Role Of Adult Hippocampal Neurogenesis Research Articles

Insight into the role of adult hippocampal neurogenesis in aging and Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia and seriously affects the quality of life of the elderly. Neurodegeneration is closely related to hippocampal dysfunction in AD patients. The hippocampus is key to creating new memories and is also one of the first areas of the brain to deteriorate with age. Mammalian neurogenesis occurs mainly in the hippocampus. Recent studies have confirmed that neurogenesis in the hippocampus is sustainable but decreases with age, which seriously affects the learning and memory function of AD patients. At present, our understanding of neurogenesis is still relatively shallow, especially pertaining to the influence and role of neurogenesis during aging and cognitive deficits in AD patients. Interestingly, many recent studies have described the characteristics of neurogenesis in animal models. This article reviews the progress of neurogenesis research in the context of aging and AD to provide new insights into neurogenesis.

Temozolomide treatment inhibits spontaneous motivation for exploring a complex object in mice: A potential role of adult hippocampal neurogenesis in "curiosity".

Intrinsic exploratory biases are an innate motivation for exploring certain types of stimuli or environments over others, and they may be associated with cognitive, emotional, and even personality-like traits. However, their neurobiological basis has been scarcely investigated. Considering the involvement of the hippocampus in novelty recognition and in spatial and pattern separation tasks, this work researched the role of adult hippocampal neurogenesis (AHN) in intrinsic exploratory bias for a perceptually complex object in mice. Spontaneous object preference tasks revealed that both male and female C57BL/6J mice showed a consistent unconditioned preference for exploring "complex"-irregular-objects over simpler ones. Furthermore, increasing objects' complexity resulted in an augmented time of object exploration. In a different experiment, male mice received either vehicle or the DNA alkylating agent temozolomide (TMZ) for 4 weeks, a pharmacological treatment that reduced AHN as evidenced by immunohistochemistry. After assessment in a behavioral test battery, the TMZ-treated mice did not show any alterations in general exploratory and anxiety-like responses. However, when tested in the spontaneous object preference task, the TMZ-treated mice did not display enhanced exploration of the complex object, as evidenced both by a reduced exploration time-specifically for the complex object-and a lack of preference for the complex object over the simple one. This study supports a novel role of AHN in intrinsic exploratory bias for perceptual complexity. Moreover, the spontaneous complex object preference task as a rodent model of "curiosity" is discussed.

Effects of 5-Aza on neurogenesis contribute to learning and memory in the mouse hippocampus

Background5-Aza-2′-deoxycytidine (5-Aza-CdR) is a demethylating agent that has various biological effects related to DNA methylation. DNA methylation plays important roles in learning and memory. We have reported that 5-Aza-CdR improved the performance of mice in the water maze and step-down tests. Some behaviours have been well recognized to be mediated by neurogenesis in the hippocampus. The Notch signalling pathway plays a key role in adult hippocampal neurogenesis. In this study, we examined whether 5-Aza-CdR (DNA methyltransferase inhibitor) affects neurogenesis and Notch1 expression. MethodsThe learning and memory behaviour of mice was evaluated by a conditioned avoidance learning 24 h after 5-Aza-CdR treatment. The mRNA and protein expression levels of Notch1 and HES1 were measured by real-time PCR and Western blotting. The 5-bromo-2′-deoxyuridine (BrdU)-positive cells and the expression of Notch1 in the hippocampal DG were observed through laser confocal microscopy. To further clarify whether 5-Aza-CdR affects behaviour through neurogenesis, the expression level of Notch1, cell viability and cell cycle were analysed using the HT22 cell line. ResultsThe behaviour in conditioned avoidance learning was improved, while neurogenesis and the Notch1 pathway were increased in the hippocampus of mice that were injected with 5-Aza-CdR. In vitro experiments showed that 5-Aza-CdR increased the expression of the Notch1 pathway and upregulated S-phase in the cell cycle and cell viability. ConclusionsOur results suggest that the effect of 5-Aza-CdR on behaviour may be related to an increase in neurogenesis with upregulation of the Notch1 pathway in the hippocampus.

