Neurogenesis In Mice Research Articles

Shati/Nat8l deficiency disrupts adult neurogenesis and causes attentional impairment through dopaminergic neuronal dysfunction in the dentate gyrus.

Successful completion of daily activities relies on the ability to select the relevant features of the environment for memory and recall. Disruption to these processes can lead to various disorders, such as attention-deficit hyperactivity disorder (ADHD). Dopamine is a neurotransmitter implicated in the regulation of several processes, including attention. In addition to the higher-order brain function, dopamine is implicated in the regulation of adult neurogenesis. Previously, we generated mice lacking Shati, an N-acetyltransferase-8-like protein on a C57BL/6J genetic background (Shati/Nat8l-/- ). These mice showed a series of changes in the dopamine system and ADHD-like behavioral phenotypes. Therefore, we hypothesized that deficiency of Shati/Nat8l would affect neurogenesis and attentional behavior in mice. We found aberrant morphology of neurons and impaired neurogenesis in the dentate gyrus of Shati/Nat8l-/- mice. Additionally, research has suggested that impaired neurogenesis might be because of the reduction of dopamine in the hippocampus. Galantamine (GAL) attenuated the attentional impairment observed in the object-based attention test via increasing the dopamine release in the hippocampus of Shati/Nat8l-/- mice. The α7 nicotinic acetylcholine receptor antagonist, methyllycaconitine, and dopamine D1 receptor antagonist, SCH23390, blocked the ameliorating effect of GAL on attentional impairment in Shati/Nat8l-/- mice. These results suggest that the ameliorating effect of GAL on Shati/Nat8l-/- attentional impairment is associated with activation of D1 receptors following increased dopamine release in the hippocampus via α7 nicotinic acetylcholine receptor. In summary, Shati/Nat8l is important in both morphogenesis and neurogenesis in the dentate gyrus and attention, possible via modulation of dopaminergic transmission. Cover Image for this issue: https://doi.org/10.1111/jnc.15061.

Toluene Inhalation Causes Early Anxiety and Delayed Depression with Regulation of Dopamine Turnover, 5-HT1A Receptor, and Adult Neurogenesis in Mice.

Inhaled solvents such as toluene are of particular concern due to their abuse potential that is easily exposed to the environment. The inhalation of toluene causes various behavioral problems, but, the effect of short-term exposure of toluene on changes in emotional behaviors over time after exposure and the accompanying pathological characteristics have not been fully identified. Here, we evaluated the behavioral and neurochemical changes observed over time in mice that inhaled toluene. The mice were exposed to toluene for 30 min at a concentration of either 500 or 2,000 ppm. Toluene did not cause social or motor dysfunction in mice. However, increased anxiety-like behavior was detected in the short-term after exposure, and depression-like behavior appeared as delayed effects. The amount of striatal dopamine metabolites was significantly decreased by toluene, which continued to be seen for up to almost two weeks after inhalation. Additionally, an upregulation of serotonin 1A (5-HT1A) receptor in the hippocampus and the substantia nigra, as well as reduced immunoreactivity of neurogenesis markers in the dentate gyrus, was observed in the mice after two weeks. These results suggest that toluene inhalation, even single exposure, mimics early anxiety- and delayed depression-like emotional disturbances, underpinned by pathological changes in the brain.

Heat Shock Protein A12A Is Essential for Hippocampal Spinogenesis, Neurogenesis and Affective Behavior Development in Mice (1725)

Heat Shock Protein A12A Is Essential for Hippocampal Spinogenesis, Neurogenesis and Affective Behavior Development in Mice (1725)

Ginsenoside Rg1 ameliorates chronic social defeat stress-induced depressive-like behaviors and hippocampal neuroinflammation

