Hippocampal Neurogenesis Research Articles

Hepcidin deficiency impairs hippocampal neurogenesis and mediates brain atrophy and memory decline in mice

BackgroundHepcidin is the master regulator of iron homeostasis. Hepcidin downregulation has been demonstrated in the brains of Alzheimer’s disease (AD) patients. However, the mechanism underlying the role of hepcidin downregulation in cognitive impairment has not been elucidated.MethodsIn the present study, we generated GFAP-Cre-mediated hepcidin conditional knockout mice (HampGFAP cKO) to explore the effect of hepcidin deficiency on hippocampal structure and neurocognition.ResultsWe found that the HampGFAP cKO mice developed AD-like brain atrophy and memory deficits. In particular, the weight of the hippocampus and the number of granule neurons in the dentate gyrus were significantly reduced. Further investigation demonstrated that the morphological change in the hippocampus of HampGFAP cKO mice was attributed to impaired neurogenesis caused by decreased proliferation of neural stem cells. Regarding the molecular mechanism, increased iron content after depletion of hepcidin followed by an elevated level of the inflammatory factor tumor necrosis factor-α accounted for the impairment of hippocampal neurogenesis in HampGFAP cKO mice. These observations were further verified in GFAP promoter-driven hepcidin knockdown mice and in Nestin-Cre-mediated hepcidin conditional knockout mice.ConclusionsThe present findings demonstrated a critical role for hepcidin in hippocampal neurogenesis and validated the importance of iron and associated inflammatory cytokines as key modulators of neurodevelopment, providing insights into the potential pathogenesis of cognitive dysfunction and related treatments.Graphical

Azithromycin preserves adult hippocampal neurogenesis and behavior in a mouse model of sepsis

The mammalian hippocampus can generate new neurons throughout life. Known as adult hippocampal neurogenesis (AHN), this process participates in learning, memory, mood regulation, and forgetting. The continuous incorporation of new neurons enhances the plasticity of the hippocampus and contributes to the cognitive reserve in aged individuals. However, the integrity of AHN is targeted by numerous pathological conditions, including neurodegenerative diseases and sustained inflammation. In this regard, the latter causes cognitive decline, mood alterations, and multiple AHN impairments. In fact, the systemic administration of Lipopolysaccharide (LPS) from E. coli to mice (a model of sepsis) triggers depression-like behavior, impairs pattern separation, and decreases the survival, maturation, and synaptic integration of adult-born hippocampal dentate granule cells. Here we tested the capacity of the macrolide antibiotic azithromycin to neutralize the deleterious consequences of LPS administration in female C57BL6J mice. This antibiotic exerted potent neuroprotective effects. It reversed the increased immobility time during the Porsolt test, hippocampal secretion of pro-inflammatory cytokines, and AHN impairments. Moreover, azithromycin promoted the synaptic integration of adult-born neurons and functionally remodeled the gut microbiome. Therefore, our data point to azithromycin as a clinically relevant drug with the putative capacity to ameliorate the negative consequences of chronic inflammation by modulating AHN and hippocampal-related behaviors.

Seizure-induced LIN28A disrupts pattern separation via aberrant hippocampal neurogenesis.

Prolonged seizures can disrupt stem cell behavior in the adult hippocampus, an important brain structure for spatial memory. Here, using a mouse model of pilocarpine-induced status epilepticus (SE), we characterized spatiotemporal expression of Lin28a mRNA and proteins after SE. Unlike Lin28a transcripts, induction of LIN28A protein after SE was detected mainly in the subgranular zone, where immunoreactivity was found in progenitors, neuroblasts, and immature and mature granule neurons. To investigate roles of LIN28A in epilepsy, we generated Nestin-Cre:Lin28aloxP/loxP (conditional KO [cKO]) and Nestin-Cre:Lin28a+/+ (WT) mice to block LIN28A upregulation in all neuronal lineages after acute seizure. Adult-generated neuron- and hippocampus-associated cognitive impairments were absent in epileptic LIN28A-cKO mice, as evaluated by pattern separation and contextual fear conditioning tests, respectively, while sham-manipulated WT and cKO animals showed comparable memory function. Moreover, numbers of hilar PROX1-expressing ectopic granule cells (EGCs), together with PROX1+/NEUN+ mature EGCs, were significantly reduced in epileptic cKO mice. Transcriptomics analysis and IHC validation at 3 days after pilocarpine administration provided potential LIN28A downstream targets such as serotonin receptor 4. Collectively, our findings indicate that LIN28A is a potentially novel target for regulation of newborn neuron-associated memory dysfunction in epilepsy by modulating seizure-induced aberrant neurogenesis.

