Hippocampal Gene Research Articles

The Utility of Prolonged Chronic Unpredictable Stress to Study the Effects of Chronic Fluoxetine, Eicosapentaenoic Acid, and Lipopolysaccharide on Anxiety-Like Behavior and Hippocampal Transcriptomic Responses in Male Rats.

Chronic stress is a common trigger of multiple neuropsychiatric illnesses. Animal models are widely used to study stress-induced brain disorders and their interplay with neuroinflammation and other neuroimmune processes. Here, we apply the prolonged 12-week chronic unpredictable stress (PCUS) model to examine rat behavioral and hippocampal transcriptomic responses to stress and to chronic 4-week treatment with a classical antidepressant fluoxetine, an anti-inflammatory agent eicosapentaenoic acid (EPA), a pro-inflammatory agent lipopolysaccharide and their combinations. Overall, PCUS evoked anxiety-like behavioral phenotype in rats, corrected by chronic fluoxetine (alone or combined with other drugs), and EPA. PCUS also evoked pronounced transcriptomic responses in rat hippocampi, involving > 200 differentially expressed genes. While pharmacological manipulations did not affect hippocampal gene expression markedly, Gpr6, Drd2 and Adora2a were downregulated in stressed rats treated with fluoxetine, EPA and fluoxetine + EPA, suggesting their respective protein products (G protein-coupled receptor 6, dopamine D2 receptor and adenosine A2A receptor) as potential evolutionarily conserved targets under chronic stress. Overall, these findings support the validity of rat PCUS paradigm as a useful model to study stress-related anxiety pathogenesis, and call for further research probing how various conventional and novel drugs may (co)modulate behavioral and neurotranscriptomic biomarkers of chronic stress.

Unveiling the Mechanisms of a Remission in Major Depressive Disorder (MDD)-like Syndrome: The Role of Hippocampal Palmitoyltransferase Expression and Stress Susceptibility.

Post-translational modifications of proteins via palmitoylation, a thioester linkage of a 16-carbon fatty acid to a cysteine residue, reversibly increases their affinity for cholesterol-rich lipid rafts in membranes, changing their function. Little is known about how altered palmitoylation affects function at the systemic level and contributes to CNS pathology. However, recent studies suggested a role for the downregulation of palmitoyl acetyltransferase (DHHC) 21 gene expression in the development of Major Depressive Disorder (MDD)-like syndrome. Here, we sought to investigate how susceptibility (sucrose preference below 65%) or resilience (sucrose preference > 65%) to stress-induced anhedonia affects DHHC gene expression in the hippocampus of C57BL/6J mice during the phase of spontaneous recovery from anhedonia. Because MDD is a recurrent disorder, it is important to understand the molecular mechanisms underlying not only the symptomatic phase of the disease but also a state of temporary remission. Indeed, molecular changes associated with the application of pharmacotherapy at the remission stage are currently not well understood. Therefore, we used a mouse model of chronic stress to address these questions. The stress protocol consisted of rat exposure, social defeat, restraint stress, and tail suspension. Mice from the stress group were not treated, received imipramine via drinking water (7 mg/kg/day), or received intraperitoneal injections of dicholine succinate (DS; 25 mg/kg/day) starting 7 days prior to stress and continuing during a 14-day stress procedure. Controls were either untreated or treated with either of the two drugs. At the 1st after-stress week, sucrose preference, forced swim, novel cage, and fear-conditioning tests were carried out; the sucrose test and 5-day Morris water maze test followed by a sacrifice of mice on post-stress day 31 for all mice were performed. Transcriptome Illumina analysis of hippocampi was carried out. Using the RT-PCR, the hippocampal gene expression of Dhhc3, Dhhc7, Dhhc8, Dhhc13, Dhhc14, and Dhhc21 was studied. We found that chronic stress lowered sucrose preference in a subgroup of mice that also exhibited prolonged floating behavior, behavioral invigoration, and impaired contextual fear conditioning, while auditory conditioning was unaltered. At the remission phase, no changes in the sucrose test were found, and the acquisition of the Morris water maze was unchanged in all groups. In anhedonic, but not resilient animals, Dhhc8 expression was lowered, and the expression of Dhhc14 was increased. Antidepressant treatment with either drug partially preserved gene expression changes and behavioral abnormalities. Our data suggest that Dhhc8 and Dhhc14 are likely to be implicated in the mechanisms of depression at the remission stage, serving as targets for preventive therapy.

