Neurons In Dentate Gyrus Research Articles

AIMP2 accumulation in brain leads to cognitive deficits and blood secretion in Parkinson’s disease

BackgroundPropagation of neuronal α-synuclein aggregate pathology to the cortex and hippocampus correlates with cognitive impairment in Parkinson’s disease (PD) dementia and dementia with Lewy body disease. Previously, we showed accumulation of the parkin substrate aminoacyl-tRNA synthetase interacting multifunctional protein-2 (AIMP2) in the temporal lobe of postmortem brains of patients with advanced PD. However, the potential pathological role of AIMP2 accumulation in the cognitive dysfunction of patients with PD remains unknown.MethodsWe performed immunofluorescence imaging to examine cellular distribution and accumulation of AIMP2 in brains of conditional AIMP2 transgenic mice and postmortem PD patients. The pathological role of AIMP2 was investigated in the AIMP2 transgenic mice by assessing Nissl-stained neuron counting in the hippocampal area and Barnes maze to determine cognitive functions. Potential secretion and cellular uptake of AIMP2 was monitored by dot blot analysis and immunofluorescence. The utility of AIMP2 as a new PD biomarker was evaluated by dot blot and ELISA measurement of plasma AIMP2 collected from PD patients and healthy control followed by ROC curve analysis.ResultsWe demonstrated that AIMP2 is toxic to the dentate gyrus neurons of the hippocampus and that conditional AIMP2 transgenic mice develop progressive cognitive impairment. Moreover, we found that neuronal AIMP2 expression levels correlated with the brain endothelial expression of AIMP2 in both AIMP2 transgenic mice and in the postmortem brains of patients with PD. AIMP2, when accumulated, was released from the neuronal cell line SH-SY5Y cells. Secreted AIMP2 was taken up by human umbilical vein endothelial cells. Consistent with the fact that AIMP2 can be released into the extracellular space, we showed that AIMP2 transgenic mice have higher levels of plasma AIMP2. Finally, ELISA-based assessment of AIMP2 in plasma samples from patients with PD and controls, and subsequent ROC curve analysis proved that high plasma AIMP2 expression could serve as a reliable molecular biomarker for PD diagnosis.ConclusionsThe pathological role in the hippocampus and the cell-to-cell transmissibility of AIMP2 provide new therapeutic avenues for PD treatment, and plasma AIMP2 combined with α-synuclein may improve the accuracy of PD diagnosis in the early stages.

Glial cells undergo rapid changes following acute chemogenetic manipulation of cortical layer 5 projection neurons

Bidirectional communication between neurons and glial cells is crucial to establishing and maintaining normal brain function. Some of these interactions are activity-dependent, yet it remains largely unexplored how acute changes in neuronal activity affect glial-to-neuron and neuron-to-glial dynamics. Here, we use excitatory and inhibitory designer receptors exclusively activated by designer drugs (DREADD) to study the effects of acute chemogenetic manipulations of a subpopulation of layer 5 cortical projection and dentate gyrus neurons in adult (Rbp4Cre) mouse brains. We show that acute chemogenetic neuronal activation reduces synaptic density, and increases microglia and astrocyte reactivity, but does not affect parvalbumin (PV+) neurons, only perineuronal nets (PNN). Conversely, acute silencing increases synaptic density and decreases glial reactivity. We show fast glial response upon clozapine-N-oxide (CNO) administration in cortical and subcortical regions. Together, our work provides evidence of fast, activity-dependent, bidirectional interactions between neurons and glial cells.

Spatiotemporal Mapping of the Oxytocin Receptor at Single-Cell Resolution in the Postnatally Developing Mouse Brain.

