Hippocampal Dysfunction Research Articles

Protective and Therapeutic Effects of Orlistat in Combination with Elettaria cardamomum “Cardamom” Extract on Learning, Memory, Anxiety, and Neuroinflammation in Obese Mice

Introduction and Objective: Obesity has increased worldwide, and existing anti-obesity medications have treatment limitations that diminish their overall benefits. This study aimed to investigate the effects of orlistat in combination with Elettaria cardamomum “Cardamom” (CAR) extract on working memory, recognition memory, anxiety, and inflammation within hippocampal tissue. Methods: Mice were categorized into two groups: a control group (CD) and a cafeteria diet (CAF) group induced with obesity (CAF) for 10 weeks. The groups were then subdivided into a CAF group treated with orlistat (CAF-ORL), a CAF group treated with orlistat and Elettaria cardamomum (CAF-ORL-CARD), and a group that continued on the CAF. The CAF-ORL group received orlistat at a dosage of 10 mg/kg/day for four weeks, while the CAF-ORL-CARD group received 10 mg/kg/day of orlistat and 500 mg/kg of CAR extract via oral gavage. In the 14th week, various assessments were conducted, including the novel object recognition (NOR) test, Y maze test, marble-burying test (MBT), open-field test, and TNF-α levels in the hippocampus. Result: TNF-α levels in the hippocampal tissue of the CAF group were elevated compared to the CD group (p < 0.01), whereas the CAF-ORL group exhibited reduced TNF-α levels compared to the CAF group (p < 0.01). Moreover, TNF-α levels in the CAF-ORL-CARD group were significantly lower than in the CAF-ORL group (p < 0.01). The recognition index was notably higher in the CAF-ORL group compared to the CAF group (p < 0.01) and higher in the CAF-ORL-CARD group compared to the CAF-ORL group (p < 0.01). However, there were no changes in the open-field test and Y maze test (p > 0.05). Conclusions: Orlistat combined with CAR has positive effects on neuroinflammation and memory, suggesting that this combination may offer potential therapeutic benefits for cognitive impairments and hippocampal dysfunction associated with obesity.

Inhibition of hippocampal interleukin-6 receptor-evoked signalling normalises long-term potentiation in dystrophin-deficient mdx mice.

Duchenne muscular dystrophy (DMD), an X-linked neuromuscular disorder, characterised by progressive immobility, chronic inflammation and premature death, is caused by the loss of the mechano-transducing signalling molecule, dystrophin. In non-contracting cells, such as neurons, dystrophin is likely to have a functional role in synaptic plasticity, anchoring post-synaptic receptors. Dystrophin-expressing hippocampal neurons are key to cognitive functions such as emotions, learning and the consolidation of memories. In the context of disease-induced chronic inflammation, we have explored the role of the pleiotropic cytokine, interleukin (IL)-6 in hippocampal dysfunction using immunofluorescence, electrophysiology and metabolic measurements in dystrophic mdx mice. Hippocampal long-term potentiation (LTP) of the Schaffer collateral-CA1 projections was suppressed in mdx slices. Given the importance of mitochondria-generated ATP in synaptic plasticity, reduced maximal respiration in the CA1 region may impact upon this process. Consistent with a role for IL-6 in this observation, early LTP was suppressed in dystrophin-expressing wildtype slices exposed to IL-6. In dystrophic mdx mice, exposure to IL-6 suppressed mitochondrial-mediated basal metabolism in CA1, CA3 and DG hippocampal regions. Furthermore, blocking IL-6-mediated signalling by administering neutralising monoclonal IL-6 receptor antibodies intrathecally, normalised LTP in mdx mice. The impact of dystrophin loss from the hippocampus was associated with modified cellular bioenergetics, which underpin energy-driven processes such as the induction of LTP. The additional challenge of pathophysiological levels of IL-6 resulted in altered cellular bioenergetics, which may be key to cognitive deficits associated with the loss of dystrophin.

Chronic stress induces depression-like behavior in rats through affecting brain mitochondrial function and inflammation.