Learned phenotypes emerge during social stress modifying hippocampal orexin receptor gene expression

Psychological distress, including anxiety or mood disorders, emanates from the onset of chronic/unpredictable stressful events. Symptoms in the form of maladaptive behaviors are learned and difficult to treat. While the origin of stress-induced disorders seems to be where learning and stress intersect, this relationship and molecular pathways involved remain largely unresolved. The hippocampus, studied for its role in learning, is divided into regions that designate the passage of neuronal signaling during memory formation, including dentate gyrus (DG), CA3, CA2, and CA1. Inputs into these hippocampal subregions, like those from hypothalamic orexinergic neurons, may modify learning outcomes. We have previously shown the orexin system to balance stress states, where receptor subtypes prompt opposing actions on behavior. Here, we explore the connection between hippocampal orexin receptors and learning during stress. In a social stress/learning paradigm separating mice into stress resilient and vulnerable populations, hippocampal Orx1R and Orx2R transcription is regulated in a phenotype-dependent fashion. We further identified Orx1R as highly expressed in the hilus of DG, while Orx2R is abundant in CA2. Finally, we designed an experiment where mice were provided prior exposure to a stressful environment, which ultimately modified behavior, as well as transcription of hippocampal orexin receptors.

Preoperative Blood-Brain Barrier Integrity Influence on the Impact of Anesthesia and Surgery on Mice Brain

BACKGROUND: Brain homeostasis imbalance, characterized by cognitive dysfunction and delirium, frequently occurs in the elderly after surgery. Investigating why this complication only affects part of patients undergoing the same surgery, and anesthesia remains intriguing. This study tested the role of preoperative blood-brain barrier (BBB) integrity in the occurrence of postoperative brain homeostasis imbalance using mice with conditional BBB damage. METHODS: Preoperative BBB breakdown was induced in End-SCL-Cre-ctnnb1fl//fl (iCKO) mice by administering tamoxifen (intraperitoneal [i.p.]). This breakdown was assessed using Evans Blue (EB) leakage and immunoglobulin G (IgG) staining. Postoperative brain homeostasis imbalance was evaluated through the Novel Object Recognition test, the Barnes Maze, and neuroinflammation tests. Synapse loss was detected by colabeling synaptophysin and PSD-95, followed by Western blotting. The role of astrocytes in this pathogenesis was evaluated by comparing cognitive behaviors, hippocampal gene expression, and astrocytic phagocytosis of synaptophysin in iCKO mice with and without genetic inhibition of perioperative astrocyte activity. RESULTS: Tamoxifen treatment (30 mg/kg/d) induced BBB breakdown of iCKO mice in a time-dependent manner (analysis of variance [ANOVA] for time, P = .0006), but not in their littermate control mice (nCKO, P > .999). A 3-day tamoxifen treatment induced slight BBB breakdown (EB leakage: 95% confidence interval [CI], 13.9–204.8, P = .013; IgG level: 95% CI, 12.6–51.4: P = .001), but did not cause significant cognitive impairment in the Novel Object Recognition test in iCKO mice (95% CI, −7.99 to 6.12; P > .999). Anesthesia and surgery-induced significant cognitive impairment (all P < .0001 for the Novel Object Recognition test, Barnes Maze test), neuroinflammation, and synaptic loss in iCKO mice with 3-day tamoxifen treatment, but not in nCKO mice with the same treatment. Inhibiting astrocyte activity alleviated the impact of anesthesia and surgery on cognitive function (all P < .0001 for the Novel Object Recognition test, Barnes Maze test), gene expression, and synapse pruning in iCKO mice with 3-day tamoxifen treatment. CONCLUSIONS: Preoperative BBB integrity influences the impact of anesthesia and surgery on the brain, with astrocytes modulating this effect. These findings partly explain the heterogeneity in the occurrence of postoperative brain homeostasis imbalance.