The oxytocin receptor (OXTR) has garnered increasing attention for its role in regulating both mature behaviors and brain development. It has been established that OXTR mediates a range of effects that are region-specific or period-specific. However, the current studies of OXTR expression patterns in mice only provide limited help due to limitations in resolution. Therefore, our objective was to generate a comprehensive, high-resolution spatiotemporal expression map of Oxtr mRNA across the entire developing mouse brain. We applied RNAscope in situ hybridization to investigate the spatiotemporal expression pattern of Oxtr in the brains of male mice at six distinct postnatal developmental stages (P7, P14, P21, P28, P42, P56). We provide detailed descriptions of Oxtr expression patterns in key brain regions, including the cortex, basal forebrain, hippocampus, and amygdaloid complex, with a focus on the precise localization of Oxtr+ cells and the variance of expression between different neurons. Furthermore, we identified some neuronal populations with high Oxtr expression levels that have been little studied, including glutamatergic neurons in the ventral dentate gyrus, Vgat+Oxtr+ cells in the basal forebrain, and GABAergic neurons in layers 4/5 of the cortex. Our study provides a novel perspective for understanding the distribution of Oxtr and encourages further investigations into its functions.

Continuous exercise training rescues hippocampal long-term potentiation in the VPA rat model of Autism: Uncovering sex-specific effects

Long‐term potentiation (LTP) impairment has been reported in many studies of autistic models. The aim of the present study was to investigate the effects of interval training (IT) and continuous training (CT) exercises on LTP in the hippocampal dentate gyrus (DG) neurons of valproic acid (VPA) rat model of autism. To induce an autism-like model, pregnant rats were injected 500 mg/kg NaVPA (intraperitoneal) on the embryonic day 12.5. IT and CT aerobic exercises started on postnatal day 56 in the offspring. Four weeks after IT and/or CT exercises, the offspring were urethane-anesthetized and placed into a stereotaxic apparatus for surgery, electrode implantation, and field potential recording. In the DG region, excitatory post synaptic potentials (EPSP) slope and population spike (PS) amplitude were measured. Sex differences in LTP were evident for control rats but not for VPA-exposed offspring. LTP was significantly smaller in VPA-exposed male offspring compared with control male rats. In contrast to males, there was no difference between VPA-exposed female offspring and control female rats. Interestingly, we observed a sex difference in the response to exercise between VPA-exposed male and female offspring. CT exercise training (but not IT) increased LTP in VPA-exposed male offspring. Both IT and CT exercise trainings had no effect on intact LTP in VPA-exposed female offspring. Our work suggests that there may be differences in the benefits of exercise interventions based on sex, and CT exercise training could be more beneficial for LTP improvements.

N-acetyltransferase 10 mediates cognitive dysfunction through the acetylation of GABABR1 mRNA in sepsis-associated encephalopathy

Sepsis-associated encephalopathy (SAE) is a critical neurological complication of sepsis and represents a crucial factor contributing to high mortality and adverse prognosis in septic patients. This study explored the contribution of NAT10-mediated messenger RNA (mRNA) acetylation in cognitive dysfunction associated with SAE, utilizing a cecal ligation and puncture (CLP)-induced SAE mouse model. Our findings demonstrate that CLP significantly upregulates NAT10 expression and mRNA acetylation in the excitatory neurons of the hippocampal dentate gyrus (DG). Notably, neuronal-specific Nat10 knockdown improved cognitive function in septic mice, highlighting its critical role in SAE. Proteomic analysis, RNA immunoprecipitation, and real-time qPCR identified GABABR1 as a key downstream target of NAT10. Nat10 deletion reduced GABABR1 expression, and subsequently weakened inhibitory postsynaptic currents in hippocampal DG neurons. Further analysis revealed that microglia activation and the release of inflammatory mediators lead to the increased NAT10 expression in neurons. Microglia depletion with PLX3397 effectively reduced NAT10 and GABABR1 expression in neurons, and ameliorated cognitive dysfunction induced by SAE. In summary, our findings revealed that after CLP, NAT10 in hippocampal DG neurons promotes GABABR1 expression through mRNA acetylation, leading to cognitive dysfunction.