Aβ-induced mitochondrial dysfunction in neural progenitors controls KDM5A to influence neuronal differentiation

Mitochondria in neural progenitors play a crucial role in adult hippocampal neurogenesis by being involved in fate decisions for differentiation. However, the molecular mechanisms by which mitochondria are related to the genetic regulation of neuronal differentiation in neural progenitors are poorly understood. Here, we show that mitochondrial dysfunction induced by amyloid-beta (Aβ) in neural progenitors inhibits neuronal differentiation but has no effect on the neural progenitor stage. In line with the phenotypes shown in Alzheimer’s disease (AD) model mice, Aβ-induced mitochondrial damage in neural progenitors results in deficits in adult hippocampal neurogenesis and cognitive function. Based on hippocampal proteome changes after mitochondrial damage in neural progenitors identified through proteomic analysis, we found that lysine demethylase 5A (KDM5A) in neural progenitors epigenetically suppresses differentiation in response to mitochondrial damage. Mitochondrial damage characteristically causes KDM5A degradation in neural progenitors. Since KDM5A also binds to and activates neuronal genes involved in the early stage of differentiation, functional inhibition of KDM5A consequently inhibits adult hippocampal neurogenesis. We suggest that mitochondria in neural progenitors serve as the checkpoint for neuronal differentiation via KDM5A. Our findings not only reveal a cell-type-specific role of mitochondria but also suggest a new role of KDM5A in neural progenitors as a mediator of retrograde signaling from mitochondria to the nucleus, reflecting the mitochondrial status.

Potential Role of Adult Hippocampal Neurogenesis in Traumatic Brain Injury

Traumatic brain injury (TBI) is a serious cause of disability and death among young and adult individuals, displaying complex pathophysiology including cellular and molecular mechanisms that are not fully elucidated. Many experimental and clinical studies investigated the potential relationship between TBI and the process by which neurons are formed in the brain, known as neurogenesis. Currently, there are no available treatments for TBI's long-term consequences being the search for novel therapeutic targets, a goal of highest scientific and clinical priority. Some studies evaluated the benefits of treatments aimed at improving neurogenesis in TBI. In this scenario, herein, we reviewed current pre-clinical studies that evaluated different approaches to improving neurogenesis after TBI while achieving better cognitive outcomes, which may consist in interesting approaches for future treatments.

Enriched environment priors to TET1 hippocampal administration for regulating psychiatric behaviors via glial reactivity in chronic cerebral hypoperfusion models

BackgroundChronic cerebral hypoperfusion (CCH) has been gradually regarded as a common etiologic mechanism for cognitive and psychiatric disturbances. Ten-eleven translocation methylcytosine dioxygenase 1 (TET1) played an important role in adult hippocampal neurogenesis (AHN), neuronal circuits formation, cognition and psychiatric disorders. Enriched environment (EE) showed a beneficial effect on cognition and depression via effectively regulating AHN and glial reactivity. This study aimed to assess which strategy was feasible to improve cognition and psychiatric disturbances by comparing the TET1 hippocampal microinjection and EE in CCH models and to investigate the possible mechanisms. MethodCCH rats were established via permanent bilateral common carotid artery occlusion (2-VO). Rats were stereotaxically injected with the human catalytic domain of TET1 (hTET1) to overexpress the hTET1 in the hippocampus 10 days before 2-VO. 3 days after 2-VO, rats were subjected to standard environment or EE with free access to food and water. Behavioral tests were used to appraise depression and cognition before sacrifice. Epigenetic molecules, adult neurogenesis, synaptic proteins expression, and glial activation were analyzed using immunofluorescent staining, qRT-PCR and western blot. ResultsIn the present study, we found both EE and genetical treatment with overexpressing hTET1 were sufficient for stimulating AHN. However, promoting ANH could not deal with the cognitive dysfunction and depressive-like behaviors in CCH rats. Notably, a healthy local brain environment with elevated BDNF and astrocytes was conducive to improving cognitive dysfunction. Meanwhile, astrocytes were involved in the cognitive regulating process of neurons, presynaptic function and microglia. In general, we held that depressive disturbances were determined by BDNF levels, neuronal and presynaptic function, as well as glial activation containing astrocytes and microglia. To further support this point, we investigated severe depressive symptoms that were strongly correlated with the activation of astroglia and microglia. Importantly, causal mediation analysis showed significant mediation by the presence of reactive glial cells in the relation between neural plasticity and depressive symptoms. Finally, we showed EE performed better than hTET1 treatment for cognitive deficits and depression. EE with less glial reactivity was much more resistant to depression, while hTET1 with more glial activation was more vulnerable to depressive disorders. ConclusionsEE was likely to be superior to TET1 hippocampal administration for cognition and psychiatric behaviors in CCH rats. Furthermore, a healthy local brain environment with elevated BDNF and astrocytes was conducive to improving cognitive dysfunction. More glial activation, and more vulnerable to depressive disorders. These results were important for our understanding of disease mechanisms and provided valuable tools for the overall management of CCH patients.

