Subgranular Zone Of Dentate Gyrus Research Articles

Intravenous Reelin rescues despair-like behavior, Reelin cells in the dentate sub-granular zone, and spleen atrophy in the cyclic corticosterone model of recurring depressive episodes.

Novel antidepressants are predominantly evaluated preclinically in rodent models of chronic stress in which animals experience a single prolonged exposure to chronic stress prior to treatment. Rodent models of a single episode of chronic stress translate poorly to human depressive disorders, which are commonly marked by recurring depressive episodes. Intravenous administration of Reelin has previously been shown to resolve immobility in the forced swim test of rats exposed to a single prolonged exposure to chronic stress. To determine whether Reelin has antidepressant-like properties in a model of recurring depressive episodes, Long-Evans rats (N = 57) were exposed to multiple cycles of chronic stress and stress-free periods before the administration of a single injection of Reelin during the final cycle of chronic stress. The animals then performed in the forced swim test and open field test before the post-mortem evaluation of Reelin cell counts in the sub-granular zone of the dentate gyrus to determine the impact of treatment on hippocampal Reelin levels and spleen white pulp to evaluate the role of Reelin treatment in peripheral inflammation. The results show a single Reelin injection reversed elevated levels of immobility in the forced swim test in both male and female subjects exposed to the cyclic chronic stress model of recurring depressive episodes. Treatment with Reelin also restored Reelin-positive cell counts in the dentate gyrus sub-granular zone and reversed atrophy of spleen white pulp. The results shown here indicate that treatment with Reelin could effectively resolve alterations in forced swim test behavior caused by the cyclic corticosterone model of recurring depressive episodes and that Reelin homeostasis is important for regulating stress-related inflammation. Future preclinical antidepressant research should incorporate models of multiple depressive episodes to improve the translation of preclinical rodent research to human depressive disorders.

Reelin has antidepressant-like effects after repeated or singular peripheral injections

Chronic stress is a significant risk factor for depression onset. The effects of chronic stress can be studied preclinically using a corticosterone (CORT)-administration paradigm that results in a phenotype of depressive-like behavior associated with neurochemical abnormalities in brain regions like the hippocampus. We have recently shown that intrahippocampal infusions of Reelin have a fast effect in normalizing CORT-induced behavioral and neurochemical alterations. Reelin is also expressed in multiple peripheral systems and is found in blood plasma which prompted us to investigate whether peripheral intravenous (i.v.) Reelin injections could also result in antidepressant (ATD)-like actions. Repeated i.v. injections of Reelin were effective in rescuing the CORT-induced increases in forced-swim-test immobility in male and female rats, decreases in Reelin-immunopositive cells in the dentate gyrus subgranular zone, the expression of hippocampal GABAAβ2/3, GluA1, and GluN2B receptors, and serotonin transporter (SERT) membrane protein clustering (MPC) in blood lymphocytes. However, Reelin had only a partial effect on the number and maturation rate of dentate gyrus newborn cells. CORT and Reelin did not affect open field test behavior. After evaluating the effects of multiple Reelin injections, we demonstrated that a single Reelin injection administered at the end of CORT treatment could rescue in 24 h the behavioral (forced-swim-test and object-in-place test), as well as SERT MPC and neurochemical effects of CORT. These findings show that i.v. injections of Reelin have fast ATD-like effects associated with the restoration of hippocampal neurochemical deficits. Although additional mechanistic and pharmacokinetic studies are necessary, our data open the possibility to develop Reelin-based therapeutics with putative fast-ATD activity.