Chronic stress is involved in pathophysiology of depression, and causes some neurochemical alterations in brain. Both mitochondrial dysfunction and neuroinflammation are implicated in mediating the depression-like behavior. The objectives of present study were, at first, to confirm that chronic unpredictable mild stress (CUMS) induces depression-like behavior and alters mitochondrial function and inflammatory responses within the brain, and then to explore the role of mitochondria in the development of this depression-like behavior. It has been found that CUMS exposure induced depression-like behavior, mitochondrial dysfunction, increased IL-1, IL-6, IFN-γ and TNF-α levels in hippocampus and PFC. Moreover, the level of ATP, the key index of mitochondrial function, was inversely correlated with the levels of proinflammatory cytokine. Intracerebroventricular (ICV) injection of the mitochondrial targeted antioxidant MnTBAP significantly alleviated depression-like behavior in CUMS group. These findings suggested that CUMS results in depression-like behavior, mitochondrial dysfunction as well as neuroinflammation, and mitochondria dysfunction contributes to depression-like behavior caused by CUMS.

Astrocyte proliferation in the hippocampal dentate gyrus is suppressed across the lifespan of dystrophin-deficient mdx mice.

Absence of the structural protein, dystrophin, results in the neuromuscular disorder Duchenne Muscular Dystrophy (DMD). In addition to progressive skeletal muscle dysfunction, this multisystemic disorder can also result in cognitive deficits and behavioural changes that are likely to be consequences of dystrophin loss from central neurons and astrocytes. Dystrophin-deficient mdx mice exhibit decreases in grey matter volume in the hippocampus, the brain region that encodes and consolidates memories, and this is exacerbated with ageing. To understand changes in cellular composition that might underpin these age-related developments, we have compared neurogenesis and the prevalence of immunofluorescently identified newly born and mature neurons, astrocytes and microglia in the dentate gyrus of mdx and wild-type mice at 2, 4, 8 and 16 months of age. The number of adult-born neurons was suppressed in the dentate gyrus subgranular zone of 2-month-old mdx mice. However, the numbers of granule cells and GABAA receptor, alpha 1-expressing cells were similar in wild-type and mdx mice at all ages. Strikingly, the numbers of astrocytes, particularly in the dentate gyrus molecular layer, were suppressed in mdx mice at all time points. Thus, dystrophin loss was associated with reduced hippocampal neurogenesis in early life but did not impact the prevalence of mature neurons across the lifespan of mdx mice. In contrast, normal age-related dentate gyrus astrocyte proliferation was suppressed in dystrophic mice. Astrocytes are the most abundant cell type in the brain and are crucial in supporting neuronal function, such that loss of these cells is likely to contribute to hippocampal dysfunction reported in mdx mice.

Fructose-Driven glycolysis supports synaptic function in subterranean rodent - Gansu Zokor (Eospalax cansus).

Several studies indicate that fructose can be used as an energy source for subterranean rodents. However, how subterranean rodents utilize fructose metabolism with no apparent physiological drawbacks remains poorly understood. In the present study, we measured field excitatory postsynaptic potentials (fEPSPs) in hippocampal slices from Gansu zokor and SD rats hippocampi before and 60 min after replacement of 10 mM glucose in the artificial cerebrospinal fluid (ACSF) with 10 mM fructose (gassed with 95 % O2 and 5 % CO2). Subsequently, we performed transcriptome analysis on Gansu zokor brains incubated with ACSF containing 10 mM fructose and determined the contents of fructose, lactate, ATP, and UA. Whole brain RNA and proteins were extracted to detect the transcriptional levels of Glut5, Khk, Aldoc, and Cs and the translational levels of GLUT5, CS, NRF2, and c-FOS. The results showed that Gansu zokor brains exhibit higher levels of GLUT5 protein and Khk mRNA levels than SD rats to facilitate fructose uptake and metabolism, resulting in increased fructose, ATP, and lactate content in the brain during fructose incubation. Stable UA levels during fructose metabolism reduce the risk of oxidative stress and neuroinflammation, and activation of the Nrf2 pathway increases downstream antioxidant capacity, thereby reducing brain damage. Persistent fEPSP signaling suggests that fructose supports excitatory synaptic transmission in the CA1 region of the hippocampus of the Gansu zokor but leads to hippocampal dysfunction in SD rats. The unique insights about fructose metabolism in the brain of Gansu zokor obtained in our study will be useful for further studies on the evolution of subterranean rodents.