OXCT1 regulates hippocampal neurogenesis and alleviates cognitive impairment via the Akt/GSK-3β/β-catenin pathway after subarachnoid hemorrhage

BackgroundSubarachnoid hemorrhage (SAH) is a life-threatening neurological disease that usually has a poor prognosis. Neurogenesis is a potential therapeutic target for brain injury. Ketone metabolism also plays neuroprotective roles in many neurological disorders. OXCT1 (3-Oxoacid CoA-Transferase 1) is the rate-limiting enzyme of ketone body oxidation. In this study, we explored whether increasing ketone oxidation by upregulating OXCT1 in neurons could promote neurogenesis after SAH, and evaluated the potential mechanism involved in this process. MethodsThe β-hydroxybutyrate content was measured using an enzymatic colorimetric assay. Adeno-associated virus targeting neurons was injected to overexpress OXCT1, and the expression and localization of proteins were evaluated by western blotting and immunofluorescence staining. Adult hippocampal neurogenesis was evaluated by dual staining with doublecortin and 5-Ethynyl-2′-Deoxyuridine. LY294002 was intracerebroventricularly administered to inhibit Akt activity. The Morris water maze and Y-maze tests were employed to assess cognitive function after SAH. ResultsThe results showed that OXCT1 expression and hippocampal neurogenesis significantly decreased in the early stage of SAH. Overexpression of OXCT1 successfully increased hippocampal neurogenesis via activation of Akt/GSK-3β/β-catenin signaling and improved cognitive function, both of which were reversed by administration of LY294002. ConclusionsOXCT1 regulated hippocampal ketone body metabolism and increased neurogenesis through mechanisms mediated by the Akt/GSK-3β/β-catenin pathway, improving cognitive impairment after SAH.

Potential role of hippocampal neurogenesis in spinal cord injury induced post-trauma depression.

It has been reported both in clinic and rodent models that beyond spinal cord injury directly induced symptoms, such as paralysis, neuropathic pain, bladder/bowel dysfunction, and loss of sexual function, there are a variety of secondary complications, including memory loss, cognitive decline, depression, and Alzheimer's disease. The large-scale longitudinal population-based studies indicate that post-trauma depression is highly prevalent in spinal cord injury patients. Yet, few basic studies have been conducted to address the potential molecular mechanisms. One of possible factors underlying the depression is the reduction of adult hippocampal neurogenesis which may come from less physical activity, social isolation, chronic pain, and elevated neuroinflammation after spinal cord injury. However, there is no clear consensus yet. In this review, we will first summarize the alteration of hippocampal neurogenesis post-spinal cord injury. Then, we will discuss possible mechanisms underlie this important spinal cord injury consequence. Finally, we will outline the potential therapeutic options aimed at enhancing hippocampal neurogenesis to ameliorate depression.

DPP-4 inhibition by linagliptin ameliorates age-related mild cognitive impairment by regulating microglia polarization in mice

Extensive preclinical evidence demonstrates a causative link between insulin signaling dysfunction and the pathogenesis of Alzheimer's disease (AD), and diabetic drugs may represent a promising approach to fighting AD. However, it remains to be determined which antidiabetic drugs are more effective in preventing cognitive impairment. Thus, the present study investigated the effect of dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin on cognitive impairment in middle-aged mice by comparing it with the effect of metformin. We found that DPP-4 activity increased in the hippocampus of middle-aged mice, and DPP-4 was mainly expressed by microglia rather than astrocytes and oligodendrocytes. DPP-4 directly regulated M1/M2 microglia polarization following LPS or IL-4 stimulation, while DPP-4 inhibitor, linagliptin, suppressed M1-polarized activation and induced M2-polarized activation. Both linagliptin and metformin enhanced cognitive ability, increased hippocampal synaptic plasticity and neurogenesis, and decreased age-related oxidative stress and inflammation by regulating microglia polarization in the hippocampus of middle-aged mice. The combination of linagliptin and metformin showed a maximum protective effect compared to the individual drugs alone. Loss of macrophage inflammatory protein-1α (MIP-1α), a DPP-4 substrate, abrogated the cognitive protection and anti-inflammation effects of linagliptin. Therefore, the current investigation exhibits a potential utility for DPP-4 inhibition in attenuating microglia-mediated inflammation and preventing mild cognitive impairment (MCI) in middle-aged mice, and the effect was partly mediated by MIP-1α.