Chronic social defeat stress (CSDS) is an ethologically relevant psychosocial stress animal model and has been widely used in depression studies. Ginsenoside Rg1 (Rg1) is the major active ingredients of ginseng with low toxicity and neuroprotective effects. The present study aims to investigate the antidepressant effects of Rg1 in CSDS mice and explore its molecular mechanism. We found that Rg1 (20 or 40 mg/kg, i.g.) administration significantly alleviated depressive-like behaviors caused by 4-week CSDS exposure, as measured by social interaction test and sucrose preference test, tail suspension test and forced swim test. Additionally, Rg1 treatment inhibited CSDS-induced production of IL-6, TNF-α and IL-1β, decreased the expression of iNOS, COX2, and caspase-9 and -3, and inhibited microglial activation (Iba1) in the hippocampus. Rg1 was found to significantly downregulate p-JNK1/2 and p-P38 MAPK levels, upregulate p-ERK1/2 levels and inhibit the expression of phosphorylated NF-κB in the hippocampus. Meanwhile, Rg1 regulated SIRT1 and decreased the levels of acetylated p65 (ac-p65) in the hippocampus. Moreover, the reduction in adult hippocampal neurogenesis in CSDS mice was reversed by Rg1 treatment. In conclusion, our findings suggest that Rg1 prevents depressive-like behavior in CSDS-exposed mice, partially through the downregulation of hippocampal neuroinflammation and the upregulation of adult hippocampal neurogenesis and that these changes presumably occur through increased anti-inflammatory effects and the inhibition of proinflammatory cytokine and neurotoxic mediator expression and microglial activation, which is partly mediated by the regulation of the MAPK and SIRT1 signaling pathways and results in the inhibition of NF-κB transcriptional activity.

Intestinal Bacteria Maintain Adult Enteric Nervous System and Nitrergic Neurons via Toll-like Receptor 2-induced Neurogenesis in Mice

The enteric nervous system (ENS) exists in close proximity to luminal bacteria. Intestinal microbes regulate ENS development, but little is known about their effects on adult enteric neurons. We investigated whether intestinal bacteria or their products affect the adult ENS via toll-like receptors (TLRs) in mice. We performed studies with conventional C57/BL6, germ-free C57/BL6, Nestin-creERT2:tdTomato, Nestin-GFP, and ChAT-cre:tdTomato. Mice were given drinking water with ampicillin or without (controls). Germ-free mice were given drinking water with TLR2 agonist or without (controls). Some mice were given a blocking antibody against TLR2 or a TLR4 inhibitor. We performed whole gut transit, bead latency, and geometric center studies. Feces were collected and analyzed by 16S ribosomal RNA gene sequencing. Longitudinal muscle myenteric plexus (LMMP) tissues were collected, analyzed by immunohistochemistry, and levels of nitric oxide were measured. Cells were isolated from colonic LMMP of Nestin-creERT2:tdTomato mice and incubated with agonists of TLR2 (receptor for gram-positive bacteria), TLR4 (receptor for gram-negative bacteria), or distilled water (control) and analyzed by flow cytometry. Stool from mice given ampicillin had altered composition of gut microbiota with reduced abundance of gram-positive bacteria and increased abundance of gram-negative bacteria, compared with mice given only water. Mice given ampicillin had reduced colon motility compared with mice given only water, and their colonic LMMP had reduced numbers of nitrergic neurons, reduced neuronal nitric oxide synthase production, and reduced colonic neurogenesis. Numbers of colonic myenteric neurons increased after mice were switched from ampicillin to plain water, with increased markers of neurogenesis. Nestin-positive enteric neural precursor cells expressed TLR2 and TLR4. In cells isolated from the colonic LMMP, incubation with the TLR2 agonist increased the percentage of neurons originating from enteric neural precursor cells to approximately 10%, compared with approximately 0.01% in cells incubated with the TLR4 agonist or distilled water. Mice given an antibody against TLR2 had prolonged whole gut transit times; their colonic LMMP had reduced total neurons and a smaller proportion of nitrergic neurons per ganglion, and reduced markers of neurogenesis compared with mice given saline. Colonic LMMP of mice given the TLR4 inhibitor did not have reduced markers of neurogenesis. Colonic LMMP of germ-free mice given TLR2 agonist had increased neuronal numbers compared with control germ-free mice. In the adult mouse colon, TLR2 promotes colonic neurogenesis, regulated by intestinal bacteria. Our findings indicate that colonic microbiota help maintain the adult ENS via a specific signaling pathway. Pharmacologic and probiotic approaches directed towards specific TLR2 signaling processes might be developed for treatment of colonic motility disorders related to use of antibiotics or other factors.