Oral exposure to high-dose ethanol for 28 days in rats reduces neural stem cells and immediate nascent neural progenitor cells as well as FOS-expressing newborn granule cells in adult hippocampal neurogenesis

Drinking alcohol during pregnancy may cause fetal alcohol spectrum disorder. In rats, developmental exposure to ethanol (EtOH) at high doses has shown to induce aberrant neurogenesis in neural progenitor cells (NPCs) during weaning and suppress synaptic plasticity of newborn granule cells after maturation; neuroinflammation was even sustained until the adult stage in the hippocampal dentate gyrus (DG). To investigate whether hippocampal neurogenesis is affected by EtOH exposure in a general toxicity study, EtOH was administered orally to 5-week-old Sprague-Dawley rats at 0%, 10%, and 16% (w/v) in drinking water for 28 days. Exposure to 16% EtOH decreased type-1 neural stem cells (NSCs) and type-2a NPCs in the DG subgranular zone. A reduction in reelin-positive (reelin+) interneurons and an increased number of parvalbumin+ interneurons in the DG hilus, as well as downregulation of Mcm6 and Calb2 in the DG, suggested that self-renewal and proliferation of type-1 NSCs were suppressed. Exposure to 16% EtOH also induced M1-type microglia/peripheral macrophages, and upregulated Il1a and Tnf, suggesting that neuroinflammation might be responsible for the suppressed neurogenesis. In contrast, Drd2 and Tgfb3 upregulation might be ameliorating responses against suppressed neurogenesis. EtOH exposure (16%) also decreased the number of FOS+ granule cells, suggesting that synaptic plasticity was suppressed; concurrent upregulation of glutamate receptor/transporter genes may have occurred as a compensatory response against suppressed synaptic plasticity. Thus, high-dose EtOH exposure in young adult rats disrupted hippocampal neurogenesis differently to exposure during development. However, induction of neuroinflammation and suppressed synaptic plasticity occurred at both EtOH exposure stages.

Microglial-glucocorticoid receptor depletion alters the response of hippocampal microglia and neurons in a chronic unpredictable mild stress paradigm in female mice

Chronic psychological stress is one of the most important triggers and environmental risk factors for neuropsychiatric disorders. Chronic stress can influence all organs via the secretion of stress hormones, including glucocorticoids by the adrenal glands, which coordinate the stress response across the body. In the brain, glucocorticoid receptors (GR) are expressed by various cell types including microglia, which are its resident immune cells regulating stress-induced inflammatory processes. To study the roles of microglial GR under normal homeostatic conditions and following chronic stress, we generated a mouse model in which the GR gene is depleted in microglia specifically at adulthood to prevent developmental confounds. We first confirmed that microglia were depleted in GR in our model in males and females among the cingulate cortex and the hippocampus, both stress-sensitive brain regions. Then, cohorts of microglial-GR depleted and wild-type (WT) adult female mice were housed for 3 weeks in a standard or stressful condition, using a chronic unpredictable mild stress (CUMS) paradigm. CUMS induced stress-related behavior in both microglial-GR depleted and WT animals as demonstrated by a decrease of both saccharine preference and progressive ratio breakpoint. Nevertheless, the hippocampal microglial and neural mechanisms underlying the adaptation to stress occurred differently between the two genotypes. Upon CUMS exposure, microglial morphology was altered in the WT controls, without any apparent effect in microglial-GR depleted mice. Furthermore, in the standard environment condition, GR depleted-microglia showed increased expression of pro-inflammatory genes, and genes involved in microglial homeostatic functions (such as Trem2, Cx3cr1 and Mertk). On the contrary, in CUMS condition, GR depleted-microglia showed reduced expression levels of pro-inflammatory genes and increased neuroprotective as well as anti-inflammatory genes compared to WT-microglia. Moreover, in microglial-GR depleted mice, but not in WT mice, CUMS led to a significant reduction of CA1 long-term potentiation and paired-pulse ratio. Lastly, differences in adult hippocampal neurogenesis were observed between the genotypes during normal homeostatic conditions, with microglial-GR deficiency increasing the formation of newborn neurons in the dentate gyrus subgranular zone independently from stress exposure. Together, these findings indicate that, although the deletion of microglial GR did not prevent the animal’s ability to respond to stress, it contributed to modulating hippocampal functions in both standard and stressful conditions, notably by shaping the microglial response to chronic stress.