APOE4 Increases Susceptibility to Amyloid, Accelerating Episodic Memory Decline.

Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Individuals with one copy of APOE4 exhibit greater amyloid-beta (Aβ) deposition compared to noncarriers, an effect that is even more pronounced in APOE4 homozygotes. Interestingly, APOE4 carriers not only show more AD pathology but also experience more rapid cognitive decline, particularly in episodic memory. The underlying mechanisms driving this domain-specific vulnerability, however, remain unclear. In this study, we examined whether the accelerated decline in episodic memory among APOE4 carriers is due to increased Aβ deposition or heightened susceptibility to Aβ-related effects. Using data from the Alzheimer's Disease Research Initiative, we modeled amyloid duration, the estimated number of years an individual has been amyloid-positive, and its impact on cognitive trajectories. Our findings reveal that APOE4 is associated with more rapid episodic memory decline as a function of amyloid duration. This decline was dose-dependent, with APOE4 homozygotes declining more rapidly than heterozygotes, and it was consistently observed across multiple episodic memory tasks and measures. Importantly, this pattern was not observed in other cognitive domains, such as processing speed, executive function, visuospatial skills, language, or crystallized intelligence. These results suggest that cognitive trajectories in AD differ by APOE genotype, with APOE4 conferring increased vulnerability to hippocampal dysfunction early in the disease course. Future research should investigate whether these cognitive differences stem from distinct pathological cascades in APOE4 carriers.

Spatial and sex‐specific hippocampal proteomic analysis of an early Alzheimer’s disease mouse model using MALDI‐imaging

AbstractBackgroundA key neuropathological feature in the early stages of Alzheimer's disease (AD) involves hippocampal dysfunction arising from the accumulation of amyloid‐β (Aβ). Previously, our laboratory identified a shift in the synaptic plasticity long term potentiation (LTP)/long term depression (LTD) induction threshold, leading to memory deficits in a non‐transgenic murine model of early AD generated by intracerebroventricular (icv.) injections Aβ1‐42 oligomers (oAβ1‐42), one of the most predominant pathogenetic factors in initial stages of the disease. However, the specific alterations in proteins within hippocampal subfields remain uninvestigated. Here, we hypothesized that there might be unique protein changes in the hippocampus induced by oAβ1‐42 and potentially influenced by sex‐dependent factors.MethodTo do so, we evaluated hippocampal‐dependent memory using a Barnes maze and the Object location memory test (OLM) in the non‐transgenic model of early AD. Both memory encoding and retrieval deficits were shown 1 hour post‐icv. injection, although no significant sex differences were found. Then, an innovative spatial proteomic study was performed to assess the hippocampal proteome using matrix‐assisted laser desorption/ionization (MALDI) imaging mass spectrometry that allows peptide detection with spatial resolution directly on tissue sections.ResultResults from sixteen brains from C57BL/6 adult male and female mice 1 hour post‐icv. injected with oAβ1‐42 or vehicle were analyzed. MALDI imaging was performed using a RapifleXTM MALDI TissuetyperTM TOF/TOF mass spectrometer followed by protein identification by traditional MS/MS directly on the tissue. To precisely delineate anatomical hippocampal region and subfields, a Nissl staining was performed at adjacent tissue sections. More than 600 peptides were detected, and several of them showed significant differences in expression levels due to treatment or sex. To further analyze the data, the protein‐protein interaction (PPI) between the identified changed proteins was analyzed using the STRING database.ConclusionThe specific hippocampal subfields changes in the proteome caused by early amyloidosis provide new insight in the pathogenesis of AD and valuable potential biomarkers for early diagnosis and potential therapies.Acknowledgements: Grants PID2020‐115823‐GB100/ MCIN/AEI/10.13039/501100011033 and SBPLY/21/180501/000150/ JCCM and “ERDF A way of making Europe” both to LJ‐D and JDN‐L. Margarita Salas Postdoctoral Research Fellow to AC funded by European Union NextGenerationEU/PRTR.