Epigenetic Modifications of GABAergic Interneurons Contribute to Deficits in Adult Hippocampus Neurogenesis and Depression-Like Behavior in Prenatally Stressed Mice.

BackgroundPrenatal stress (PRS) is considered a risk factor for depressive disorder. Adult hippocampal neurogenesis is believed to play a role in the regulation of affective behaviors. GABAergic interneuron is a key modulator in adult hippocampal neurogenesis. Growing evidence indicates that PRS has adverse effects on adult hippocampal neurogenesis and DNA epigenetic modifications of the GABAergic system. The aim of this study was to investigate whether epigenetic GABAergic dysfunction participates in the negative impact of PRS on adult hippocampal neurogenesis and related emotional behaviors.MethodsBehavioral tests were used to explore PRS-induced depression-like behaviors of adult female mice. Immunohistochemistry staining, real-time reverse transcription-polymerase chain reaction, western blot, and chromatin immunoprecipitation were employed to detect adult neurogenesis and epigenetic changes of the GABAergic system in the hippocampus of PRS mice.ResultsPRS mice developed a depression phenotype accompanied by the inhibited maturation of hippocampal newborn neurons. Compared with control mice, PRS mice showed decreased expression of glutamic acid decarboxylase 67 at the mRNA and protein levels. GABAA receptor agonist phenobarbital could rectify the decrease of 5-bromo-2-deoxyuridine/neuronal nuclei double-positive (BrdU+/NeuN+) cells in PRS mice. PRS mice also showed increased expression of DNA methyltransferase 1 and increased binding of DNA methyltransferase 1 to glutamic acid decarboxylase 67 promoter region. The treatment with DNA methyltransferase 1 inhibitor 5-aza-deoxycytidine restored the decrease of BrdU+/NeuN+ cells and depression-like behaviors in PRS mice via improving GABAergic system.ConclusionsThe present results indicate that epigenetic changes of the GABAergic system are responsible for adult hippocampus neurogenesis and depression-like behaviors in PRS mice.

CXCR5 Knockdown Attenuates Hippocampal Neurogenesis Deficits and Cognitive Impairment in a Mouse Model of Sepsis-associated Encephalopathy

In this study, we investigated the potential role of C-X-C chemokine receptor type (CXCR) 5 in neurocognitive function in a mouse model of sepsis-associated encephalopathy (SAE). Adult male C57BL/6J mice received intracerebroventricular injections of small interfering RNAs (siRNAs) against CXCR5 or scrambled control siRNA. After 3 days, SAE was induced by cecal ligation and puncture (CLP, n = 16 per group). Memory and learning ability were tested using the Morris water maze (MWM) on days 5–9 after CLP. Hippocampal expression of CXCR5, interleukin (IL)-1β and IL-6 were measured by western blot. Cell proliferation and the numbers of immature and mature neurons in the dentate gyrus were assessed by immunohistochemistry. CLP mice had deficits in memory and learning, as shown by increased latency in the MWM training sessions and decreased time spent in and crossing the target quadrant on day 9. CLP also increased the number of proliferating and immature neurons and decreased the number of mature neurons. This was accompanied by increased expression of CXCR5, IL-1β and IL-6 in the hippocampus. CXCR5 knockdown attenuated the memory and learning deficits induced by CLP and partially reversed the effects of CLP on numbers of proliferating, immature and mature neurons, and on expression of IL-1β and IL-6 in the hippocampus. These results suggest that CXCR5 knockdown can attenuate sepsis-induced deficits in hippocampal neurogenesis and cognitive function in mice with SAE.