Adult neurogenesis improves spatial information encoding in the mouse hippocampus

Adult neurogenesis is a unique form of neuronal plasticity in which newly generated neurons are integrated into the adult dentate gyrus in a process that is modulated by environmental stimuli. Adult-born neurons can contribute to spatial memory, but it is unknown whether they alter neural representations of space in the hippocampus. Using in vivo two-photon calcium imaging, we find that male and female mice previously housed in an enriched environment, which triggers an increase in neurogenesis, have increased spatial information encoding in the dentate gyrus. Ablating adult neurogenesis blocks the effect of enrichment and lowers spatial information, as does the chemogenetic silencing of adult-born neurons. Both ablating neurogenesis and silencing adult-born neurons decreases the calcium activity of dentate gyrus neurons, resulting in a decreased amplitude of place-specific responses. These findings are in contrast with previous studies that suggested a predominantly inhibitory action for adult-born neurons. We propose that adult neurogenesis improves representations of space by increasing the gain of dentate gyrus neurons and thereby improving their ability to tune to spatial features. This mechanism may mediate the beneficial effects of environmental enrichment on spatial learning and memory.

Electrophysiological activity pattern of mouse hippocampal CA1 and dentate gyrus under isoflurane anesthesia.

General anesthesia can impact a patient's memory and cognition by influencing hippocampal function. The CA1 and dentate gyrus (DG), serving as the primary efferent and gateway of the hippocampal trisynaptic circuit facilitating cognitive learning and memory functions, exhibit significant differences in cellular composition, molecular makeup, and responses to various stimuli. However, the effects of isoflurane-induced general anesthesia on CA1 and DG neuronal activity in mice are not well understood. In this study, utilizing electrophysiological recordings, we examined neuronal population dynamics and single-unit activity (SUA) of CA1 and DG in freely behaving mice during natural sleep and general anesthesia. Our findings reveal that isoflurane anesthesia shifts local field potential (LFP) to delta frequency and reduces the firing rate of SUA in both CA1 and DG, compared to wakefulness. Additionally, the firing rates of DG neurons are significantly lower than CA1 neurons during isoflurane anesthesia, and the recovery of theta power is slower in DG than in CA1 during the transition from anesthesia to wakefulness, indicating a stronger and more prolonged impact of isoflurane anesthesia on DG. This work presents a suitable approach for studying brain activities during general anesthesia and provides evidence for distinct effects of isoflurane anesthesia on hippocampal subregions.

Lithocarpus polystachyus Rehd. leaves aqueous extract inhibits learning and memory impairment in Alzheimer's disease rats: Involvement of the SIRT6/NLRP3 signaling pathway

AbstractAlzheimer's disease (AD) is a chronic and progressive neurodegenerative condition that is influenced by multiple factors along with neuroinflammation and oxidative stress. Our previous study proved that Lithocarpus polystachyus Rehd. aqueous extract (sweet tea aqueous extract, STAE) effectively inhibits hydrogen peroxide‐induced neuronal cell injury. However, it is not clear whether STAE can protect against AD, and its underlying mechanisms are still uncertain. Therefore, the present study was designed to evaluate the possible behavioral and neurochemical effects of STAE on Aβ25‐35‐induced AD rats administered STAE (20, 40, 80 mg/mL) for 14 days. We showed that STAE administration significantly and dose‐dependently ameliorated the cognitive deficits in the AD rat models, assessed in the Morris water maze (MWM) test, Y‐maze test, and novel object recognition (NOR) test. The results of hematoxylin and eosin (H&E) staining and Nissl staining showed that after treatment with STAE, the pathological damage to the hippocampal CA1, CA3, and dentate gyrus (DG) neurons of rats was significantly improved. Furthermore, STAE dose‐dependently inhibited microglia and astrocyte activation in the hippocampus of rats accompanied by increased protein expression of silent mating‐type information regulation 2 homolog 6 (SIRT6) and decreased protein expression of nod‐like receptor thermal protein domain‐associated protein 3 (NLRP3) and its downstream pyroptosis‐related genes after following Aβ25‐35. In summary, our findings indicate that STAE effectively inhibits Aβ25‐35‐induced learning and memory impairment in rats, and the mechanism is, at least partially, related to the regulation of SIRT6/NLRP3 signaling pathway.