Distinct microglial transcriptomic signatures within the hippocampus.

Microglia, the resident immune cells of the brain, are crucial in the development of the nervous system. Recent evidence demonstrates that microglia modulate adult hippocampal neurogenesis by inhibiting cell proliferation of neural precursors and survival both in vitro and in vivo, thus maintaining a balance between cell division and cell death in the neural stem cell pool. There are increasing reports suggesting these microglia found in neurogenic niches differ from their counterparts in non-neurogenic areas. Here, we present evidence that hippocampal microglia exhibit transcriptomic heterogeneity, with some cells expressing genes associated with neurogenesis. By comprehensively profiling myeloid lineage cells in the hippocampus using single cell RNA-sequencing, we have uncovered a small, yet distinct population of microglia which exhibit depletion in genes associated with homeostatic microglia and enrichment of genes associated with phagocytosis. Intriguingly, this population also expresses a gene signature with substantial overlap with previously characterized phenotypes, including disease associated microglia (DAM), a particularly unique and compelling microglial state.

Gut microbiome promotes mice recovery from stress-induced depression by rescuing hippocampal neurogenesis

Studies from rodents to primates and humans indicate that individuals vary in how resilient they are to stress, and understanding the basis of these variations may help improve treatments for depression. Here we explored the potential contribution of the gut microbiome to such variation. Mice were exposed to chronic unpredictable mild stress (CUMS) for 4 weeks then allowed to recover for 3 weeks, after which they were subjected to behavioral tests and categorized as showing low or high stress resilience. The two types of mouse were compared in terms of hippocampal gene expression using RNA sequencing, fecal microbiomes using 16S RNA sequencing, and extent of neurogenesis in the hippocampus using immunostaining of brain sections. Fecal microbiota were transplanted from either type of mouse into previously stress-exposed and stress-naïve animals, and the effects of the transplantation on stress-induced behaviors and neurogenesis in the hippocampus were examined. Finally, we blocked neurogenesis using temozolomide to explore the role of neurogenesis promoted by fecal microbiota transplantation in enhancing resilience to stress. Results showed that highly stress-resilient mice, but not those with low resilience, improved significantly on measures of anhedonia, behavioral despair, and anxiety after 3-week recovery from CUMS. Their feces showed greater abundance of Lactobacillus, Bifidobacterium and Romboutsia than feces from mice with low stress resilience, as well as lower abundance of Staphylococcus, Psychrobacter and Corynebacterium. Similarly, highly stress-resilient mice showed greater neurogenesis in hippocampus than animals with low stress resilience. Transplanting fecal microbiota from mice with high stress resilience into previously CUMS-exposed recipients rescued neurogenesis in hippocampus, facilitating recovery from stress-induced depression and cognitive decline. Blockade of neurogenesis with temozolomide abolished recovery of recipients from CUMS-induced depression and cognitive decline in mice transplanted with fecal microbiota from mice with high stress resilience. In conclusion, our results suggested that remodeling of the gut microbiome after stress may reverse stress-induced impairment of hippocampal neurogenesis and thereby promote recovery from stress-induced depression.

Sex-specific effects of intermittent fasting on hippocampal neurogenesis via the gut-brain axis.

Intermittent fasting (IF) is a widely used dietary strategy that has shown several advantageous impacts on general health and aging. IF has recently been linked to the control of neurogenesis, a crucial process for emotional control, memory, and learning, in the hippocampus. Nevertheless, there is little knowledge about the sex-specific impacts of IF on hippocampal neurogenesis and the related mechanisms, which were investigated in this study among both male and female rats, together with analyzing the involvement of the flora-gut-brain axis in facilitating these effects. Our findings show that IF favorably affects hippocampus neurogenesis in female mice relative to male mice, suggesting a sex-specific mechanism. In addition, IF influenced the diversity of the gut microbiota and decreased the synthesis of fructose-1-phosphate (F-1-P), which is believed together with fructose metabolism to be linked to neurological damage and cognitive decline. Collectively, these data indicate that the connection between the flora-gut-brain axis and hippocampus neurogenesis is significant.