Reduced neuroinflammation and enhanced neurogenesis following chronic agomelatine treatment in rats undergoing chronic constant light

Experimental studies have revealed the involvement of neuroinflammation mediated by activated microglia in the pathophysiology of depression, suggesting a novel target for treatment. The atypical antidepressant Agomelatine (Ago) has an advantage compared to the classical antidepressants due to its chronobiotic activity and unique pharmacological profile as a selective agonist at the melatonin receptors and an antagonist at the 5HT2C receptors. We have recently revealed that Ago can exert a potent antidepressant effect in rats exposed to a chronic constant light (CCL). In the present study, we hypothesized that the anti-inflammatory activity of this melatonin analog on activated neuroglia in specific brain structures might contribute to its antidepressant effect in this model. Chronic Ago treatment (40 mg/kg, i.p. for 21 days) was executed during the last 3 weeks of a 6-week period of CCL exposure in rats. The CCL-vehicle-treated rats showed a profound neuroinflammation characterized by microgliosis and astrogliosis in the hippocampus, basolateral amygdala (BL) and partly in the piriform cortex (Pir) confirmed by immunohistochemistry. With the exception of the Pir, the CCL regime was accompanied by neuronal damage, identified by Nissl staining, in the hippocampus and basolateral amygdala and impaired neurogenesis with reduced dendritic complexity of hippocampal neuroprogenitor cells detected by doublecortin-positive cells in the dentate gyrus (DG) subgranular zone compared to the control group. Ago reversed the gliosis in a region-specific manner and partially restored the suppressed DG neurogenesis. Ago failed to produce neuroprotection in CCL exposed rats. The present results suggest that the beneficial effects of Ago represent an important mechanism underlying its antidepressant effect in models characterized by impaired circadian rhythms.

Cyclical administration of corticosterone results in aggravation of depression-like behaviors and accompanying downregulations in reelin in an animal model of chronic stress relevant to human recurrent depression

Depression is recognized as a highly chronic and recurrent disorder. Each successive episode increases susceptibility to future relapses. The current study aimed to develop an animal model of chronic stress relevant to human recurrent depression in order to examine possible neurobiological mechanisms behind this increased vulnerability. We hypothesized that rats with a prior depression-like episode would be sensitized to subsequent stress, developing depression-like behaviors in response to shorter glucocorticoid exposures. Rats were given corticosterone (CORT) or vehicle injections for one, two, or three 21-day cycles, followed by recovery periods. A series of behavioural assessments were conducted at specific time points after CORT treatment or the recovery period. After behavioral testing, the rats were sacrificed for immunohistochemical analyses of the extracellular matrix protein reelin, which is involved in regulating neural plasticity and is decreased in the hippocampus of depression patients. We found that repeated and cyclic exposure to high levels of CORT escalated depression-like behavior (i.e., forced swim test, sucrose preference test) without altering general locomotor activity (i.e., open field test). Changes in depression-like behaviors were accompanied by cumulative and persistent decreases in reelin-positive cells in the dentate gyrus subgranular zone. These data support the idea of an exacerbation of behavioral and neurochemical alterations with recurrent episodes, which highlights the importance of early therapeutic interventions.

Memory-related process in physiological status and alzheimer's disease.

Rejecting central dogma around static status of adult mammalian brain, CNS has the nascent neurons generated in subgranular zone of dentate gyrus in hippocampus which develop to novel glutamatergic granule cells, with the innate feature of transmuting to memory disks. Structural plasticity proceeds with synaptic plasticity to process all the developing stages required to successful maturation and functional integration, whereby the memory context is ready to leave the hippocampus toward cortex network through consolidation process, for being installed and run the memory disk forever. However, in Alzheimer's disease, brain deal with subtle deadly progressive loss of synapsis, neuronal dysfunction and ultimately network failure, resulting in memory decay and cognitive decline-concluding that AD destroys memory formation related-pathways.

Fast-acting antidepressant-like effects of Reelin evaluated in the repeated-corticosterone chronic stress paradigm.