Exploring the parity paradox: Differential effects on neuroplasticity and inflammation by APOEe4 genotype at middle age

Female sex and Apolipoprotein E (APOE) ε4 genotype are top non-modifiable risk factors for Alzheimer’s disease (AD). Although female-unique experiences like parity (pregnancy and motherhood) have positive effects on neuroplasticity at middle age, previous pregnancy may also contribute to AD risk. To explore these seemingly paradoxical long-term effects of parity, we investigated the impact of parity with APOEε4 genotype by examining behavioural and neural biomarkers of brain health in middle-aged female rats. Our findings show that primiparous (parous one time) hAPOEε4 rats display increased use of a non-spatial cognitive strategy and exhibit decreased number and recruitment of new-born neurons in the ventral dentate gyrus of the hippocampus in response to spatial working memory retrieval. Furthermore, primiparity and hAPOEε4 genotype synergistically modulate inflammatory markers in the ventral hippocampus. Collectively, these findings demonstrate that previous parity in hAPOEε4 rats confers an added risk to present with reduced activity and engagement of the hippocampus as well as elevated pro-inflammatory signaling, and underscore the importance of considering female-specific factors and genotype in health research.

Altered Expression of PDE4 Genes in Schizophrenia: Insights from a Brain and Blood Sample Meta-Analysis and iPSC-Derived Neurons

Schizophrenia symptomatology includes negative symptoms and cognitive impairment. Several studies have linked schizophrenia with the PDE4 family of enzymes due to their genetic association and function in cognitive processes such as long-term potentiation. We conducted a systematic gene expression meta-analysis of four PDE4 genes (PDE4A-D) in 10 brain sample datasets (437 samples) and three blood sample datasets (300 samples). Subsequently, we measured mRNA levels in iPSC-derived hippocampal dentate gyrus neurons generated from fibroblasts of three groups: healthy controls, healthy monozygotic twins (MZ), and their MZ siblings with schizophrenia. We found downregulation of PDE4B in brain tissues, further validated by independent data of the CommonMind consortium (515 samples). Interestingly, the downregulation signal was present in a subgroup of the patients, while the others showed no differential expression or even upregulation. Notably, PDE4A, PDE4B, and PDE4D exhibited upregulation in iPSC-derived neurons compared to healthy controls, whereas in blood samples, PDE4B was found to be upregulated while PDE4A was downregulated. While the precise mechanism and direction of altered PDE4 expression necessitate further investigation, the observed multilevel differential expression across the brain, blood, and iPSC-derived neurons compellingly suggests the involvement of PDE4 genes in the pathophysiology of schizophrenia.

Dentate gyrus is needed for memory retrieval

The hippocampus is crucial for acquiring and retrieving episodic and contextual memories. In previous studies, the inactivation of dentate gyrus (DG) neurons by chemogenetic- and optogenetic-mediated hyperpolarization led to opposing conclusions about DG’s role in memory retrieval. One study used Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-mediated clozapine N-oxide (CNO)-induced hyperpolarization and reported that the previously formed memory was erased, thus concluding that denate gyrus is needed for memory maintenance. The other study used optogenetic with halorhodopsin induced hyperpolarization and reported and dentate gyrus is needed for memory retrieval. We hypothesized that this apparent discrepancy could be due to the length of hyperpolarization in previous studies; minutes by optogenetics and several hours by DREADD/CNO. Since hyperpolarization interferes with anterograde and retrograde neuronal signaling, it is possible that the memory engram in the dentate gyrus and the entorhinal to hippocampus trisynaptic circuit was erased by long-term, but not with short-term hyperpolarization. We developed and applied an advanced chemogenetic technology to selectively silence synaptic output by blocking neurotransmitter release without hyperpolarizing DG neurons to explore this apparent discrepancy. We performed in vivo electrophysiology during trace eyeblink in a rabbit model of associative learning. Our work shows that the DG output is required for memory retrieval. Based on previous and recent findings, we propose that the actively functional anterograde and retrograde neuronal signaling is necessary to preserve synaptic memory engrams along the entorhinal cortex to the hippocampal trisynaptic circuit.