The role of adult hippocampal neurogenesis in epilepsy and comorbidities

<p indent="0mm">Epilepsy is a clinically common chronic brain disorder, characterized by recurrent seizures. More than 50% patients with epilepsy suffered from depression, anxiety, migraine, or sleep disturbances. Anti-epileptic drugs are the first-choice treatment to control seizures in clinical practice but with some problems, e.g., high ratio of intractable epilepsy, serious side effects, little effect on epileptogenesis and the comorbidities of epilepsy. Thus, progress towards understanding the mechanisms of epileptogenesis is critical for developing better therapies to prevent epilepsy. Cumulative evidence indicates that the adult hippocampal neurogenesis may be involved in epileptogenesis, because pathological changes of adult hippocampal neurogenesis occur in epileptic brain, and the regulation of adult hippocampal neurogenesis affects epilepsy. Meanwhile, adult hippocampal neurogenesis is also implicated in cognitive deficits, depression, anxiety and other comorbidities of epilepsy, suggesting the significance of adult hippocampal neurogenesis in treating epilepsy and its comorbidities. In this article, we reviewed the pathological changes of adult hippocampal neurogenesis in the epileptic brain, the functional relevance of adult hippocampal neurogenesis in epileptogenesis through different interventions, and the potential association between adult hippocampal neurogenesis and comorbidities of epilepsy. It provides perspectives for the future research on mechanisms and treatment strategies of epilepsy.

Role of adult hippocampal neurogenesis in the antidepressant actions of lactate

In addition to its role as a neuronal energy substrate and signaling molecule involved in synaptic plasticity and memory consolidation, recent evidence shows that lactate produces antidepressant effects in animal models. However, the mechanisms underpinning lactate’s antidepressant actions remain largely unknown. In this study, we report that lactate reverses the effects of corticosterone on depressive-like behavior, as well as on the inhibition of both the survival and proliferation of new neurons in the adult hippocampus. Furthermore, the inhibition of adult hippocampal neurogenesis prevents the antidepressant-like effects of lactate. Pyruvate, the oxidized form of lactate, did not mimic the effects of lactate on adult hippocampal neurogenesis and depression-like behavior. Finally, our data suggest that conversion of lactate to pyruvate with the concomitant production of NADH is necessary for the neurogenic and antidepressant effects of lactate.

Increasing Adult Hippocampal Neurogenesis Promotes Resilience in a Mouse Model of Depression.