The present report examines the effects of repeated or single intrahippocampal Reelin infusions on measures of depressive-like behavior, cognition, and hippocampal neurogenesis in the repeated-corticosterone (CORT) paradigm. Rats received subcutaneous injections of CORT for 3 weeks and Reelin was infused through an inserted canula in the left hippocampus on days 7, 14, and 21, or only on day 21 of CORT injections. CORT increased immobility in the forced-swim test and impaired object-location memory. Notably, these effects were reversed by both repeated and single-Reelin infusions. CORT decreased both the number and complexity of doublecortin-labeled maturing newborn neurons in the dentate gyrus subgranular zone, and a single-Reelin infusion increased the number but not complexity of newborn neurons, while repeated Reelin infusions restored both. Injection of the AMPA antagonist CNQX blocked the rescue of the behavioral phenotype by Reelin but did completely block the effects of Reelin on hippocampal neurogenesis. Reelin is able to rescue the deficits in AMPA, NMDA, GABAA receptors, mTOR and p-mTOR induced by CORT. These novel results demonstrate that a single intrahippocampal Reelin infusion into the dorsal hippocampus has fast-acting antidepressant-like effects, and that some of these effects may be at least partially independent of Reelin actions on hippocampal neurogenesis.

The Microtubule Severing Protein Katanin Regulates Proliferation of Neuronal Progenitors in Embryonic and Adult Neurogenesis

Microtubule severing regulates cytoskeletal rearrangement underlying various cellular functions. Katanin, a heterodimer, consisting of catalytic (p60) and regulatory (p80) subunits severs dynamic microtubules to modulate several stages of cell division. The role of p60 katanin in the mammalian brain with respect to embryonic and adult neurogenesis is poorly understood. Here, we generated a Katna1 knockout mouse and found that consistent with a critical role of katanin in mitosis, constitutive homozygous Katna1 depletion is lethal. Katanin p60 haploinsufficiency induced an accumulation of neuronal progenitors in the subventricular zone during corticogenesis, and impaired their proliferation in the adult hippocampus dentate gyrus (DG) subgranular zone. This did not compromise DG plasticity or spatial and contextual learning and memory tasks employed in our study, consistent with the interpretation that adult neurogenesis may be associated with selective forms of hippocampal-dependent cognitive processes. Our data identify a critical role for the microtubule-severing protein katanin p60 in regulating neuronal progenitor proliferation in vivo during embryonic development and adult neurogenesis.

Adult neurogenesis in the mammalian dentate gyrus.

Earlier observations in neuroscience suggested that no new neurons form in the mature central nervous system. Evidence now indicates that new neurons do form in the adult mammalian brain. Two regions of the mature mammalian brain generate new neurons: (a) the border of the lateral ventricles of the brain (subventricular zone) and (b) the subgranular zone (SGZ) of the dentate gyrus of the hippocampus. This review focuses only on new neuron formation in the dentate gyrus of the hippocampus. During normal prenatal and early postnatal development, neural stem cells (NSCs) give rise to differentiated neurons. NSCs persist in the dentate gyrus SGZ, undergoing cell division, with some daughter cells differentiating into functional neurons that participate in learning and memory and general cognition through integration into pre-existing neural networks. Axons, which emanate from neurons in the entorhinal cortex, synapse with dendrites of the granule cells (small neurons) of the dentate gyrus. Axons from granule cells synapse with pyramidal cells in the hippocampal CA3 region, which send axons to synapse with CA1 hippocampal pyramidal cells that send their axons out of the hippocampus proper. Adult neurogenesis includes proliferation, differentiation, migration, the death of some newly formed cells and final integration of surviving cells into neural networks. We summarise these processes in adult mammalian hippocampal neurogenesis and discuss the roles of major signalling molecules that influence neurogenesis, including neurotransmitters and some hormones. The recent controversy raised concerning whether or not adult neurogenesis occurs in humans also is discussed.

Genetic Increases in Olfactory Bulb BDNF Do Not Enhance Survival of Adult-Born Granule Cells.