Peripherally Restricted Activation of Opioid Receptors Influences Anxiety-Related Behaviour and Alters Brain Gene Expression in a Sex-Specific Manner.

Although effects of stress-induced anxiety on the gastrointestinal tract and enteric nervous system (ENS) are well studied, how ENS dysfunction impacts behaviour is not well understood. We investigated whether ENS modulation alters anxiety-related behaviour in rats. We used loperamide, a potent μ-opioid receptor agonist that does not cross the blood-brain barrier, to manipulate ENS function and assess changes in behaviour, gut and brain gene expression, and microbiota profile. Sprague Dawley (male/female) rats were acutely dosed with loperamide (subcutaneous) or control solution, and their behavioural phenotype was examined using open field and elevated plus maze tests. Gene expression in the proximal colon, prefrontal cortex, hippocampus, and amygdala was assessed by RNA-seq and caecal microbiota composition determined by shotgun metagenome sequencing. In female rats, loperamide treatment decreased distance moved and frequency of supported rearing, indicating decreased exploratory behaviour and increased anxiety, which was associated with altered hippocampal gene expression. Loperamide altered proximal colon gene expression and microbiome composition in both male and female rats. Our results demonstrate the importance of the ENS for communication between gut and brain for normo-anxious states in female rats and implicate corticotropin-releasing hormone and gamma-aminobutyric acid gene signalling pathways in the hippocampus. This study also sheds light on sexually dimorphic communication between the gut and the brain. Microbiome and colonic gene expression changes likely reflect localised effects of loperamide related to gut dysmotility. These results suggest possible ENS pharmacological targets to alter gut to brain signalling for modulating mood.

Microglial and neuronal subpopulations associated with cognitive resilience to amyloid deposition in genetically diverse mice

AbstractBackgroundData from human and model organism studies suggest that genetic background influences susceptibility and resilience to Alzheimer’s Disease (AD) neuropathology. We previously showed that, wild‐derived PWK/PhJ (PWK) mice carrying the APP/PS1 transgene (PWK.APP/PS1) exhibit cognitive and synaptic resilience compared to traditionally‐studied B6.APP/PS1 inbred mice in presence of amyloid beta (Aβ) plaque deposition. PWK.APP/PS1 mice also contain different proportions of transcriptionally‐defined microglia compared to B6.APP/PS1. The precise molecular mechanisms underlying these differences between strains remain unknown. In this study, we aim to identify and characterize cell populations in the hippocampi of genetically distinct B6 and PWK mouse strains, and investigate cell‐type specific gene expression patterns associated with cognitive resilience in presence of amyloid deposition.MethodWe generated cohorts of B6.APP/PS1 and PWK.APP/PS1 transgenic female mice and wild‐type (WT) littermates as controls (n = 4 per strain/genotype group). At 8 months of age mice were euthanized, hippocampi collected, and single nuclear RNA sequencing (snRNAseq) was performed using 10x Genomics Chromium platform. Seurat R package (version 5.0.1) was used for major data analysis.ResultWe identified subpopulations of microglial cells characterized by varying expression patterns of a set of genes including Hk2, Itgam and Dock8. Neuronal subtypes were clustered by top marker genes Plk5 and Adarb2. Oligodendrocytes, oligodendrocyte progenitor cells, and endothelial cells were marked by expression of Mog, Neu4 and Abcc9, respectively. Differential expression and pathway enrichment analysis revealed strain‐specific immune and cell signaling pathways altered in distinct cell populations in response to amyloid pathogenesis. Cross‐species mapping of these transcriptomic signatures with human hippocampal gene modules identified AD‐relevant molecular mechanisms observed in mouse models of AD at the cell‐type level.ConclusionThis study suggests that cell‐type specific transcriptomic response to amyloid is modulated by genetic background and our findings re‐iterate the importance of incorporating genetic diversity to model phenotypic and molecular heterogeneity in AD. Since the nuclei enriched in this dataset are enriched for neurons, future interrogations will provide evidence for specific neuronal populations and molecular mechanisms that differentiate cognitively resilient PWK from susceptible B6 mice, providing insights into mechanisms that can be leveraged to promote AD resilience.