Thyroid hormone imbalance and the mechanism by which it causes memory loss

Thyroid hormone imbalance is the cause of many cognitive dysfunctions such as memory loss, anxiety and depression. A study conducted by Yu et al suggests that hypothyroidism as well as hyperthyroidism causes depression, anxiety and hippocampal dysfunction in rats. The mechanism of these dysfunctions is not yet completely understood.

P2X7 expression patterns in the developing Fmr1-knockout mouse hippocampus.

Fragile-X Syndrome (FXS)is the leading monogenetic cause of intellectual disability among children but remains without a cure. Using the Fmr1 KO mouse model of FXS, much work has been done to understand FXS hippocampus dysfunction. Purinergic signaling, where ATP and its metabolites are used as signaling molecules, participates in hippocampus development, but it is unknown if purinergic signaling is affected in the developing Fmr1 KO hippocampus. In our study, we characterized the purinergic receptor P2X7. We first found that P2X7 was reduced in Fmr1 KO whole hippocampus tissue at P14 and P21, corresponding to the periods of neurite outgrowth and synaptic refinement in the hippocampus. We then evaluated the cell-specific expression of P2X7 with immunofluorescenceand found differences between WT and Fmr1 KO mice in P2X7 colocalization with hippocampal microglia and neurons. P2X7 colocalized more with microglia at P14 and P21, but there was a sex-specific reduction in P2X7 colocalization with neurons. In contrast, male mice at P14 and P21 showed reduced neuronal P2X7 colocalization compared to females, but only females showed reduced absolute neuronal P2X7 expression across the dorsal hippocampal formation. Together, our results suggest that P2X7 expression is altered during Fmr1-KO hippocampal development, potentially influencing several developmental processes in the Fmr1-KO hippocampus formation.

Gut microbiota dysbiosis-mediated ceramides elevation contributes to corticosterone-induced depression by impairing mitochondrial function

The role of gut microbiota (GM) dysbiosis in the pathogenesis of depression has received widespread attention, but the mechanism remains elusive. Corticosterone (CORT)-treated mice showed depression-like behaviors, reduced hippocampal neurogenesis, and altered composition of the GM. Fecal microbial transplantation from CORT-treated mice transferred depression-like phenotypes and their dominant GM to the recipients. Fecal metabolic profiling exposed remarkable increase of gut ceramides in CORT-treated and recipient mice. Oral gavage with Bifidobacterium pseudolongum and Lactobacillus reuteri could induce elevations of gut ceramides in mice. Ceramides-treated mice showed depressive-like phenotypes, significant downregulation of oxidative phosphorylation-associated genes, and hippocampal mitochondrial dysfunction. Our study demonstrated a link between chronic exposure to CORT and its impact on GM composition, which induces ceramides accumulation, ultimately leading to hippocampal mitochondrial dysfunction. This cascade of events plays a critical role in reducing adult hippocampal neurogenesis and is strongly associated with the development of depression-like behaviors.

Schizophrenia pathology reverse-translated into mouse shows hippocampal hyperactivity, psychosis behaviors and hyper-synchronous events.

Decades of research into the function of the medial temporal lobe has driven curiosity around clinical outcomes associated with hippocampal dysfunction, including psychosis. Post-mortem analyses of brain tissue from human schizophrenia brain show decreased expression of the NMDAR subunit GluN1 confined to the dentate gyrus with evidence of downstream hippocampal hyperactivity in CA3 and CA1. Little is known about the mechanisms of the emergence of hippocampal hyperactivity as a putative psychosis biomarker. We have developed a reverse-translation mouse to study critical neural features. We had previously studied a dentate gyrus (DG)-specific GluN1 KO, which displays hippocampal hyperactivity and a psychosis-relevant behavioral phenotype. Here, we expressed an inhibitory DREADD (pAAV-CaMKIIa-hM4D(Gi)-mCherry) in granule cells of the mouse dentate gyrus, and continuously inhibited the region for 21 days in adolescent (6 weeks) and adult (10 weeks) C57BL/6 J mice with DREADD agonist Compound 21 (C21). Following this period, we quantified activity in the hippocampal subfields by assessing cFos expression, hippocampally mediated behaviors, and hippocampal local field potential with an intracerebral probe with continual monitoring over time. DG inhibition during adolescence generates an increase in hippocampal activity in CA3 and CA1, impairs social cognition and spatial working memory, as well as shows evidence of increased activity in local field potentials as spontaneous synchronous bursts of activity, which we term hyper-synchronous events (HSEs) in hippocampus. The same DG inhibition delivered during adulthood in the mouse lacks these outcomes. These results suggest a sensitive period in development in which the hippocampus is susceptible to DG inhibition resulting in hippocampal hyperactivity and psychosis-like behavioral outcomes.