Adult-born neurons produced in the dentate gyrus subgranular zone (SGZ) develop as excitatory hippocampal granule cells (GCs), while those from the subventricular zone (SVZ) migrate to the olfactory bulb (OB), where most develop as GABAergic olfactory GCs. Both types of neurons express TrkB as they mature. Normally ~50% of new olfactory GCs survive, but survival declines if sensory drive is reduced. Increases in endogenous brain-derived neurotrophic factor (BDNF) in hippocampus, particularly with wheel running, enhance dentate GC survival. Whether survival of new olfactory GCs is impacted by augmenting BDNF in the OB, where they mature and integrate, is not known. Here, we determined if increasing OB BDNF expression enhances survival of new GCs, and if it counters their loss under conditions of reduced sensory activity. Neurogenesis was assessed under normal conditions, and following unilateral naris occlusion, in mice overexpressing BDNF in the granule cell layer (GCL). OB BDNF levels were significantly higher in transgenic mice compared to controls, and this was maintained following sensory deprivation. Bromodeoxyuridine (BrdU) cell birth dating showed that at 12-14 days post-BrdU, numbers of new GCs did not differ between genotypes, indicating normal recruitment to the OB. At later intervals, transgenic and control mice showed levels of GC loss in deprived and nondeprived animals that were indistinguishable, as was the incidence of apoptotic cells in the GCL. These results demonstrate that, in contrast to new dentate GCs, elevations in endogenous BDNF do not enhance survival of adult-born olfactory GCs.

Effect of the HDAC Inhibitor, Sodium Butyrate, on Neurogenesis in a Rat Model of Neonatal Hypoxia\u2013Ischemia: Potential Mechanism of Action

Neonatal hypoxic–ischemic (HI) brain injury likely represents the major cause of long-term neurodevelopmental disabilities in surviving babies. Despite significant investigations, there is not yet any known reliable treatment to reduce brain damage in suffering infants. Our recent studies in an animal model of HI revealed the therapeutic potential of a histone deacetylase inhibitor (HDACi). The neuroprotective action was connected with the stimulation of neurogenesis in the dentate gyrus subgranular zone. In the current study, we investigated whether HDACi—sodium butyrate (SB)—would also lead to neurogenesis in the subventricular zone (SVZ). By using a neonatal rat model of hypoxia–ischemia, we found that SB treatment stimulated neurogenesis in the damaged ipsilateral side, based on increased DCX labeling, and restored the number of neuronal cells in the SVZ ipsilateral to lesioning. The neurogenic effect was associated with inhibition of inflammation, expressed by a transition of microglia to the anti-inflammatory phenotype (M2). In addition, the administration of SB increased the activation of the TrkB receptor and the phosphorylation of the transcription factor—CREB—in the ipsilateral hemisphere. In contrast, SB administration reduced the level of HI-induced p75NTR. Together, these results suggest that BDNF–TrkB signaling plays an important role in SB-induced neurogenesis after HI. These findings provide the basis for clinical approaches targeted at protecting the newborn brain damage, which may prove beneficial for treating neonatal hypoxia–ischemia.

Effect of voluntary running on expression of myokines in brains of rats with depression.

This study aimed to demonstrate the histopathology and immunoexpression of exercise-derived myokines in dentate gyrus (DG), medial prefrontal cortex (mPFC) and cerebellum of depressed Wistar rats during depression and after practising voluntary running. Depression was developed by forced swimming for 2 weeks. Voluntary running was performed by voluntary running for 3 weeks. Brain sections were processed and immunostained to detect brain-derived neurotrophic factor (BDNF), macrophage migration inhibitory factor (MIF), vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6). ImageJ software was used to measure the optical density (OD). BDNF was expressed in neurons in DG, mPFC and granular and Purkinje cells in cerebellum. MIF was expressed in neurons of sub-granular zone in DG, mPFC and Purkinje cells. VEGF was expressed in many neurons in DG, mPFC and Purkinje cells. IL-6 was expressed in some neurons in DG, in neuropil of mPFC and in Purkinje cells. In depression, the OD of studied myokines significantly decreased in all examined areas. After voluntary running, the OD of myokines significantly increased in all areas. This study defines the immunohistochemical expression of myokines in brain areas in depression and after voluntary running and reveals the involvement of the mPFC and cerebellum in the pathophysiology of depression.

NFIX-Mediated Inhibition of Neuroblast Branching Regulates Migration Within the Adult Mouse Ventricular-Subventricular Zone.