Seizure-induced neuroinflammation contributes to ectopic neurogenesis and aggressive behavior in pilocarpine-induced status epilepticus mice

Epilepsy is a chronic neurological disorder often associated with recurrent seizures. A growing body of evidence suggests that seizures cause structural and functional alterations of the brain. It is reported that behavioral abnormalities frequently occur in patients with epilepsy and experimental epilepsy models. However, the precise pathological mechanisms associated with these epilepsy comorbidities remain largely unknown. Neurogenesis persists throughout life in the hippocampal dentate gyrus (DG) to maintain proper brain function. However, aberrant neurogenesis usually generates abnormal neural circuits and consequently causes neuronal dysfunction. Neuroinflammatory responses are well known to affect neurogenesis and lead to aberrant reorganization of neural networks in the hippocampal DG. Here, in this study, we observed a significant increase in neuroinflammation and in the proliferation and survival of newborn granular cells in the hippocampus of pilocarpine-induced status epilepticus (SE) mice. More importantly, these proliferating and surviving newborn granular cells are largely ectopically located in the hippocampal DG hilus region. Our behavior test demonstrated that SE mice displayed severe aggressive behavior. Pharmacological inhibition of neuroinflammation, however, suppressed the ectopic neurogenesis and countered the enhanced aggressive behavior in SE mice, indicating that seizure-induced neuroinflammation may contribute to ectopic neurogenesis and aggressive behavior in SE mice. These findings establish a key role for neuroinflammation in seizure-induced aberrant neurogenesis and aggressive behavior. Suppressing neuroinflammation in the epileptic brain may reduce ectopic neurogenesis and effectively block the pathophysiological process that leads to aggressive behavior in TLE mice.

Neuroprotective Role of Dietary Supplementation with Omega-3 Fatty Acids in the Presence of Basal Forebrain Cholinergic Neurons Degeneration in Aged Mice.

As major components of neuronal membranes, omega-3 polyunsaturated fatty acids (n-3 PUFA) exhibit a wide range of regulatory functions. Recent human and animal studies indicate that n-3 PUFA may exert beneficial effects on aging processes. Here we analyzed the neuroprotective influence of n-3 PUFA supplementation on behavioral deficits, hippocampal neurogenesis, volume loss, and astrogliosis in aged mice that underwent a selective depletion of basal forebrain cholinergic neurons. Such a lesion represents a valid model to mimic a key component of the cognitive deficits associated with dementia. Aged mice were supplemented with n-3 PUFA or olive oil (as isocaloric control) for 8 weeks and then cholinergically depleted with mu-p75-saporin immunotoxin. Two weeks after lesioning, mice were behaviorally tested to assess anxious, motivational, social, mnesic, and depressive-like behaviors. Subsequently, morphological and biochemical analyses were performed. In lesioned aged mice the n-3 PUFA pre-treatment preserved explorative skills and associative retention memory, enhanced neurogenesis in the dentate gyrus, and reduced volume and VAChT levels loss as well as astrogliosis in hippocampus. The present findings demonstrating that n-3 PUFA supplementation before cholinergic depletion can counteract behavioral deficits and hippocampal neurodegeneration in aged mice advance a low-cost, non-invasive preventive tool to enhance life quality during aging.