Diagnosis of Alzheimer's Disease in Clinical Practice: Time to Incorporate Biomarkers?

Hippocampal dysfunction is associated with early clinical signs of Alzheimer's disease (AD). Due to the limited availability or invasiveness of current biomarkers, the AD diagnosis is usually based on cognitive assessment and structural brain imaging. The recent study by Lalive and colleagues examined the specificity of brain morphometry for the AD diagnosis in a memory clinic cohort with hippocampal-type amnestic syndrome. The results indicate that memory deficits and hippocampal atrophy are similar in AD and non-AD patients, highlighting their low diagnostic specificity. These findings challenge the traditional AD diagnosis and underscore the need for biomarkers to differentiate specific neuropathological entities.

Co-activation of selective nicotinic acetylcholine receptor subtypes is required to reverse hippocampal network dysfunction and prevent fear memory loss in Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia with no known cause and cure. Research suggests that a reduction of GABAergic inhibitory interneurons' activity in the hippocampus by beta-amyloid peptide (Aβ) is a crucial trigger for cognitive impairment in AD via hyperexcitability. Therefore, enhancing hippocampal inhibition is thought to be protective against AD. However, hippocampal inhibitory cells are highly diverse, and these distinct interneuron subtypes differentially regulate hippocampal inhibitory circuits and cognitive processes. Moreover, Aβ unlikely affects all subtypes of inhibitory interneurons in the hippocampus equally. Hence, identifying the affected interneuron subtypes in AD to enhance hippocampal inhibition optimally is conceptually and practically challenging. We have previously found that Aβ selectively binds to two of the three major hippocampal nicotinic acetylcholine receptor (nAChR) subtypes, α7- and α4β2-nAChRs, but not α3β4-nAChRs, and inhibits these two receptors in cultured hippocampal inhibitory interneurons to decrease their activity, leading to hyperexcitation and synaptic dysfunction in excitatory neurons. We have also revealed that co-activation of α7- and α4β2-nAChRs is required to reverse the Aβ-induced adverse effects in hippocampal excitatory neurons. Here, we discover that α7- and α4β2-nAChRs predominantly control the nicotinic cholinergic signaling and neuronal activity in hippocampal parvalbumin-positive (PV+) and somatostatin-positive (SST+) inhibitory interneurons, respectively. Furthermore, we reveal that co-activation of these receptors is necessary to reverse hippocampal network dysfunction and fear memory loss in the amyloid pathology model mice. We thus suggest that co-activation of PV+ and SST+ cells is a novel strategy to reverse hippocampal dysfunction and cognitive decline in AD.

Ketamine induced gut microbiota dysbiosis and barrier and hippocampal dysfunction in rats

Ketamine induced gut microbiota dysbiosis and barrier and hippocampal dysfunction in rats

Assessing rapid spatial working memory in community-living older adults in a virtual adaptation of the rodent water maze paradigm