Many studies evaluated the functional role of adult hippocampal neurogenesis (AHN) and its key role in cognitive functions and mood regulation. The effects of promoting AHN on the recovery of stress-induced symptoms have been well studied, but its involvement in stress resilience remains elusive. We used a mouse model enabling us to foster AHN before the exposure to unpredictable chronic mild stress (UCMS) to evaluate the potential protective effects of AHN on stress, assessing the depressive-like phenotype and executive functions. For this purpose, an inducible transgenic mouse model was used to delete the pro-apoptotic gene Bax from neural progenitors four weeks before UCMS, whereby increasing the survival of adult-generated neurons. Our results showed that UCMS elicited a depressive-like phenotype, highlighted by a deteriorated coat state, a higher immobility duration in the tail suspension test (TST), and a delayed reversal learning in a water maze procedure. Promoting AHN before UCMS was sufficient to prevent the development of stressed-induced behavioral changes in the TST and the water maze, reflecting an effect of AHN on stress resilience. Taken together, our data suggest that increasing AHN promotes stress resilience on some depressive-like symptoms but also in cognitive symptoms, which are often observed in MD.

Long-term exposure to a hypomagnetic field attenuates adult hippocampal neurogenesis and cognition

Adult hippocampal neurogenesis contributes to learning and memory, and is sensitive to a variety of environmental stimuli. Exposure to a hypomagnetic field (HMF) influences the cognitive processes of various animals, from insects to human beings. However, whether HMF exposure affect adult hippocampal neurogenesis and hippocampus-dependent cognitions is still an enigma. Here, we showed that male C57BL/6 J mice exposed to HMF by means of near elimination of the geomagnetic field (GMF) exhibit significant impairments of adult hippocampal neurogenesis and hippocampus-dependent learning, which is strongly correlated with a reduction in the content of reactive oxygen species (ROS). However, these deficits seen in HMF-exposed mice could be rescued either by elevating ROS levels through pharmacological inhibition of ROS removal or by returning them back to GMF. Therefore, our results suggest that GMF plays an important role in adult hippocampal neurogenesis through maintaining appropriate endogenous ROS levels.

Cav3.1 t-type calcium channel is critical for cell proliferation and survival in newly generated cells of the adult hippocampus.

Adult hippocampal neurogenesis plays an important role in neuronal plasticity and maintenance in mammals. Low-threshold voltage-gated T-type calcium channels produce calcium spikes that increase fast action potentials in newborn cells in the hippocampal dentate gyrus (DG); however, their role in adult hippocampal neurogenesis remains unclear. Here, we demonstrate impaired adult hippocampal neurogenesis in Cav3.1T-type calcium channel knockout mice. Cav3.1T-type calcium channel was predominantly localized in neuronal progenitor cells of the mouse hippocampal DG. By counting the number of 5-bromo-2'-deoxyuridine-labeled cells, decreased proliferation and survival of newly generated cells were observed in the adult hippocampal DG in Cav3.1 knockout mice as compared to wild-type (WT) mice. Moreover, the degree of maturation of doublecortin-positive cells in Cav3.1 knockout mice was lower than that in WT mice, suggesting that Cav3.1 deletion may impair neuronal differentiation. Consistent with impaired hippocampal neurogenesis, Cav3.1 knockout mice showed decreased social interaction. Reduced phosphorylation levels of calcium/calmodulin-dependent protein kinase II and protein kinase B were closely associated with impaired hippocampal neurogenesis in Cav3.1 knockout mice. Moreover, the mRNA and protein expression levels of brain-derived neurotrophic factor, important for neurogenesis, were significantly decreased in Cav3.1 knockout mice. Finally, gene ontology analysis revealed alterations in genes related to the promotion of cell death/apoptosis and suppression of cell proliferation/neuronal differentiation pathways, including Bdnf. These results suggest that the Cav3.1T-type calcium channel may be a key molecule required for cell proliferation, survival and neuronal differentiation in newly generated cells of the adult mouse hippocampus.