Stimulation of the muscarinic receptor M4 regulates neural precursor cell proliferation and promotes adult hippocampal neurogenesis.

Cholinergic signaling plays a crucial role in the regulation of adult hippocampal neurogenesis; however, the mechanisms by which acetylcholine mediates neurogenic effects are not completely understood. Here, we report the expression of muscarinic acetylcholine receptor subtype M4 (M4 mAChR) on a subpopulation of neural precursor cells (NPCs) in the adult mouse hippocampus, and demonstrate that its pharmacological stimulation promotes their proliferation, thereby enhancing the production of new neurons in vivo. Using a targeted ablation approach, we also show that medial septum (MS) and the diagonal band of Broca (DBB) cholinergic neurons support both the survival and morphological maturation of adult-born neurons in the mouse hippocampus. Although the systemic administration of an M4-selective allosteric potentiator fails to fully rescue the MS/DBB cholinergic lesion-induced decrease in hippocampal neurogenesis, it further exacerbates the impairment in the morphological maturation of adult-born neurons. Collectively, these findings reveal stage-specific roles of M4 mAChRs in regulating adult hippocampal neurogenesis, uncoupling their positive role in enhancing the production of new neurons from the M4-induced inhibition of their morphological maturation, at least in the context of cholinergic signaling dysfunction.

Taurine Improved Autism-Like Behaviours and Defective Neurogenesis of the Hippocampus in BTBR Mice through the PTEN/mTOR/AKT Signalling Pathway.

Effective treatment of patients with autism spectrum disorder (ASD) is still absent so far. Taurine exhibits therapeutic effects towards the autism-like behaviour in ASD model animals. Here, we determined the mechanism of taurine effect on hippocampal neurogenesis in genetically inbred BTBR T+ tf/J (BTBR) mice, a proposed model of ASD. In this ASD mouse model, we explored the effect of oral taurine supplementation on ASD-like behaviours in an open field test, elevated plus maze, marble burying test, self-grooming test, and three-chamber test. The mice were divided into four groups of normal controls (WT) and models (BTBR), who did or did not receive 6-week taurine supplementation in water (WT, WT+ Taurine, BTBR, and BTBR+Taurine). Neurogenesis-related effects were determined by Ki67 immunofluorescence staining. Western blot analysis was performed to detect the expression of phosphatase and tensin homologue deleted from chromosome 10 (PTEN)/mTOR/AKT pathway-associated proteins. Our results showed that taurine improved the autism-like behaviour, increased the proliferation of hippocampal cells, promoted PTEN expression, and reduced phosphorylation of mTOR and AKT in hippocampal tissue of the BTBR mice. In conclusion, taurine reduced the autism-like behaviour in partially inherited autism model mice, which may be associa-ted with improving the defective neural precursor cell proliferation and enhancing the PTEN-associated pathway in hippocampal tissue.

Volume of the Dentate Gyrus/CA4 Hippocampal subfield mediates the interplay between sleep quality and depressive symptoms

BackgroundEmerging evidence increasingly suggests that poor sleep quality is associated with depressive symptoms. The hippocampus might play a crucial role in the interplay between sleep disturbance and depressive symptomatology, e.g., hippocampal atrophy is typically seen in both insomnia disorder and depression. Thus, examining the role of hippocampal volume in the interplay between poor sleep quality and depressive symptoms in large healthy populations is vital. MethodsWe investigated the association between self-reported sleep quality, depressive symptoms, and hippocampal total and subfields’ volumes in 1603 healthy young adults from the Behavioral Brain Research Project. Mediation analysis explored the mediating role of hippocampal volumes between sleep quality and depressive symptoms. ResultsSelf-reported sleep quality and depressive symptoms were positively correlated. In addition, it negatively related to three hippocampal subfields but not total hippocampal volume. In particular, hippocampal subfield DG and CA4 volumes mediated the interrelationship between poor sleep quality and depressive symptoms. ConclusionsOur findings improved the current understanding of the relationship between sleep disturbance, depressive symptomatology, and hippocampal subfields in healthy populations. Considering the crucial role of DG in hippocampal neurogenesis, our results suggest that poor sleep quality may contribute to depression through a reduction of DG volume leading to impaired neurogenesis which is crucial for the regulation of mood.