The gut metabolite indole-3-propionic acid activates ERK1 to restore social function and hippocampal inhibitory synaptic transmission in a 16p11.2 microdeletion mouse model

BackgroundMicrodeletion of the human chromosomal region 16p11.2 (16p11.2+/-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{+/-}$$\\end{document}) is a prevalent genetic factor associated with autism spectrum disorder (ASD) and other neurodevelopmental disorders. However its pathogenic mechanism remains unclear, and effective treatments for 16p11.2+/-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{+/-}$$\\end{document} syndrome are lacking. Emerging evidence suggests that the gut microbiota and its metabolites are inextricably linked to host behavior through the gut-brain axis and are therefore implicated in ASD development. Despite this, the functional roles of microbial metabolites in the context of 16p11.2+/-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{+/-}$$\\end{document} are yet to be elucidated. This study aims to investigate the therapeutic potential of indole-3-propionic acid (IPA), a gut microbiota metabolite, in addressing behavioral and neural deficits associated with 16p11.2+/-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{+/-}$$\\end{document}, as well as the underlying molecular mechanisms.ResultsMice with the 16p11.2+/-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{+/-}$$\\end{document} showed dysbiosis of the gut microbiota and a significant decrease in IPA levels in feces and blood circulation. Further, these mice exhibited significant social and cognitive memory impairments, along with hyperactivation of hippocampal dentate gyrus neurons and reduced inhibitory synaptic transmission in this region. However, oral administration of IPA effectively mitigated the histological and electrophysiological alterations, thereby ameliorating the social and cognitive deficits of the mice. Remarkably, IPA treatment significantly increased the phosphorylation level of ERK1, a protein encoded by the Mapk3 gene in the 16p11.2 region, without affecting the transcription and translation of the Mapk3 gene.ConclusionsOur study reveals that 16p11.2+/-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{+/-}$$\\end{document} leads to a decline in gut metabolite IPA levels; however, IPA supplementation notably reverses the behavioral and neural phenotypes of 16p11.2+/-\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${}^{+/-}$$\\end{document} mice. These findings provide new insights into the critical role of gut microbial metabolites in ASD pathogenesis and present a promising treatment strategy for social and cognitive memory deficit disorders, such as 16p11.2 microdeletion syndrome.92Bbfs5rK2Gd_SbL4an2CwVideo

TAAR1 in dentate gyrus is involved in chronic stress-induced impairments in hippocampal plasticity and cognitive function

Multiple lines of evidence suggest that the trace amine-associated receptor 1 (TAAR1) holds promise as a potential target for stress-related disorders, such as treating major depressive disorder (MDD). The role of TAAR1 in the regulation of adult neurogenesis is recently supported by transcriptomic data. However, it remains unknown whether TAAR1 in dentate gyrus (DG) mediate chronic stress-induced negative effects on hippocampal plasticity and related behavior in mice. The present study consisted of a series of experiments using RNAscope, genetic approaches, behavioral tests, immunohistochemical staining, Golgi-Cox technique to unravel the effects of TAAR1 on alterations of dentate neuronal plasticity and cognitive function in the chronic social defeat stress model. The mice subjected to chronic defeat stress exhibited a noteworthy decrease in the mRNA level of TAAR1 in DG. Additionally, they exhibited compromised social memory and spatial object recognition memory, as well as impaired proliferation and maturation of adult-born dentate granule cells. Moreover, the selective knockout TAAR1 in DG mostly mimicked the cognitive function deficits and neurogenesis impairment induced by chronic stress. Importantly, the administration of the selective TAAR1 partial agonist RO5263397 during stress exposure attenuated the adverse effects of chronic stress on cognitive function, adult neurogenesis, dendritic arborization, and the synapse number of dentate neurons in DG. In summary, our findings suggest that TAAR1 plays a crucial role in mediating the detrimental effects of chronic stress on hippocampal plasticity and cognition. TAAR1 agonists exhibit therapeutic potential for individuals suffering from cognitive impairments associated with MDD.

Ketamine’s rapid and sustained antidepressant effects are driven by distinct mechanisms