Understanding the migration of newborn neurons within the brain presents a major challenge in contemporary biology. Neuronal migration is widespread within the developing brain but is also important within the adult brain. For instance, stem cells within the ventricular-subventricular zone (V-SVZ) and the subgranular zone of dentate gyrus of the adult rodent brain produce neuroblasts that migrate to the olfactory bulb and granule cell layer of the dentate gyrus, respectively, where they regulate key brain functions including innate olfactory responses, learning, and memory. Critically, our understanding of the factors mediating neuroblast migration remains limited. The transcription factor nuclear factor I X (NFIX) has previously been implicated in embryonic cortical development. Here, we employed conditional ablation of Nfix from the adult mouse brain and demonstrated that the removal of this gene from either neural stem and progenitor cells, or neuroblasts, within the V-SVZ culminated in neuroblast migration defects. Mechanistically, we identified aberrant neuroblast branching, due in part to increased expression of the guanylyl cyclase natriuretic peptide receptor 2 (Npr2), as a factor contributing to abnormal migration in Nfix-deficient adult mice. Collectively, these data provide new insights into how neuroblast migration is regulated at a transcriptional level within the adult brain.

Expression Profiles of Metallothionein I/II and Megalin in Cuprizone Model of De- and Remyelination

Copper chelator cuprizone (CPZ) is neurotoxicant, which selectively disrupts oligodendroglial respiratory chain, leading to oxidative stress and subsequent apoptosis. Demyelination is, however, followed by spontaneous remyelination owing to the activation of intrinsic CNS repair mechanisms. To explore the participation of metallothioneins (MTs) in these processes, in this study we analyzed the expression profiles of MT-I/II and their receptor megalin (low-density lipoprotein receptor related protein-2) in the brain of mice subjected to different protocols of CPZ feeding.Experiments were performed in female C57BL/6 mice fed with 0.25% CPZ during 1, 3 and 5 weeks. They were sacrificed immediately after feeding with CPZ or 2 weeks after the withdrawal of CPZ. The data showed that CPZ-induced demyelination was followed by high astrogliosis and enhanced expression of MTs and megalin in white (corpus callosum and internal capsule) and gray matter of the brain (cortex, hippocampus, and cerebellum). Moreover, in numerous cortical neurons and progenitor cells the signs of MT/megalin interactions and Akt1 phosphorylation was found supporting the hypothesis that MTs secreted from the astrocytes might directly affect the neuronal differentiation and survival. Furthermore, in mice treated with CPZ for 5 weeks the prominent MTs and megalin immunoreactivities were found on several neural stem cells and oligodendrocyte progenitors in subgranular zone of dentate gyrus and subventricular zone of lateral ventricles pointing to high modulatory effect of MTs on adult neuro- and oligodendrogenesis.The data show that MT I/II perform important cytoprotective and growth-regulating functions in remyelinating processes activated after toxic demyelinating insults.

AhR Deletion Promotes Aberrant Morphogenesis and Synaptic Activity of Adult-Generated Granule Neurons and Impairs Hippocampus-Dependent Memory

Newborn granule cells are continuously produced in the subgranular zone of dentate gyrus throughout life. Once these cells mature, they integrate into pre-existing circuits modulating hippocampus-dependent memory. Subsequently, mechanisms controlling generation and maturation of newborn cells are essential for proper hippocampal function. Therefore, we have studied the role of aryl hydrocarbon receptor (AhR), a ligand-activated bHLH-PAS transcription factor, in hippocampus-dependent memory and granule neuronal morphology and function using genetic loss-of-function approaches based on constitutive and inducible-nestin AhR-/- mice. The results presented here show that the impaired hippocampus-dependent memory in AhR absence is not due to its effects on neurogenesis but to aberrant dendritic arborization and an increased spine density, albeit with a lower number of mature mushrooms spines in newborn granule cells, a finding that is associated with an immature electrophysiological phenotype. Together, our data strongly suggest that AhR plays a pivotal role in the regulation of hippocampal function, by controlling hippocampal granule neuron morphology and synaptic maturation.

Histone Deacetylase Inhibitor Alleviates the Neurodegenerative Phenotypes and Histone Dysregulation in Presenilins-Deficient Mice.