Aging often leads to a decline in various cognitive domains, potentially contributing to spatial navigation challenges among older individuals. While the Morris water maze is a common tool in rodents research for evaluating allocentric spatial memory function, its translation to studying aging in humans, particularly its association with hippocampal dysfunction, has predominantly focused on spatial reference memory assessments. This study expanded the adaptation of the Morris water maze for older adults to assess flexible, rapid, one-trial working memory. This adaptation involved a spatial search task guided by allocentric cues within a 3-D virtual reality (VR) environment. The sensitivity of this approach to aging was examined in 146 community-living adults from three Chinese cities, categorized into three age groups. Significant performance deficits were observed in participants over 60 years old compared to younger adults aged between 18 and 43. However, interpreting these findings was complicated by factors such as psychomotor slowness and potential variations in task engagement, except during the probe tests. Notably, the transition from the 60 s to the 70 s was not associated with a substantial deterioration of performance. A distinction only emerged when the pattern of spatial search over the entire maze was examined in the probe tests when the target location was never revealed. The VR task's sensitivity to overall cognitive function in older adults was reinforced by the correlation between Montreal Cognitive Assessment (MoCA) scores and probe test performance, demonstrating up to 17 % shared variance beyond that predicted by chronological age alone. In conclusion, while implementing a VR-based adaptation of rodent water maze paradigms in older adults was feasible, our experience highlighted specific interpretative challenges that must be addressed before such a test can effectively supplement traditional cognitive assessment tools in evaluating age-related cognitive decline.

Ketamine reverses chronic corticosterone-induced behavioral deficits and hippocampal synaptic dysfunction by regulating eIF4E/BDNF signaling

Major depressive disorder (MDD) is a debilitating illness with a high global burden. While Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, offers rapid-acting antidepressant effects, its mechanism remains incompletely understood. Recent research suggests that dysregulation of mRNA translation via the Eukaryotic initiation factor 4E (eIF4E) pathway might contribute to depression pathophysiology. This study investigates whether Ketamine modulates eIF4E signaling in the hippocampus during its antidepressant action. Herein, adult male mice were exposed to Corticosterone, a well-established model for anxiety and depression, followed by behavioral testing and biochemical analysis. Corticosterone induced depression-like symptoms and disrupted synaptic function, including reduced TrkB/BDNF and eIF4E/MNK1/p-eIF2α/ubiquitin signaling. Ketamine treatment reversed these deficits. Notably, the eIF4E/MNK1 signaling inhibitor, eFT508, blocked Ketamine's antidepressant effect, leading to a return of depression-like phenotype and impaired synaptic signaling. Importantly, these effects were reversed by 7,8-DHF, a BDNF/TrkB signaling agonist. Mice treated with Corticosterone, Ketamine, and eFT508 and subsequently exposed to 7,8-DHF displayed normalized depression-like behaviors and restored synaptic signaling, including increased eIF4E phosphorylation and MNK1 expression. Besides, 7,8-DHF treatment enhanced p-eIF2α levels compared to the eFT508-treated group. These findings suggest that Ketamine exerts its antidepressant action through the regulation of the eIF4E/BDNF signaling pathway in the hippocampus. This study provides novel insights into the molecular mechanisms underlying Ketamine's therapeutic effects and highlights the potential of targeting this pathway for future MDD treatment strategies.

Modeling Cortical Versus Hippocampal Network Dysfunction in a Human Brain Assembloid Model of Epilepsy and Intellectual Disability.

Neurodevelopmental disorders often impair multiple cognitive domains. For instance, a genetic epilepsy syndrome might cause seizures due to cortical hyperexcitability and present with memory impairments arising from hippocampal dysfunction. This study examines how a single disorder differentially affects distinct brain regions by using human patient iPSC-derived cortical- and hippocampal-ganglionic eminence assembloids to model Developmental and Epileptic Encephalopathy 13 (DEE-13), a condition arising from gain-of-function mutations in the SCN8A gene. While cortical assembloids showed network hyperexcitability akin to epileptogenic tissue, hippocampal assembloids did not, and instead displayed network dysregulation patterns similar to in vivo hippocampal recordings from epilepsy patients. Predictive computational modeling, immunohistochemistry, and single-nucleus RNA sequencing revealed changes in excitatory and inhibitory neuron organization that were specific to hippocampal assembloids. These findings highlight the unique impacts of a single pathogenic variant across brain regions and establish hippocampal assembloids as a platform for studying neurodevelopmental disorders.

Curcumin and exercise prevent depression via alleviating hippocampus injury and improve depressive-like behaviors in chronically stressed depression rats.