Brain Endothelial Cells Are Exquisite Sensors of Age-Related Circulatory Cues

Brain endothelial cells (BECs) are key constituents of the blood-brain barrier (BBB), protecting the brain from pathogens and restricting access of circulatory factors. Yet, because circulatory proteins have prominent age-related effects on adult neurogenesis, neuroinflammation, and cognitive function in mice, we wondered whether BECs receive and potentially relay signals between the blood and brain. Using single-cell RNA sequencing of hippocampal BECs, we discover that capillary BECs-compared with arterial and venous BECs-undergo the greatest transcriptional changes in normal aging, upregulating innate immunity and oxidative stress response pathways. Short-term infusions of aged plasma into young mice recapitulate key aspects of this aging transcriptome, and remarkably, infusions of young plasma into aged mice exert rejuvenation effects on the capillary transcriptome. Together, these findings suggest that the transcriptional age of BECs is exquisitely sensitive to age-related circulatory cues and pinpoint the BBB itself as a promising therapeutic target to treat brain disease.

Morphine modulates hippocampal neurogenesis and contextual memory extinction via miR-34c/Notch1 pathway in male ICR mice

AbstractBackgroundThe opioid Morphine is known to affect neurogenesis in the hippocampus. Evidence has shown that several microRNAs modulate morphine-induced neurogenesis, and hence morphine-induced contextual memory. This complex network has yet to be elucidated. In this study, we screened for morphine addiction related microRNA and determined its effects on hippocampal neurogenesis and morphine-induced contextual memory using the conditioned place preference (CPP) model.MethodsThe previously established CPP model was utilized in this study. For differential expression of miRNA in the hippocampus, the GeneChip miRNA array was used. Lentivirus technology was used to overexpress or downregulate the miRNA, and changes in expression level was verified with qRT-PCR. Protein expression levels were measured with western blot. Immunofluorescence was used to observe the protein expression during the differentiation of NSCs.ResultsThe results showed that morphine administration upregulated microRNA-34c (miR-34c) and Notch1. Downregulating miR-34c in vivo decreased Notch1 expression and partially rescued the morphine-induced inhibition of the differentiation of neural stem cells (NSCs). This did not affect the morphine-induced proliferation of cells. Furthermore, downregulating miR-34c in vivo prolonged the extinction of morphine-induced contextual memory without affecting acquired CPP response.ConclusionThe miR-34c regulates the hippocampal neurogenesis in addicted mice by up-regulating Notch1 expression, by inhibiting differentiation of neural precursor cells. The miR-34c/Notch1 pathway may be a new potential target for the prevention and treatment of opioid psychotic dependence.

Tetrabromobisphenol A-Induced Apoptosis in Neural Stem Cells Through Oxidative Stress and Mitochondrial Dysfunction.

Tetrabromobisphenol A (TBBPA) is widely used in materials like plastics and textiles as a fire retardant. In a previous study, we reported TBBPA might disrupt hippocampal neurogenesis and neurocognitive function in mice. However, the mechanism responsible for these effects has not been established. The present study was undertaken to investigate the potential involvement of oxidative stress and mitochondrial dysfunction in TBBPA-mediated neurotoxicity in neural stem cells. We confirmed TBBPA was more cytotoxic to neural stem cells than to neurons, astrocytes, or fibroblasts, and found that TBBPA-induced neural stem cell apoptosis was accompanied by increased reactive oxygen species generation and mitochondrial dysfunction. At a molecular level, TBBPA-induced apoptosis was determined to be mediated by c-Jun N-terminal kinase-p53 pathway activation. Taken together, these findings suggest that the adverse effects of TBBPA on hippocampal neurogenesis are due to the inhibition of neural stem cell expansion.

The Role of Histone Acetylation in the Sevoflurane-induced Inhibition of Neurogenesis in the Hippocampi of Young Mice

