Science, and Scopus. All literature published until December 2023 was screened and assessed for eligibility. A total of 32 studies with original data were included, and the process is reported in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement and checklist. Results: The studies evaluated various models of spatial complexity in rodents, including environmental enrichment, changes to in-cage elements, complex layouts, and navigational mazes featuring novelty and intermittent complexity. A regression equation was formulated to synthesize key factors influencing neurogenesis, such as duration, physical activity, frequency of changes, diversity of complexity, age, living space size, and temperature. Conclusion: Findings underscore the cognitive benefits of spatial complexity interventions and inform future translational research from rodents to humans. Home-cage enrichment and models like the Hamlet complex maze and the Marlau cage offer insight into how architectural design and urban navigational complexity can impact neurogenesis in humans. In-space changing complexity, with and without physical activity, is effective for stimulating neurogenesis. While evidence on intermittent spatial complexity in humans is limited, data from the COVID-19 pandemic lockdowns provide preliminary evidence. Existing equations relating rodent and human ages may allow for the translation of enrichment protocol durations from rodents to humans.

Critical role of checkpoint kinase 1 in spinal cord injury-induced motor dysfunction in mice.

Spinal cord injury (SCI) is a devastating neurotraumatic condition characterized by severe motor dysfunction and paralysis. Accumulating evidence suggests that DNA damage is involved in SCI pathology. However, the underlying mechanisms remain elusive. Although checkpoint kinase 1 (Chk1)-regulated DNA damage is involved in critical cellular processes, its role in SCI regulation remains unclear. This study aimed to explore the role and potential mechanism of Chk1 in SCI-induced motor dysfunction. Adult female C57BL/6J mice subjected to T9-T10 spinal cord contusions were used as models of SCI. Western blotting, immunoprecipitation, histomorphology, and Chk1 knockdown or overexpression achieved by adeno-associated virus were performed to explore the underlying mechanisms. Levels of p-Chk1 and γ-H2AX (a cellular DNA damage marker) were upregulated, while ferroptosis-related protein levels, including glutathione peroxidase 4 (GPX4) and x-CT were downregulated, in the spinal cord and hippocampal tissues of SCI mice. Functional experiments revealed increased Basso Mouse Scale (BMS) scores, indicating that Chk1 downregulation promoted motor function recovery after SCI, whereas Chk1 overexpression aggravated SCI-induced motor dysfunction. In addition, Chk1 downregulation reversed the SCI-increased levels of GPX4 and x-CT expression in the spinal cord and hippocampus, while immunoprecipitation assays revealed strengthened interactions between p-Chk1 and GPX4 in the spinal cord after SCI. Finally, Chk1 downregulation promoted while Chk1 overexpression inhibited NeuN cellular immunoactivity in the spinal cord after SCI, respectively. Collectively, these preliminary results imply that Chk1 is a novel regulator of SCI-induced motor dysfunction, and that interventions targeting Chk1 may represent promising therapeutic targets for neurotraumatic diseases such as SCI.