Administration of multiple subanesthetic doses of ketamine increases the duration of antidepressant effects relative to a single ketamine dose, but the mechanisms mediating this sustained effect are unclear. Here, we demonstrate that ketamine’s rapid and sustained effects on affective behavior are mediated by separate and temporally distinct mechanisms. The rapid effects of a single dose of ketamine result from increased activity of immature neurons in the hippocampal dentate gyrus without an increase in neurogenesis. Treatment with six doses of ketamine over two weeks doubled the duration of behavioral effects after the final ketamine injection. However, unlike ketamine’s rapid effects, this more sustained behavioral effect did not correlate with increased immature neuron activity but instead correlated with increased numbers of calretinin-positive and doublecortin-positive immature neurons. This increase in neurogenesis was associated with a decrease in bone morphogenetic protein (BMP) signaling, a known inhibitor of neurogenesis. Injection of a BMP4-expressing lentivirus into the dentate gyrus maintained BMP signaling in the niche and blocked the sustained – but not the rapid – behavioral effects of ketamine, indicating that decreased BMP signaling is necessary for ketamine’s sustained effects. Thus, although the rapid effects of ketamine result from increased activity of immature neurons in the dentate gyrus without requiring an increase in neurogenesis, ketamine’s sustained effects require a decrease in BMP signaling and increased neurogenesis along with increased neuron activity. Understanding ketamine’s dual mechanisms of action should help with the development of new rapid-acting therapies that also have safe, reliable, and sustained effects.

Engram reactivation mimics cellular signatures of fear

Engrams, or the physical substrate of memory, recruit heterogeneous cell types. Targeted reactivation of neurons processing discrete memories drives the behavioral expression of memory, though the underlying landscape of recruited cells and their real-time responses remain elusive. To understand how artificial stimulation of fear affects intra-hippocampal neuron-astrocyte dynamics as well as their behavioral consequences, we express channelrhodopsin-2 in an activity-dependent manner within dentate gyrus neurons while recording both cell types with fiber photometry in hippocampal ventral CA1 across learning and memory. Both cell types exhibit shock responsiveness, with astrocytic calcium events uniquely modulated by fear conditioning. Optogenetic stimulation of a hippocampus-mediated engram recapitulates coordinated calcium signatures time locked to freezing, mirroring those observed during natural fear memory recall. Our findings reveal cell-type-specific dynamics in the hippocampus during freezing behavior, emphasizing neuronal-astrocytic coupling as a shared mechanism enabling both natural and artificially induced memory retrieval and the behavioral expression of fear.

Depression-like Behavior Induced by Repeated Administration of Dexamethasone to Lipopolysaccharide-inflamed Mice.

Over the years, animal models of depression have been developed by loading chronic stress, inducing neuroinflammation, or administering drugs that induce depression; however, these results have poor reproducibility. Therefore, it is necessary to develop animal models that exhibit definitive symptoms of depression for studies on potential therapeutics. This study was aimed at investigating depression-like symptoms and their pathogenesis in lipopolysaccharide (LPS)-inflamed mice treated with dexamethasone (DEX). Male ICR mice were injected with LPS, followed by injection with DEX a day later and each day for 6 consecutive days. Depression-like behavior, expression of the glial markers glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba1), and the number of the immature neuronal marker doublecortin (DCX)-positive cells were assessed using tail-suspension test (TST), forced swim test (FST), western blot analysis, and immunohistochemical analysis. Mice in the LPS+DEX group had significantly longer immobility time in the TST and FST than did those in the LPS- or DEX-only and control groups on day 7 post-LPS administration. GFAP and Iba1 expression was significantly elevated in the hippocampus of mice in the LPS group than in those of mice in the control group. Moreover, a significantly lower number of DCX-positive cells was observed in the hippocampal dentate gyrus of mice in the LPS+DEX group compared with that in mice in the LPS- or DEX-only and control groups on day 7 after LPS administration. Repeated DEX administration to LPS-inflamed mice may induce definitive depression-like symptoms by decreasing the number of immature neurons in the hippocampal dentate gyrus. This novel mouse model of depression was produced by repeated administration of steroids to inflamed mice.

The changes of neurogenesis in the hippocampal dentate gyrus of SAMP8 mice and the effects of acupuncture and moxibustion