The possibility that exposure to inhalation anaesthetics inhibits neurogenesis and results in memory deficits has attracted considerable interest over the past decade. This study was designed to investigate the mechanism of the sevoflurane exposure-induced decline in hippocampal neurogenesis. Young mice were anaesthetized with a gaseous mixture of 3.0% sevoflurane/60% oxygen 2 h daily for three consecutive days. Sodium butyrate (NaB) administration began 2 h prior to anaesthesia and continued daily until the end of behavioural tests. The Morris water maze (MWM) test was used to determine spatial learning and memory performance. We assessed the effect of repeated sevoflurane exposure on histone acetylation and the expression of brain-derived neurotropic factor (BDNF) and its receptor, tropomyosin-related kinase receptor B (TrkB), in the hippocampus by Western blot (WB). To detect neurogenesis, we first counted the number of neural stem cells (NSCs); we then assessed their proliferation level by immunohistochemistry and estimated the number of new-born cells by immunofluorescence. We found that sevoflurane induced learning and memory deficits in young mice 4 weeks after sevoflurane exposure and that NaB injection restored histone acetylation and improved the performance of the mice in the MWM. NaB also increased the number and proliferation of NSCs and neonatal cells, which were inhibited by sevoflurane. Concomitantly, BDNF and TrkB expression, which was decreased by sevoflurane, was also restored by NaB. Our study showed that sevoflurane affects long-term neurocognitive function and neurogenesis in young mice. Normalization of histone acetylation may alleviate the neurodevelopmental side effects of this anaesthetic.

Spindle Orientation-Independent Control of Cell Fate Determination by RGS3 and KIF20A.

It was proposed that similar to its role in the invertebrate nervous system, mitotic spindle orientation (or cell cleavage plane orientation) of a dividing neural progenitor cell specifies the fate of daughter cells in the mammalian brain, modulating the production of neurons via symmetric versus asymmetric cell divisions during the course of neurogenesis. Experimental tests of the sufficiency of spindle/cleavage plane orientation in mammalian cell fate determination have yielded conflicting results. On the other hand, the necessity of spindle/cleavage plane orientation in mammalian cell fate determination has not yet been addressed. Here we examined the necessity of spindle/cleavage plane orientation during cortical neurogenesis in mice with loss-of-function of the RGS3-KIF20A interaction axis. We present evidence that while inactivation of RGS3 or KIF20A was linked to a shift in neural progenitor cells from proliferative to differentiative divisions in the developing cortex, these genetic mutations did not lead to anticipated alteration in the orientation of spindle/cleavage plane. Our results indicate that the RGS3-KIF20A axis regulates the balance between proliferation and differentiation in the mammalian cortex employing a mechanism independent of spindle/cleavage plane orientation. These data also caution against using spindle/cleavage plane orientation as the synonym for cell fate determination.

Arginase Inhibition Supports Survival and Differentiation of Neuronal Precursors in Adult Alzheimer's Disease Mice.

Adult neurogenesis is a complex physiological process, which plays a central role in maintaining cognitive functions, and consists of progenitor cell proliferation, newborn cell migration, and cell maturation. Adult neurogenesis is susceptible to alterations under various physiological and pathological conditions. A substantial decay of neurogenesis has been documented in Alzheimer’s disease (AD) patients and animal AD models; however, several treatment strategies can halt any further decline and even induce neurogenesis. Our previous results indicated a potential effect of arginase inhibition, with norvaline, on various aspects of neurogenesis in triple-transgenic mice. To better evaluate this effect, we chronically administered an arginase inhibitor, norvaline, to triple-transgenic and wild-type mice, and applied an advanced immunohistochemistry approach with several biomarkers and bright-field microscopy. Remarkably, we evidenced a significant reduction in the density of neuronal progenitors, which demonstrate a different phenotype in the hippocampi of triple-transgenic mice as compared to wild-type animals. However, norvaline showed no significant effect upon the progenitor cell number and constitution. We demonstrated that norvaline treatment leads to an escalation of the polysialylated neuronal cell adhesion molecule immunopositivity, which suggests an improvement in the newborn neuron survival rate. Additionally, we identified a significant increase in the hippocampal microtubule-associated protein 2 stain intensity. We also explore the molecular mechanisms underlying the effects of norvaline on adult mice neurogenesis and provide insights into their machinery.