Histone acetylation has been shown to play a crucial role in memory formation, and histone deacetylase (HDAC) inhibitor sodium butyrate (NaB) has been demonstrated to improve memory performance and rescue the neurodegeneration of several Alzheimer’s Disease (AD) mouse models. The forebrain presenilin-1 and presenilin-2 conditional double knockout (cDKO) mice showed memory impairment, forebrain degeneration, tau hyperphosphorylation and inflammation that closely mimics AD-like phenotypes. In this article, we have investigated the effects of systemic administration of NaB on neurodegenerative phenotypes in cDKO mice. We found that chronic NaB treatment significantly restored contextual memory but did not alter cued memory in cDKO mice while such an effect was not permanent after treatment withdrawal. We further revealed that NaB treatment did not rescue reduced synaptic numbers and cortical shrinkage in cDKO mice, but significantly increased the neurogenesis in subgranular zone of dentate gyrus (DG). We also observed that tau hyperphosphorylation and inflammation related protein glial fibrillary acidic protein (GFAP) level were decreased in cDKO mice by NaB. Furthermore, GO and pathway analysis for the RNA-Seq data demonstrated that NaB treatment induced enrichment of transcripts associated with inflammation/immune processes and cytokine-cytokine receptor interactions. RT-PCR confirmed that NaB treatment inhibited the expression of inflammation related genes such as S100a9 and Ccl4 found upregulated in the brain of cDKO mice. Surprisingly, the level of brain histone acetylation in cDKO mice was dramatically increased and was decreased by the administration of NaB, which may reflect dysregulation of histone acetylation underlying memory impairment in cDKO mice. These results shed some lights on the possible molecular mechanisms of HDAC inhibitor in alleviating the neurodegenerative phenotypes of cDKO mice and provide a promising target for treating AD.

Adult Neural Stem Cells Show Regional and Sex‐Dependent Responses to Chronic Poly‐Drug Administration

Cocaine use disorder (CUD) and alcohol use disorder (AUD) are highly prevalent substance use disorders in the US. Cocaine and alcohol co‐abuse is the third most lethal substance combination and affects 12 million Americans annually. Interestingly, it has been reported that females experience greater euphoria when cocaine and alcohol are combined. Individual use of cocaine and alcohol cause neurodegeneration; however little is known about the combined effects of these substances on the neural stem cell (NSC) population. NSCs are a population of cells in the brain maintained throughout life that are characterized by their ability to self‐renew and give rise to new neurons and astrocytes. Efforts in drug addiction research primarily focus on preventing or stopping abuse, however little work is being done to reverse brain damage incurred by chronic drug abuse. Therefore, the NSC population represents a potential therapeutic target due to their regenerative capabilities. The aim of our study is to evaluate regional and sex differences of endogenous adult neural stem cells to chronic treatment with alcohol and/or cocaine. We sought to elucidate the response of adult endogenous NSCs to chronic alcohol and cocaine treatment using an inducible lineage tracing mouse model. Adult mice were randomly divided into 1 of 4 groups: control, cocaine, ethanol, or combination treatment. Daily i.p. injections of cocaine were administered and ethanol was provided in a complete nutrient liquid diet to appropriate groups. Brain tissue was analyzed for markers of NSC survival and differentiation in two distinct brain regions, the subventricular zone of lateral ventricle (SVZ), and subgranular zone of dentate gyrus (SGZ). The SGZ was also evaluated for changes in metabolic enzymes associated with ethanol and cocaine metabolism. We found that NSCs have a unique response to drug depending on the regional location and sex of the animal. Females had more robust decreases in neural stem cell (NSC) survival in the SVZ compared to males. SGZ neurogenesis was reduced drastically in the combination group. There were significant increases in metabolic enzyme expression in response to drug treatment, with notable differences between sexes. Overall, we show drastic changes to the NSC population following exposure to cocaine and ethanol, as well as alterations in metabolic enzyme expression.Support or Funding InformationJohn S. Dunn Foundation NIDA T32 Award (Grant# 5T32DA007287‐17 and 3T32DA007287‐18S1)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Decrease in glucose transporter 1 levels and translocation of glucose transporter 3 in the dentate gyrus of C57BL/6 mice and gerbils with aging