Microglia-dependent peripheral neuropathic pain in adulthood following adolescent exposure to morphine in male rats

Persistent effects of adolescent morphine exposure on neurobiological processes and behaviors in adulthood have been partially identified. Hypersensitivity following adolescent exposure to morphine is a complex and multifaceted phenomenon whose underlying mechanisms remain largely unknown. This study aimed to investigate the involvement of microglia in neuropathic pain sensitivity following adolescent morphine exposure, focused on hippocampal genes expression and plasticity. To achieve this, adolescent male Wistar rats received morphine, along with minocycline, to inhibit microglial activity. The allodynia and hyperalgesia of adult rats were evaluated using von-Frey filaments and the Hargreaves plantar test in both baseline and neuropathic pain conditions. Hippocampal genes expression was analyzed following the behavioral tests. The plasticity of the Schaffer-CA1 hippocampal synapses was also assessed using field potential recording following neuropathy. Results showed that adolescent morphine exposure exacerbated the allodynia and hyperalgesia in both baseline and neuropathic pain states in adult rats, which was significantly reduced by the co-administration of minocycline during adolescence. Neuropathy in adult rats was found to increase hippocampal expression of inflammatory mediators, but adolescent morphine prevented this effect. Additionally, we observed a reduction in the baseline synaptic transmission and long-term potentiation (LTP) at the Schaffer-CA1 hippocampal synapses after neuropathy in adult rats following adolescent exposure to morphine. The reduction of synaptic activity was not altered by the co-administration of minocycline with morphine during adolescence. It is concluded that microglia play an important role in mediating hypersensitivity induced by adolescent morphine exposure, although hippocampal microglia may not be directly involved in this process.

Natto-derived dipeptide Gln-Gln attenuates scopolamine-induced memory impairment by enhancing cholinergic function in mice

Natto-derived dipeptide Gln-Gln attenuates scopolamine-induced memory impairment by enhancing cholinergic function in mice

Regular exercise ameliorates high-fat diet-induced depressive-like behaviors by activating hippocampal neuronal autophagy and enhancing synaptic plasticity

Exercise enhances synaptic plasticity and alleviates depression symptoms, but the mechanism through which exercise improves high-fat diet-induced depression remains unclear. In this study, 6-week-old male C57BL/6J mice were administered a high-fat diet (HFD, 60% kcal from fat) to a HFD model for 8 weeks. The RUN group also received 1 h of daily treadmill exercise in combination with the HFD. Depressive-like behaviors were evaluated by behavioral assessments for all groups. The key mediator of the effect of exercise on high-fat diet-induced depressive-like behaviors was detected by RNA-seq. The morphology and function of the neurons were evaluated via Nissl staining, Golgi staining, electron microscopy and electrophysiological experiments. The results showed that exercise attenuated high-fat diet-induced depressive-like behavior and reversed hippocampal gene expression changes. RNA-seq revealed Wnt5a, which was a key mediator of the effect of exercise on high-fat diet-induced depressive-like behaviors. Further work revealed that exercise significantly activated neuronal autophagy in the hippocampal CA1 region via the Wnt5a/CamkII signaling pathway, which enhanced synaptic plasticity to alleviate HFD-induced depressive-like behavior. However, the Wnt5a inhibitor Box5 suppressed the ameliorative effects of exercise. Therefore, this work highlights the critical role of Wnt5a, which is necessary for exercise to improve high-fat diet-induced depression.

Hippocampal PDHA1 gene knockout inhibits the Warburg effect leading to cognitive dysfunction and attenuates the beneficial effects of ZiBuPiYin recipe on cognition