Downregulation of the Arg/N-degron Pathway Sensitizes Cancer Cells to Chemotherapy In Vivo

The N-degron pathway is an emerging target for anti-tumor therapies, because of its capacity to positively regulate many hallmarks of cancer, including angiogenesis, cell proliferation, motility, and survival. Thus, inhibition of the N-degron pathway offers the potential to be a highly effective anti-cancer treatment. With the use of a small interfering RNA (siRNA)-mediated approach for selective downregulation of the four Arg/N-degron-dependent ubiquitin ligases, UBR1, UBR2, UBR4, and UBR5, we demonstrated decreased cell migration and proliferation and increased spontaneous apoptosis in cancer cells. Chronic treatment with lipid nanoparticles (LNPs) loaded with siRNA in mice efficiently downregulates the expression of UBR-ubiquitin ligases in the liver without any significant toxic effects but engages the immune system and causes inflammation. However, when used in a lower dose, in combination with a chemotherapeutic drug, downregulation of the Arg/N-degron pathway E3 ligases successfully reduced tumor load by decreasing proliferation and increasing apoptosis in amouse model of hepatocellular carcinoma, while avoiding theinflammatory response. Our study demonstrates that UBR-ubiquitin ligases of the Arg/N-degron pathway are promising targets for the development of improved therapies for many cancer types.

Dexmedetomidine attenuates ethanol-induced inhibition of hippocampal neurogenesis in neonatal mice

Background/AimsEthanol (EtOH) exposure during a period comparable to the third trimester in human results in obvious neurotoxicity in the developing hippocampus and persistent deficits in hippocampal neurogenesis. Dexmedetomidine (DEX), a highly selective α-2-adrenergic agonist has been demonstrated to restore the impaired neurogenesis and neuronal plasticity in the dentate gyrus (DG) that follows neurological insult. However, the protective roles of DEX in the EtOH-induced deficits of postnatal neurogenesis in the hippocampus are still unknown. MethodsMice were pretreated with DEX prior to EtOH exposure to determine its protective effects on impaired postnatal hippocampal neurogenesis. Six-day-old neonatal mice were treated with DEX (125 μg/kg) or saline, followed by EtOH at a total of 5 g/kg or an equivalent volume of saline on P7. Immunohistochemistry and immunofluorescence were used to evaluate the neurogenesis and activated microglia in the DG. Quantitative real time PCR (qRT-PCR) was utilized to assess the expression of inflammatory factors in the hippocampus. ResultsDEX pretreatment attenuated the inhibition of EtOH-mediated hippocampal neurogenesis and the reduction of hippocampal neural precursor cells (NPCs). We further confirmed that DEX pretreatment reversed the EtOH-induced microglia activation in the DG as well as the upregulation of the hippocampal TNFα, MCP-1, IL-6, and IL-1β mRNA levels. ConclusionOur findings indicate that DEX pretreatment protects against EtOH-mediated inhibition of hippocampal neurogenesis in postnatal mice and reverses EtOH-induced neuroinflammation via repressing microglia activation and the expression of inflammatory cytokines.

The intellectual disability PAK3 R67C mutation impacts cognitive functions and adult hippocampal neurogenesis.

The link between mutations associated with intellectual disability (ID) and the mechanisms underlying cognitive dysfunctions remains largely unknown. Here, we focused on PAK3, a serine/threonine kinase whose gene mutations cause X-linked ID. We generated a new mutant mouse model bearing the missense R67C mutation of the Pak3 gene (Pak3-R67C), known to cause moderate to severe ID in humans without other clinical signs and investigated hippocampal-dependent memory and adult hippocampal neurogenesis. Adult male Pak3-R67C mice exhibited selective impairments in long-term spatial memory and pattern separation function, suggestive of altered hippocampal neurogenesis. A delayed non-matching to place paradigm testing memory flexibility and proactive interference, reported here as being adult neurogenesis-dependent, revealed a hypersensitivity to high interference in Pak3-R67C mice. Analyzing adult hippocampal neurogenesis in Pak3-R67C mice reveals no alteration in the first steps of adult neurogenesis, but an accelerated death of a population of adult-born neurons during the critical period of 18-28days after their birth. We then investigated the recruitment of hippocampal adult-born neurons after spatial memory recall. Post-recall activation of mature dentate granule cells in Pak3-R67C mice was unaffected, but a complete failure of activation of young DCX + newborn neurons was found, suggesting they were not recruited during the memory task. Decreased expression of the KCC2b chloride cotransporter and altered dendritic development indicate that young adult-born neurons are not fully functional in Pak3-R67C mice. We suggest that these defects in the dynamics and learning-associated recruitment of newborn hippocampal neurons may contribute to the selective cognitive deficits observed in this mouse model of ID.