Diet enriched with high-phenolic cocoa potentiates hippocampal brain-derived neurotrophic factor expression and neurogenesis in healthy adult micewith subtle effects on memory.

Cocoa is widely known for its health benefits, but its neurocognitive impact remains underexplored. This preclinical study aimed to investigate the effects of cocoa and cocoa polyphenols on hippocampal neuroplasticity, cognitive function and emotional behavior. Seventy young-adult C57BL/6JRj male and female mice were fed either a standard diet (CTR) or a diet enriched with 10% high-phenolic content cocoa (HPC) or low-phenolic content cocoa (LPC) for at least four weeks. In a first experiment, behavioral tests assessing exploratory behavior, emotional responses and hippocampal-dependent memory were conducted four weeks into the diet, followed by animal sacrifice a week later. Adult hippocampal neurogenesis and brain-derived neurotrophic factor (BDNF) expression in the hippocampus and prefrontal cortex were evaluated using immunohistochemistry and western blot. In a different experiment, hippocampal synaptic response, long-term potentiation and presynaptic-dependent short-term plasticity were studied by electrophysiology. Cocoa-enriched diets had minimal effects on exploratory activity and anxiety-like behavior, except for reduced locomotion in the LPC group. Only the HPC diet enhanced object recognition memory, while place recognition memory and spatial navigation remained unaffected. The HPC diet also increased adult hippocampal neurogenesis, boosting the proliferation, survival and number of young adult-born neurons. However, both cocoa-enriched diets increased immobility in the forced swimming test and hippocampal BDNF expression. Hippocampal electrophysiology revealed no alterations in neuroplasticity among diets. The results were mostly unaffected by sex. Overall, the HPC diet demonstrated greater potential regarding cognitive and neuroplastic benefits, suggesting a key role of cocoa flavanols in dietary interventions aimed at enhancing brain health.

Unlocking the pathological pathway in urinary tract infection-induced brain fog: A literature review

Brain fog is a common and bothersome symptom caused by urinary tract infections. Along with other symptoms like delirium, memory issues, confusion, and disorientation, this cognitive impairment may include trouble thinking clearly. Sudden confusion or delirium can be brought on by urinary tract infections, especially in elderly or dementia patients. It is hypothesized that urinary tract infections affect hippocampal neurogenesis and other aspects of brain homeostasis, which may be linked to their effects on cognitive function. Moreover, mental anguish and confusion are linked to urinary tract infections, though not all symptoms that resemble urinary tract infections are caused by urinary tract infections. Our search turned up articles about delirium, brain fog, and urinary tract infections in PubMed, Google Scholar, Scopus, and other online databases. Urinary tract infections (UTIs) can cause a variety of symptoms, including brain fog, confusion, and delirium. These symptoms can impair cognitive function and require a thorough diagnosis. This review describes the various symptoms that are linked to urinary tract infections, ranging from traditional indications like fever and frequent urination to non-specific symptoms like delirium and confusion. It emphasizes how important it is to diagnose and comprehend non-specific symptoms by including assessment tools such as the Glasgow Coma Scale, DSM-V, and the Brief Confusion Assessment Method. In addition, it discusses the current controversy regarding the management of individuals with asymptomatic bacteriuria or urinary tract infections, emphasizing the difficulties in avoiding and treating urinary tract infections -related mental impairment. Confusion and delirium brought on by urinary tract infections are better understood when underlying causes, such as immunological, genetic, and microbiological factors, are investigated. Evaluating underlying factors such as immunological, genetic, microbiological aspects can lead to a better understanding of the confusion and uncertainty caused by UTI. This knowledge can help healthcare professionals in conditions, in order to improve diagnostic, therapeutic and management strategies for patients experiencing UTI and possibly cognitive impairment.

Gene expression profiles of neuroinflammatory responses in broad brain regions in rats repeatedly administered with N-methyl-N-nitrosourea for 28 days.