In the present study, we compared the cell-specific expression and changes protein levels in the glucose transporters (GLUTs) 1 and 3, the major GLUTs in the mouse and gerbil brains using immuno-histochemistry and Western blot analysis. In both mouse and gerbils, GLUT1 immunoreactivity was mainly found in the blood vessels in the dentate gyrus, while GLUT3 immunoreactivity was detected in the subgranular zone and the molecular layer of the dentate gyrus. GLUT1-immunoreactivity in blood vessels and GLUT1 protein levels were significantly decreased with age in the mice and gerbils, respectively. In addition, few GLUT3-immunoreactive cells were found in the subgranular zone in aged mice and gerbils, but GLUT3-immunoreactivity was abundantly found in the polymorphic layer of dentate gyrus in mice and gerbils with a dot-like pattern. Based on the double immunofluorescence study, GLUT3-immunoreactive structures in gerbils were localized in the glial fibrillary acidic protein-immunoreactive astrocytes in the dentate gyrus. Western blot analysis showed that GLUT3 expression in the hippocampal homogenates was slightly, although not significantly, decreased with age in mice and gerbils, respectively. These results indicate that the reduction in GLUT1 in the blood vessels of dentate gyrus and GLUT3 in the subgranular zone of dentate gyrus may be associated with the decrease in uptake of glucose into brain and neuroblasts in the dentate gyrus. In addition, the expression of GLUT3 in the astrocytes in polymorphic layer of dentate gyrus may be associated with metabolic changes in glucose in aged hippocampus.

The effect of maternal separation on the expression of glucocorticoid receptor and doublecortin in brain regions of young mice

Objective To observe the effect of maternal separation(MS)on the expression of glucocorticoid receptor(GR)and doublecortin(DCX)in hippocampus and prefrontal cortex of young mice. Methods Fifteen pregnant mice were randomly divided into 5 groups: the experimental group(3 d, 7 d, 14 d, 21 d)and the control group, n=3 in each group. Neonatal mice in experimental group were separated from mother for 3 h once a day, and the mice in control group were caged with mother without any processing after birth. All mice were weaned in postanal day 23. Separating female and male mice, and the male mice were killed and the brains were taken in postanal day 42. The expression and distribution of GR and DCX in hippocampus and prefrontal cortex were determined by immunohistochemical staining and Image J image analysis technique. Results The average optical density values of GR positive cells in hippocampus and prefrontal cortex, the average optical density values of DCX positive cells in hippocampal dentate gyrus subgranular zone in 3 d, 7 d, 14 d and 21 d group were(GR in hippocampus: 3 d((0.332±0.054)OD/μm2, 7 d(0.258±0.045)OD/μm2, 14 d(0.197±0.043)OD/μm2, 21 d(0.164±0.053)OD/μm2), (GR in prefrontal cortex: 3 d(0.356±0.043)OD/μm2, 7 d(0.278±0.041)OD/μm2, 14 d(0.220±0.039)OD/μm2, 21 d(0.157±0.034)OD/μm2)and(DCX in hippocampus: 3 d(0.193±0.020)OD/μm2, 7 d(0.146±0.033)OD/μm2, 14 d(0.110±0.032)OD/μm2, 21 d(0.060±0.017)OD/μm2)were lower than those in control group, which showed a decreasing trend with the increase of seperation time, and the average optical density values in 7 d, 14 d and 21 d group were obviously lower than those in control group(P<0.05). The average optical density values had statistical significance among the experimental groups(P <0.05). Conclusion MS can cause the decrease of GR in hippocampus and prefrontal cortex and reduce neurogenesis in the hippocampal dentate gyrus subgranular zone in young mice. It shows that the longer the seperation time, the greater the effect on hypothalamic-pituitary-adrenal(HPA) axis and neurogenesis. Key words: Maternal separation; Hippocampus; Prefrontal cortex; Glucocorticoid receptor; Doublecortin