Prenatal and postnatal bisphenol A exposure inhibits postnatal neurogenesis in the hippocampal dentate gyrus.

Bisphenol A (BPA), an endocrine disruptor with estrogenic effects, is widely used as a raw material for manufacturing polycarbonate plastic and epoxy resins. Prenatal and postnatal exposure to BPA affects brain morphogenesis. However, the effects of prenatal and postnatal BPA exposure on postnatal neurogenesis in mice are poorly understood. In this study, we developed a mouse model of prenatal and postnatal BPA exposure and analyzed its effects on hippocampal neurogenesis. The hippocampal dentate gyrus is vulnerable to chemical exposure, as neurogenesis continues in this region even after birth. Our results showed that in mice, prenatal and postnatal BPA exposure decreased the number of type-1, 2a, 2b, and 3 neural progenitor cells, as well as in granule cells, in the hippocampal dentate gyrus on postnatal days 16 and 70. The effect of prenatal and postnatal BPA exposure on neural progenitors were affected at all differentiation stages. In addition, prenatal and postnatal BPA exposure affects the maintenance of long-term memory on postnatal day 70. Our results suggest that neurodevelopmental toxicity due to prenatal and postnatal BPA exposure might affect postnatal morphogenesis and functional development of the hippocampal dentate gyrus.

GSK-3β activation accelerates early-stage consumption of Hippocampal Neurogenesis in senescent mice.

Adult hippocampal neurogenesis (AHN) deficits contribute to the progression of cognitive impairments during accelerated senescence, with the mechanistic causes poorly understood. Glycogen synthase kinase-3β (GSK-3β) is a critical regulator in prenatal neurodevelopment. The present study aims to study whether and how GSK-3β regulates AHN during the accelerated senescence.Methods: AHN and AHN-dependent cognition and GSK-3β were evaluated in 3- and 6-month senescence-accelerated mice prone 8 (SAM-P8) and senescence resistant 1 (SAM-R1) mice, respectively. GSK-3β was selectively overexpressed in wild-type mice using adeno-associated virus, or knocked-out by crossbreeding with GSK-3β floxed mice in the neural stem cells (NSCs) of Nestin-Cre mice, or pharmacologically inhibited with SB216763 in SAM-P8 mice. AHN was evaluated by BrdU-, DCX-staining and retrovirus-labeling.Results: AHN transiently increased at 3-month, but dramatically dropped at 6-month of age in SAM-P8 mice with a simultaneous activation of GSK-3β at 3-month. Selective overexpression of GSK-3β in hippocampal NSCs of wildtype mice induced long-term AHN deficits due to an accelerated depletion of NSC pool, although it transiently increased the proliferation and survival of the newborn neurons. Pharmacologically inhibiting GSK-3β by SB216763 efficiently preserved AHN and improved contextual memory in 6-month SAM-P8 mice, while conditional knock-out of GSK-3β in NSCs impaired AHN.Conclusion: Early-stage activation of GSK-3β in NSCs impairs AHN by accelerating the depletion of NSC pool, and pharmacological inhibition of GSK-3β is efficient to preserve AHN during the accelerated aging. These results reveal novel mechanisms underlying the AHN impairments during accelerated senescence and provide new targets for pro-neurogenic therapies for related diseases.