Depression is a growing public health concern worldwide, characterized by cognitive impairment and structural abnormalities of the hippocampus. Current antidepressant treatment sometimes causes the late onset of results and the much faster occurrence of side effects. For this reason, the interest in new treatment strategies including exercise and natural products such as curcumin has increased to treat depression. The present study investigated the role of curcumin and exercise in improving depressive-like behavior and hippocampal damage induced by mild unpredictable chronic stress in male rats. This study analyzed the effects of curcumin (100 mg/kg/day, P.O for 14 days) and exercise (treadmill running, 45 min/day for 14 days) on immobility behavior (forced swimming test), locomotor activity (open field test), anhedonia (sucrose preference test) and cell survival (Nissl staining) of the hippocampal CA3 region in chronically stressed depression rats. In the current study, curcumin treatment combined with exercise effectively improved immobility behavior, locomotor activity, and increased hippocampal cell survival resulted in preventing the development of hippocampus dysfunction and depressive-like behaviors. This study demonstrated a new prospect for treating depression. The current findings give researchers the confidence to continue the investigations on the effects of curcumin accompanied with exercise as a novel therapy for the treatment of depression.

Herbal Formula Extract Ameliorates Anxiety and Cognitive Impairment via Regulation of the Reelin/Dab-1 Pathway in a Murine Model of Post-Traumatic Stress Disorder.

We investigated the effects of epigenetic modifications on post-traumatic stress disorder (PTSD) using a novel combination of herbal medicines from Panax ginseng, Astragalus membranaceus, Atractylodes macrocephala, and Glycyrrhiza uralensis. The herbal formula extract (HFE) (250 mg/kg) was administered orally once daily for 14 days to determine its effects on PTSD in mice by combining prolonged stress and foot shock. The open field and Y-maze tests determined the effect of HFE on PTSD-induced anxiety and cognition. Hippocampal neuronal plastic changes and molecular mechanism were verified. Treatment with HFE decreased anxiety-like behavior and enhanced cognition. Moreover, it reduced the number of PTSD-related hilar ectopic granule cells in the dentate gyrus (DG). PTSD mice showed reduced neuronal plasticity of doublecortin+ cells in the DG, which was restored by HFE treatment. HFE reversed PTSD-induced inhibition of the Reelin/Dab1 pathway, a critical signaling cascade involved in brain development, and regulated Reelin methylation. Furthermore, DNA methylation, methyl-CpG binding protein 2, and DNA methyltransferase 1, which were elevated in the hippocampus of PTSD mice, were restored following HFE treatment. HFE increased the expression of synaptic plasticity-related factors in the hippocampus of PTSD mice. Our findings suggest that HFE can facilitate PTSD treatment by alleviating behavioral abnormalities through the restoration of hippocampal dysfunction via regulation of the Reelin/Dab-1 pathway and DNA methylation in the hippocampus.

Recent Insights into Hippocampal Dysfunction and Neuroplasticity in Sleep Disorders: An Update from Preclinical Studies.

Sleep disorders are prevalent neurological conditions linked to neurocognitive impairments. Understanding the neuroplasticity changes in the hippocampus, which plays a central role in regulating neurocognitive function, is crucial in the context of sleep disorders. However, research on neurodegenerative disorders and the influence of sleep disorders on hippocampal neuroplasticity remains largely unclear. Therefore, this review aims to highlight the latest advancements regarding hippocampal neuroplasticity and functional changes during sleep disorders, drawing insights from clinical and preclinical research involving sleep-deprived animal models. These articles were gathered through comprehensive literature searches across databases, including Google Scholar, PubMed, Web of Science, and Scopus. Maternal sleep deprivation has been observed to cause neurocognitive impairment in offspring, along with changes in protein expression levels associated with neuroplasticity. Similarly, sleep deprivation in adult mice has been shown to affect several cognitive functions and fear extinction without influencing the acquisition of fear conditioning. While mechanistic research on neurocognitive dysfunction induced by maternal and adult sleep deprivation is limited, it suggests the involvement of several signaling pathways, including neurotrophic factors, synaptic proteins, and inflammatory molecules, which are triggered by sleep deprivation. Further studies are needed to clarify the mechanistic pathways underlying hippocampal dysfunction and synaptic alterations associated with sleep disturbances.