N-methyl-N-nitrosourea (MNU) exposure impairs hippocampal neurogenesis in rats. The present study investigated the gene expression profiles that were commonly up or downregulated across different brain substructures in response to repeated MNU administration in rats. Five-week-old rats were orally administered MNU at 0, 5, 15 mg/kg body weight/day for 28 days and subjected to gene expression microarray analysis in the hippocampal dentate gyrus, corpus callosum, cerebral cortex and cerebellar vermis. MNU at 15 mg/kg revealed multiple functional clusters of upregulated genes related to immune and inflammatory responses in all brain regions, and also clusters of up or downregulated genes related to regulation of apoptotic process in several regions. Specifically, the upregulated genes commonly found in all four regions were enriched in clusters of "immune response" and/or "inflammatory response" (Cd74, Ccl3, Fcgr3a, Serping1, Lgals3, Fcgr2b, Hcst, Kcnn4, Tnf, Gpr18, Tyrobp and Cyba) and "metal-binding proteins" (Mt1, Mt2A and Apobec1). Meanwhile, downregulated genes common to all four regions (Bmp4, Vcan and Fhit) were included in clusters of "cell proliferation", "glial cell migration" and "nucleotide metabolism". Immunohistochemical analysis of representative gene products revealed that in all brain regions examined, MNU treatment increased metallothionein-I/II + cells and galectin-3+ cells co-expressing Iba1, and also increased Iba1+ and CD68+ cells. These results suggest that repeated MNU administration in rats causes neuroinflammation and oxidative stress accompanied by apoptosis of neural cell components in the brain, as well as concurrent anti-inflammatory responses for neuroprotection from MNU exposure, involving activation of microglia producing metallothionein-I/II and galectin-3 on these responses.

Adult Neurogenesis, Context Encoding, and Pattern Separation: A Pathway for Treating Overgeneralization.

In mammals, the subgranular zone of the dentate gyrus is one of two brain regions (with the subventricular zone of the olfactory bulb) that continues to generate new neurons throughout adulthood, a phenomenon known as adult hippocampal neurogenesis (AHN) (Eriksson et al., Nat Med 4:1313-1317, 1998; García-Verdugo et al., J Neurobiol 36:234-248, 1998). The integration of these new neurons into the dentate gyrus (DG) has implications for memory encoding, with unique firing and wiring properties of immature neurons that affect how the hippocampal network encodes and stores attributes of memory. In this chapter, we will describe the process of AHN and properties of adult-born cells as they integrate into the hippocampal circuit and mature. Then, we will discuss some methodological considerations before we review evidence for the role of AHN in two major processes supporting memory that are performed by the DG. First, we will discuss encoding of contextual information for episodic memories and how this is facilitated by AHN. Second, will discuss pattern separation, a major role of the DG that reduces interference for the formation of new memories. Finally, we will review clinical and translational considerations, suggesting that stimulation of AHN may help decrease overgeneralization-a common endophenotype of mood, anxiety, trauma-related, and age-related disorders.

Sex specific effects of buprenorphine on adult hippocampal neurogenesis and behavioral outcomes during the acute phase after pediatric traumatic brain injury in mice

Traumatic brain injury (TBI) in children often causes cognitive and mental dysfunctions, as well as acute and chronic pain. Adult hippocampal neurogenesis plays a key role in cognition, depression, and pain. Adult hippocampal neurogenesis can be modulated by genetic and environmental factors, such as TBI and opioids. Buprenorphine (BPN), a semisynthetic opioid, is commonly used for pain management in children, however, the effects of BPN on adult hippocampal neurogenesis after pediatric TBI are still unclear. This study investigated the sex-specific effects of BPN on adult hippocampal neurogenesis during acute phase after pediatric TBI. Male and female littermates were randomized on postnatal day 20–21(P20-21) into Sham, TBI+saline and TBI+BPN groups. BPN was administered intraperitoneally to the TBI+BPN mice at 30 min after injury, and then every 6–12 h (h) for 2 days (d). Bromodeoxyuridine (BrdU) was administered intraperitoneally to all groups at 2, 4, 6, and 8-h post-injury. All outcomes were evaluated at 3-d post-BrdU administration. We found that TBI induced significant cognitive impairment, depression, and reduced adult hippocampal neurogenesis in both male and female mice, with more prominent effects in females. BPN significantly improved adult hippocampal neurogenesis and depression in males, but not in females. We further demonstrated that differential expressions of opioid receptors, transcription factors and neuroinflammatory markers at the neurogenic niche might be responsible for the differential effects of BPN in males and females. In conclusion, this study elucidates the effects of BPN on adult hippocampal neurogenesis and behavioral outcomes at the acute phase after pediatric TBI.