The attenuation of the Warburg effect is an important pathological feature of cognitive dysfunction, and enhancing the Warburg effect is conducive to improving cognitive function. However, the pathogenic mechanisms underlying cognitive dysfunction remain incompletely elucidated. ZiBuPiYin Recipe (ZBPYR) is a traditional Chinese herbal compound used clinically for the treatment of cognitive dysfunction with significant efficacy. Nonetheless, the molecular mechanism underlying its beneficial effects remains elusive. The objective of this study is to investigate whether the attenuation of the Warburg effect exists in a mouse model of cognitive dysfunction induced by knockout of the pyruvate dehydrogenase E1 component subunit alpha (PDHA1) gene in the hippocampus, as well as the interventional effect of ZBPYR. Using mice with PDHA1 gene knockout in the hippocampus and their littermate control mice as study subjects, behavioral experiments were conducted to assess the impact of PDHA1 gene knockout on cognitive function and the interventional effect of ZBPYR. We detected the expression of the Warburg effect-associated rate-limiting enzymes and PI3K/AKT pathway-related proteins. Subsequently, in PC12cells, we explored the effect of the Warburg effect on cell apoptosis as well as the role of PDHA1 in the regulation of the PI3K/AKT-Warburg effect and the potential mechanism of ZBPYR in improving cognitive function. Mice with knockout of the PDHA1 gene in the hippocampus exhibited cognitive dysfunction, inhibition of the PI3K/AKT pathway, reduction of the Warburg effect, and neuronal damage. In vitro experiments indicated that silencing of PDHA1 in the hippocampus inhibited the PI3K/AKT-Warburg effect, leading to cell apoptosis and mediated the effect of ZBPYR in improving cognitive function. Our data not only suggest that the hippocampal PDHA1-PI3K/AKT-Warburg effect may be involved in the pathogenesis of cognitive dysfunction, but also demonstrate that PDHA1 knockout can abolish the beneficial effects of ZBPYR on cognition. This research aids in unraveling the cause of cognitive dysfunction and, therefore, offers a promising and innovative therapeutic target for these patients.

Activation of the Gut-Brain Interaction by Urolithin A and Its Molecular Basis.

Background: Urolithin A (Uro-A), a type of polyphenol derived from pomegranate, is known to improve memory function when ingested, in addition to its direct effect on the skin epidermal cells through the activation of longevity gene SIRT1. However, the molI ecular mechanism by which orally ingested Uro-A inhibits cognitive decline via the intestine remains unexplored. Objectives: This study aimed to evaluate the role of Uro-A in improving cognitive function via improved intestinal function and the effect of Uro-A on the inflammation levels and gene expression in hippocampus. Methods: Research to clarify the molecular basis of the functionality of Uro-A was also conducted. Results: The results demonstrated that Uro-A suppressed age-related memory impairment in Aged mice (C57BL/6J Jcl, male, 83 weeks old) by reducing inflammation and altering hippocampal gene expression. Furthermore, exosomes derived from intestinal cells treated with Uro-A and from the serum of Aged mice fed with Uro-A both activated neuronal cells, suggesting that exosomes are promising candidates as mediators of the Uro-A-induced activation of gut-brain interactions. Additionally, neurotrophic factors secreted from intestinal cells may contribute to the Uro-A-induced activation of gut-brain interactions. Conclusions: This study suggests that Uro-A suppresses age-related cognitive decline and that exosomes and other secreted factors may contribute to the activation of the gut-brain interaction. These findings provide new insights into the therapeutic potential of Uro-A for cognitive health.

Unveiling mitochondria as central components driving cognitive decline in alzheimer's disease through cross-transcriptomic analysis of hippocampus and entorhinal cortex microarray datasets

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by symptoms such as memory loss and impaired learning. This study conducted a cross-transcriptomic analysis of AD using existing microarray datasets from the hippocampus (HC) and entorhinal cortex (EC), comparing them with age-matched non-AD controls. Both of these brain regions are critical for learning and memory processing and are vulnerable areas that exhibit abnormalities in early AD. The cross-transcriptomic analysis identified 564 significantly differentially expressed genes in HC and 479 in EC. Among these, 151 genes were significantly differentially expressed in both tissues, with functions related to synaptic vesicle clustering, synaptic vesicle exocytosis/endocytosis, mitochondrial ATP synthesis, hydrogen ion transmembrane transport, and structural constituent of cytoskeleton, suggesting a potential association between cognitive decline in AD, synaptic vesicle dynamics, dysregulation of cytoskeleton organization, and mitochondrial dysfunction. Further gene ontology analysis specific to the HC revealed the gene ontology enrichment in aerobic respiration, synaptic vesicle cycle, and oxidative phosphorylation. The enrichment analysis in CA1 of HC revealed differentiation in gene expression related to mitochondrial membrane functions involved in bioenergetics, mitochondrial electron transport, and biological processes associated with microtubule-based process, while analysis in the EC region showed enrichment in synaptic vesicle dynamics which is associated with neurotransmitter release and the regulation of postsynaptic membrane potential and synaptic transmission of GABAergic and glutamatergic synapse. Protein-protein interaction analysis highlighted central hub proteins predominantly expressed in mitochondria, involved in regulation of oxidative stress and ATP synthesis. These hub proteins interact not only within the mitochondria but also with proteins in the vesicular membrane and neuronal cytoskeleton, indicating a central role of mitochondria. This finding underscores the association between clinical symptoms and mitochondrial dysregulation of synaptic vesicle dynamics, cytoskeleton organization, and mitochondrial processes in both the HC and EC of AD. Therefore, targeting these dysregulated pathways could provide promising therapeutic targets aimed at cognitive decline and memory impairment in early AD stages.