BackgroundInfluenced by the global aging population, the incidence of Alzheimer's disease (AD) has increased sharply. In addition to increasing β-amyloid plaque deposition and tau tangle formation, neurogenesis dysfunction has recently been observed in AD. Therefore, promoting regeneration to improve neurogenesis and cognitive dysfunction can play an effective role in AD treatment. Acupuncture and moxibustion have been widely used in the clinical treatment of neurodegenerative diseases because of their outstanding advantages such as early, functional, and benign two-way adjustment. It is urgent to clarify the effectiveness, greenness, and safety of acupuncture and moxibustion in promoting neurogenesis in AD treatment. MethodsSenescence-accelerated mouse prone 8 (SAMP8) mice at various ages were used as experimental models to simulate the pathology and behaviors of AD mice. Behavioral experiments, immunohistochemistry, Western blot, and immunofluorescence experiments were used for comparison between different groups. ResultsAcupuncture and moxibustion could increase the number of PCNA+ DCX+ cells, Nissl bodies, and mature neurons in the hippocampal Dentate gyrus (DG) of SAMP8 mice, restore the hippocampal neurogenesis, delay the AD-related pathological presentation, and improve the learning and memory abilities of SAMP8 mice. ConclusionThe pathological process underlying AD and cognitive impairment were changed positively by improving the dysfunction of neurogenesis. This indicates the promising role of acupuncture and moxibustion in the prevention and treatment of AD.

Potential Isoform Interactions Between GRs May Modulate Hippocampal Plasticity Under Different Stress Paradigms

This paper explores the potential interactions between glucocorticoid receptor (GR) isoforms in modulating hippocampal plasticity under varying stress conditions. The relationship between GR activity and hippocampal neurogenesis is complex, with evidence pointing to an inverted U-shaped association. We hypothesize that the hippocampus may differentially express GR-α and GR-β subtypes to fine-tune glucocorticoid signaling and neurogenesis. To test this, we propose utilizing CRISPR-Cas9-mediated genetic editing to generate mouse models with selective GR subtype expression in hippocampal dentate gyrus neurons. We would then expose these mice to controllable (wheel running) and uncontrollable (noise, social Defeat) stresses and quantify GR subtype expression using an advanced NanoBiT protein-interaction assay. The findings would provide insights into the nuanced roles of GR isoforms in mediating stress effects on neuroplasticity. This could inform potential interventions targeting GR balances for stress-related disorders.

Reactivation of memory-encoding dentate gyrus neurons during memory consolidation is associated with subregion-specific, learning- and sleep-mediated biosynthetic changes

Reactivation of memory-encoding dentate gyrus neurons during memory consolidation is associated with subregion-specific, learning- and sleep-mediated biosynthetic changes

Environmental enrichment improves social isolation-induced memory impairment: The possible role of ITSN1-Reelin-AMPA receptor signaling pathway.

Environmental enrichment (EE) through combination of social and non-biological stimuli enhances activity-dependent synaptic plasticity and improves behavioural performance. Our earlier studies have suggested that EE resilience the stress induced depression/ anxiety-like behaviour in Indian field mice Mus booduga. This study was designed to test whether EE reverses the social isolation (SI) induced effect and improve memory. Field-caught mice M. booduga were subjected to behaviour test (Direct wild, DW), remaining animals were housed under SI for ten days and then housed for short-term at standard condition (STSC)/ long-term at standard condition (LTSC) or as group in EE cage. Subsequently, we have examined reference, working memory and expression of genes associated with synaptic plasticity. Our analysis have shown that EE reversed SI induced impairment in reference, working memory and other accompanied changes i.e. increased level of Intersectin 1 (ITSN1), Huntingtin (Htt), Synaptotagmin -IV (SYT4), variants of brain-derived neurotrophic factor (Bdnf - III), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (GluR1) expression, and decreased variants of Bdnf (IV), BDNF, Reelin, Apolipoprotein E receptor 2 (ApoER2), very low-density lipoprotein receptor (VLDLR), Src family tyrosine kinase (SFKs), Disabled protein (Dab)-1, Protein kinase B (PKB/Akt), GluR2, Mitogen-activated protein kinase (MAPK) and Extracellular signal-regulated kinase (ERK1/2) expression. In addition, SI induced reduction in BDNF expressing neurons in dentate gyrus of hippocampus reversed by EE. Further, we found that SI decreases small neuro-active molecules such as Benzenedicarboxylic acid, and increases 2-Pregnene in the hippocampus and feces reversed by EE. Overall, this study demonstrated that EE is effectively reversed the SI induced memory impairment by potentially regulating the molecules associated with the ITSN1-Reelin-AMPA receptor pathway to increase synaptic plasticity.