Down-regulating nuclear factor of activated T cells 1 alleviates cognitive deficits in a mouse model of sepsis-associated encephalopathy, possibly by stimulating hippocampal neurogenesis

Sepsis-associated encephalopathy (SAE) is a common complication of sepsis, and has been associated with increased morbidity and mortality. Nuclear factor of activated T cells (NFATs) 1, a transcriptional factor that regulates T cell development, activation and differentiation, has been implicated in neuronal plasticity. Here we examined the potential role of NFAT1 in sepsis-associated encephalopathy in mice. Adult male C57BL/6J mice received intracerebroventricular injections of short interfering RNA against NFAT1 or sex-determining region Y-box 2 (SOX2), or a scrambled control siRNA prior to cecal ligation and perforation (CLP). A group of mice receiving sham surgery were included as an additional control. CLP increased escape latency and decreased the number of crossings into, and total time spent within, the target quadrant in the Morris water maze test. CLP also decreased the freezing time in context-dependent, but not context-independent, fear conditioning test. Knockdown of either NFAT1 or SOX2 attenuated these behavioral deficits. NFAT1 knockdown also attenuated CLP-induced upregulation of SOX2, increased the numbers of nestin-positive cells and newborn astrocytes, reduced the number of immature newborn neurons, and promoted the G1 to S transition of neural stem cells in hippocampus. These findings suggest that NFAT1 may contribute to sepsis-induced behavioral deficits, possibly by promoting SOX2 signaling and neurogenesis.

The Mef2c Gene Dose-Dependently Controls Hippocampal Neurogenesis and the Expression of Autism-Like Behaviors.

Mutations in the activity-dependent transcription factor MEF2C have been associated with several neuropsychiatric disorders. Among these, autism spectrum disorder (ASD)-related behavioral deficits are manifested. Multiple animal models that harbor mutations in Mef2c have provided compelling evidence that Mef2c is indeed an ASD gene. However, studies in mice with germline or global brain knock-out of Mef2c are limited in their ability to identify the precise neural substrates and cell types that are required for the expression of Mef2c-mediated ASD behaviors. Given the role of hippocampal neurogenesis in cognitive and social behaviors, in this study we aimed to investigate the role of Mef2c in the structure and function of newly generated dentate granule cells (DGCs) in the postnatal hippocampus and to determine whether disrupted Mef2c function is responsible for manifesting ASD behaviors. Overexpression of Mef2c (Mef2cOE ) arrested the transition of neurogenesis at progenitor stages, as indicated by sustained expression of Sox2+ in Mef2cOE DGCs. Conditional knock-out of Mef2c (Mef2ccko ) allowed neuronal commitment of Mef2ccko cells; however, Mef2ccko impaired not only dendritic arborization and spine formation but also synaptic transmission onto Mef2ccko DGCs. Moreover, the abnormal structure and function of Mef2ccko DGCs led to deficits in social interaction and social novelty recognition, which are key characteristics of ASD behaviors. Thus, our study revealed a dose-dependent requirement of Mef2c in the control of distinct steps of neurogenesis, as well as a critical cell-autonomous function of Mef2c in newborn DGCs in the expression of proper social behavior in both sexes.

Generation of adult hippocampal neural stem cells occurs in the early postnatal dentate gyrus and depends on cyclin D2.

Lifelong hippocampal neurogenesis is maintained by a pool of multipotent adult neural stem cells (aNSCs) residing in the subgranular zone of the dentate gyrus (DG). The mechanisms guiding transition of NSCs from the developmental to the adult state remain unclear. We show here, by using nestin-based reporter mice deficient for cyclin D2, that the aNSC pool is established through cyclin D2-dependent proliferation during the first two weeks of life. The absence of cyclin D2 does not affect normal development of the dentate gyrus until birth but prevents postnatal formation of radial glia-like aNSCs. Furthermore, retroviral fate mapping reveals that aNSCs are born on-site from precursors located in the dentate gyrus shortly after birth. Taken together, our data identify the critical time window and the spatial location of the precursor divisions that generate the persistent population of aNSCs and demonstrate the central role of cyclin D2 in this process.