IGF 1, BDNF, and NGF mediate the neuro-modulatory role of stem cells in acrylamide-induced hippocampal toxic changes in rats.

Acrylamide (ACR), a common industrial chemical, is a strong neurotoxic material. The hippocampus is a brain area of interest mostly affected by Alzheimer's disease. Mesenchymal stem cells (MSCs) usefulness in various neurological diseases including Alzheimer's is being debated. In this work, the authors aim to explore the role of MSCs in ACR-induced hippocampal neurodegeneration and elucidate the mediating mechanism. For this purpose, ten rats served as control, another ten were injected ACR (i.p. 50 mg/kg/day for 2 weeks), and the last ten rats were injected ACR in addition to MSCs (i.p. 1 × 10⁷ MSCs single injection). ACR induced neurodegenerative histopathological hippocampal changes and adversely altered hippocampal oxidative stress markers SOD, MDA, and GSH. ACR had induced hippocampal demyelination as detected by silver staining. ACR significantly (P < 0.05) up-regulated the ELISA hippocampal TNF-alpha and IL-6 and produced microglial & astrocyte activation (as tracked by Iba1 & GFAP immunohistochemistry respectively). ACR significantly reduced hippocampal PCR gene expression of IGF 1 (insulin growth factor-1), BDNF (brain-derived neurotrophic factor), and NGF (nerve growth factor). MSCs administration had mitigated all the previous deleterious changes. Acrylamide caused detrimental effects on the hippocampus and demonstrably altered the hippocampal architecture. Bone marrow mesenchymal stem cells offered a promising therapeutic role against these neurotoxic effects of acrylamide, presumably through modulation of IGF 1, BDNF, and NGF gene expressions.

Acetate enhances spatial memory in females via sex- and brain region-specific epigenetic and transcriptional remodeling.

Metabolic control of chromatin and gene expression is emerging as a key, but largely unexplored aspect of gene regulation. In the brain, metabolic-epigenetic interactions can influence critical neuronal functions. Here, we use a combination of behavioral, proteomic and genomic approaches to demonstrate that the intermediary metabolite acetate enhances memory in a brain region- and sex-specific manner. We show that acetate facilitates the formation of dorsal hippocampus-dependent spatial memories in female but not in male mice, while having no effect on cortex-dependent non-spatial memories in either sex. Acetate-enhanced spatial memory is driven by increased acetylation of histone variant H2A.Z, and upregulation of genes implicated in spatial learning in the dorsal hippocampus of female mice. In line with the sex-specific behavioral outcomes, the effect of acetate on dorsal hippocampal histone modifications and gene expression shows marked differences between the sexes during critical windows of memory formation (consolidation and recall). Overall, our findings elucidate a novel role for acetate, a ubiquitous and abundant metabolite, in regulating dorsal hippocampal chromatin, gene expression and learning, and outline acetate exposure as a promising new approach to enhance memory formation.

Impact of JQ1 treatment on seizures, hippocampal gene expression, and gliosis in a mouse model of temporal lobe epilepsy.