Adult hypothalamic neurogenesis and sleep–wake dysfunction in aging

In the mammalian brain, adult neurogenesis has been extensively studied in the hippocampal sub-granular zone and the sub-ventricular zone of the anterolateral ventricles. However, growing evidence suggests that new cells are not only "born" constitutively in the adult hypothalamus, but many of these cells also differentiate into neurons and glia and serve specific functions. The preoptic-hypothalamic area plays a central role in the regulation of many critical functions, including sleep-wakefulness and circadian rhythms. While a role for adult hippocampal neurogenesis in regulating hippocampus-dependent functions, including cognition, has been extensively studied, adult hypothalamic neurogenic process and its contributions to various hypothalamic functions, including sleep-wake regulation are just beginning to unravel. This review is aimed at providing the current understanding of the hypothalamic adult neurogenic processes and the extent to which it affects hypothalamic functions, including sleep-wake regulation. We propose that hypothalamic neurogenic processes are vital for maintaining the proper functioning of the hypothalamic sleep-wake and circadian systems in the face of regulatory challenges. Sleep-wake disturbance is a frequent and challenging problem of aging and age-related neurodegenerative diseases. Aging is also associated with a decline in the neurogenic process. We discuss a hypothesis that a decrease in the hypothalamic neurogenic process underlies the aging of its sleep-wake and circadian systems and associated sleep-wake disturbance. We further discuss whether neuro-regenerative approaches, including pharmacological and non-pharmacological stimulation of endogenous neural stem and progenitor cells in hypothalamic neurogenic niches, can be used for mitigating sleep-wake and other hypothalamic dysfunctions in aging.

The effects of microglia- and astrocyte-derived factors on neurogenesis in health and disease.

Hippocampal neurogenesis continues throughout life and has been suggested to play an essential role in maintaining spatial cognitive function under physiological conditions. An increasing amount of evidence has indicated that adult neurogenesis is tightly controlled by environmental conditions in the neurogenic niche, which consists of multiple types of cells including microglia and astrocytes. Microglia maintain the environment of neurogenic niche through their phagocytic capacity and interaction with neurons via fractalkine‐CX3CR1 signaling. In addition, microglia release growth factors such as brain‐derived neurotrophic factor (BDNF) and cytokines such as tumor necrosis factor (TNF)‐α to support the development of adult born neurons. Astrocytes also manipulate neurogenesis by releasing various soluble factors including adenosine triphosphate and lactate. Whereas, under pathological conditions such as Alzheimer's disease, depression, and epilepsy, microglia and astrocytes play a leading role in inflammation and are involved in attenuating the normal process of neurogenesis. The modulation of glial functions on neurogenesis in these brain diseases are attracting attention as a new therapeutic target. This review describes how these glial cells play a role in adult hippocampal neurogenesis in both health and disease, especially focusing glia‐derived factors.

ATP and repetitive electric stimulation increases leukemia inhibitory factor expression in astrocytes: A potential role for astrocytes in the action mechanism of electroconvulsive therapy.

Electroconvulsive therapy (ECT) is effective for psychiatric disorders. However, its action mechanism remains unclear. We previously reported that transcription factor 7 (TCF7) was increased in patients successfully treated with ECT. TCF7 regulates Wnt pathway, which regulates adult hippocampal neurogenesis. Adult hippocampal neurogenesis is involved in the pathophysiology of psychiatric disorders. Astrocytes play a role in adult hippocampal neurogenesis via neurogenic factors. Of astrocyte-derived neurogenic factors, leukemia inhibitory factor (LIF) and fibroblast growth factor 2 (FGF2) activate Wnt pathway. In addition, adenosine triphosphate (ATP), released from excited neurons, activates astrocytes. Therefore, we hypothesized that ECT might increase LIF and/or FGF2 in astrocytes. To test this, we investigated the effects of ATP and electric stimulation (ES) on LIF and FGF2 expressions in astrocytes. Astrocytes were derived from neonatal mouse forebrain and administered ATP and ES. The mRNA expression was estimated with quantitative reverse-transcription polymerase chain reaction. Protein concentration was measured with ELISA. ATP increased LIF, but not FGF2, expression. Multiple ES, but not single, increased LIF expression. Knockdown of P2X2 receptor (P2X2R) attenuated ATP-induced increase of LIF mRNA expression. In contrast, P2X3 and P2X4 receptors intensified it. P2X2R may mediate ATP-induced LIF expression in astrocytes and multiple ES directly increases LIF expression in astrocytes. Therefore, both ATP/P2X2R and multiple ES-induced increases of LIF expression in astrocytes might mediate the efficacy of ECT on psychiatric disorders. Elucidating detailed mechanisms of ATP/P2X2R and multiple ES-induced LIF expression is expected to result in the identification of new therapeutic targets for psychiatric disorders.