Epilepsy is a neurological disease characterised by recurrent seizures with complex aetiology. Temporal lobe epilepsy, the most common form in adults, can be acquired following brain insults including trauma, stroke, infection or sustained status epilepticus. The mechanisms that give rise to the formation and maintenance of hyperexcitable networks following acquired insults remain unknown, yet an extensive body of literature points towards persistent gene and epigenomic dysregulation as a potential mediator of this dysfunction. While much is known about the function of specific classes of epigenetic regulators (writers and erasers) in epilepsy, much less is known about the enzymes, which read the epigenome and modulate gene expression accordingly. Here, we explore the potential role for the epigenetic reader bromodomain and extra-terminal domain (BET) proteins in epilepsy. Using the intra-amygdala kainic acid model of temporal lobe epilepsy, we initially identified widespread dysregulation of important epigenetic regulators including EZH2 and REST as well as altered BRD4 expression in chronically epileptic mice. BRD4 activity was also notably affected by epilepsy-provoking insults as seen by elevated binding to and transcriptional regulation of the immediate early gene Fos. Despite influencing early aspects of epileptogenesis, blocking BET protein activity with JQ1 had no overt effects on epilepsy development in mice but did alter glial reactivity and influence gene expression patterns, promoting various neurotransmitter signalling mechanisms and inflammatory pathways in the hippocampus. Together, these results confirm that epigenetic reader activity is affected by epilepsy-provoking brain insults and that BET activity may exert cell-specific actions on inflammation in epilepsy.

Long-term saturated fat-enriched diets impair hippocampal learning and memory processes in a sex-dependent manner

Consumption of saturated fat-enriched diets during adolescence has been closely associated with the reduction of hippocampal synaptic plasticity and the impairment of cognitive function. Nevertheless, the effect of long-term intake of these foods has not yet been studied. In the present study, we have investigated the effect of a treatment, lasting for 40 weeks, with a diet enriched in saturated fat (SOLF) on i) spatial learning and memory, ii) hippocampal synaptic transmission and plasticity, and iii) hippocampal gene expression levels in aged male and female mice. Our findings reveal that SOLF has a detrimental impact on spatial memory and synaptic plasticity mechanisms, such as long-term potentiation (LTP), and downregulates Gria1 expression specifically in males. In females, SOLF downregulates the gene expression of Gria1/2/3 and Grin1/2A/2B glutamate receptor subunits as well as some proinflammatory interleukins. These findings highlight the importance of considering sex-specific factors when assessing the long-term effects of high-fat diets on cognition and brain plasticity.

Endocannabinoid and neuroplasticity-related changes as susceptibility factors in a rat model of posttraumatic stress disorder

Traumatic experiences result in the development of posttraumatic stress disorder (PTSD) in 10-25% of exposed individuals. While human clinical studies suggest that susceptibility is potentially linked to endocannabinoid (eCB) signaling, neurobiological PTSD susceptibility factors are poorly understood. Employing a rat model of contextual conditioned fear, we characterized distinct resilient and susceptible subpopulations based on lasting generalized fear, a core symptom of PTSD. In these groups, we assessed i.) eCB levels by mass spectrometry and ii.) expression variations of eCB system- and iii.) neuroplasticity-related genes by real-time quantitative PCR in the circuitry relevant in trauma-induced changes. Furthermore, employing unsupervised and semi-supervised machine learning based statistical analytical models, we assessed iv.) gene expression patterns with the most robust predictive power regarding PTSD susceptibility. According to our findings, in our model, generalized fear responses occurred with sufficient variability to characterize distinct resilient and susceptible subpopulations. Resilient subjects showed elevated prelimbic and lower ventral hippocampal levels of eCB 2-arachidonoyl-glycerol (2-AG) compared to resilient and non-shocked control subjects. Ventral hippocampal 2-AG content positively correlated with the strength of fear generalization. Furthermore, susceptibility was associated with i.) prefrontal, hippocampal and amygdalar neuronal hypoactivity, ii.) marked decrease in the expression of genes of transcription factors modulating neuroplasticity and iii.) an altered expression pattern of eCB-related genes, including enzymes involved in eCB metabolism. Unsupervised and semi-supervised statistical approaches highlighted that hippocampal gene expression patterns possess strong predictive power regarding susceptibility. Taken together, the marked eCB and neuroplasticity changes in susceptible individuals associated with abnormal activity patterns in the fear circuitry possibly contribute to context coding deficits, resulting in generalized fear.

The influence of Black Cohosh on hippocampal and hypothalamic gene expression profiles in ovariectomized rats and its potential to treat menopausal decrease in smell discrimination

PurposeMenopause is associated with a decrease in smell discrimination ability. This study assessed the impact of black cohosh on hippocampal (HC) and hypothalamic (HT) gene expression profiles in rats, to understand, if herbal treatment has an impact on neurologic changes due to menopause and whether this could address a decrease in smell discrimination.MethodsHC and HT tissues from female Sprague Dawley rats (total n = 19) were analyzed at three different life stages: intact tissues of the HC (n = 4) and the HT (n = 4), oophorectomized tissues 3 months after oophorectomy (OVX) of the HC (n = 4) and the HT (n = 3), and tissues after treatment with an isopropanolic extract (iCR) from the rhizomes of black cohosh (60 mg/kg) for 3 months after OVX of the HC (n = 2) and the HT (n = 2).Main outcome measuresTo reveal underlying biological processes a gene set enrichment analysis (GSEA) was performed.ResultsThe GSEA revealed gene ontology terms that were significantly enriched, including several genes associated with the olfactory system, indicating biological processes regulated by treatment with iCR. Six olfactory receptor genes were further analyzed by another GSEA, demonstrating the possibility of iCR treatment to compensate for oophorectomy-induced changes.ConclusionFindings suggest that herbal treatment, such as iCR, has an esteeming impact on HC and HT genes that are changed through menopause. Further studies are needed to suggest black cohosh as a treatment option for decreased smell discrimination.

Cognitive rejuvenation in old rats by hippocampal OSKM gene therapy.

Several studies have indicated that interrupted epigenetic reprogramming using Yamanaka transcription factors (OSKM) can rejuvenate cells from old laboratory animals and humans. However, the potential of OSKM-induced rejuvenation in brain tissue has been less explored. Here, we aimed to restore cognitive performance in 25.3-month-old female Sprague-Dawley rats using OSKM gene therapy for 39days. Their progress was then compared with the cognitive performance of untreated 3.5-month-old rats as well as old control rats treated with a placebo adenovector. The Barnes maze test, used to assess cognitive performance, demonstrated enhanced cognitive abilities in old rats treated with OSKM compared to old control animals. In the treated old rats, there was a noticeable trend towards improved spatial memory relative to the old controls. Further, OSKM gene expression did not lead to any pathological alterations within the 39days. Analysis of DNA methylation following OSKM treatment yielded three insights. First, epigenetic clocks for rats suggested a marginally significant epigenetic rejuvenation. Second, chromatin state analysis revealed that OSKM treatment rejuvenated the methylome of the hippocampus. Third, an epigenome-wide association analysis indicated that OSKM expression in the hippocampus of old rats partially reversed the age-related increase in methylation. In summary, the administration of Yamanaka genes via viral vectors rejuvenates the functional capabilities and the epigenetic landscape of the rat hippocampus.

Mitochondrial regulation of adult hippocampal neurogenesis: Insights into neurological function and neurodevelopmental disorders

Mitochondria are essential regulators of cellular energy metabolism and play a crucial role in the maintenance and function of neuronal cells. Studies in the last decade have highlighted the importance of mitochondrial dynamics and bioenergetics in adult neurogenesis, a process that significantly influences cognitive function and brain plasticity. In this review, we examine the mechanisms by which mitochondria regulate adult neurogenesis, focusing on the impact of mitochondrial function on the behavior of neural stem/progenitor cells and the maturation and plasticity of newborn neurons in the adult mouse hippocampus. In addition, we explore the link between mitochondrial dysfunction, adult hippocampal neurogenesis and genes associated with cognitive deficits in neurodevelopmental disorders. In particular, we provide insights into how alterations in the transcriptional regulator NR2F1 affect mitochondrial dynamics and may contribute to the pathophysiology of the emerging neurodevelopmental disorder Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS). Understanding how genes involved in embryonic and adult neurogenesis affect mitochondrial function in neurological diseases might open new directions for therapeutic interventions aimed at boosting mitochondrial function during postnatal life.