Apolipoprotein E regulates the maturation of injury-induced adult-born hippocampal neurons following traumatic brain injury.

Various brain injuries lead to the activation of adult neural stem/progenitor cells in the mammalian hippocampus. Subsequent injury-induced neurogenesis appears to be essential for at least some aspects of the innate recovery in cognitive function observed following traumatic brain injury (TBI). It has previously been established that Apolipoprotein E (ApoE) plays a regulatory role in adult hippocampal neurogenesis, which is of particular interest as the presence of the human ApoE isoform ApoE4 leads to significant risk for the development of late-onset Alzheimer's disease, where impaired neurogenesis has been linked with disease progression. Moreover, genetically modified mice lacking ApoE or expressing the ApoE4 human isoform have been shown to impair adult hippocampal neurogenesis under normal conditions. Here, we investigate how controlled cortical impact (CCI) injury affects dentate gyrus development using hippocampal stereotactic injections of GFP-expressing retroviruses in wild-type (WT), ApoE-deficient and humanized (ApoE3 and ApoE4) mice. Infected adult-born hippocampal neurons were morphologically analyzed once fully mature, revealing significant attenuation of dendritic complexity and spine density in mice lacking ApoE or expressing the human ApoE4 allele, which may help inform how ApoE influences neurological diseases where neurogenesis is defective.

Role of adult hippocampal neurogenesis in the antidepressant effects of lactate

In addition to its role as a neuronal energy substrate and signaling molecule involved in synaptic plasticity and memory consolidation, recent evidence shows that lactate produces antidepressant effects in animal models. However, the mechanisms underpinning lactate's antidepressant actions remain largely unknown. In this study, we report that lactate reverses the effects of corticosterone on depressive-like behavior, as well as on the inhibition of both the survival and proliferation of new neurons in the adult hippocampus. Furthermore, the inhibition of adult hippocampal neurogenesis prevents the antidepressant-like effects of lactate. Pyruvate, the oxidized form of lactate, did not mimic the effects of lactate on adult hippocampal neurogenesis and depression-like behavior. Finally, our data suggest that conversion of lactate to pyruvate with the concomitant production of NADH is necessary for the neurogenic and antidepressant effects of lactate.

DSCR1-mediated TET1 splicing regulates miR-124 expression to control adult hippocampal neurogenesis.

Whether epigenetic factors such as DNA methylation and microRNAs interact to control adult hippocampal neurogenesis is not fully understood. Here, we show that Down syndrome critical region 1 (DSCR1) protein plays a key role in adult hippocampal neurogenesis by modulating two epigenetic factors: TET1 and miR-124. We find that DSCR1 mutant mice have impaired adult hippocampal neurogenesis. DSCR1 binds to TET1 introns to regulate splicing of TET1, thereby modulating TET1 level. Furthermore, TET1 controls the demethylation of the miRNA-124 promoter to modulate miR-124 expression. Correcting the level of TET1 in DSCR1 knockout mice is sufficient to prevent defective adult neurogenesis. Importantly, restoring DSCR1 level in a Down syndrome mouse model effectively rescued adult neurogenesis and learning and memory deficits. Our study reveals that DSCR1 plays a critical upstream role in epigenetic regulation of adult neurogenesis and provides insights into potential therapeutic strategy for treating cognitive defects in Down syndrome.

The pharmacological reduction of hippocampal neurogenesis attenuates the protective effects of cannabidiol on cocaine voluntary intake.

The administration of cannabidiol has shown promising evidence in the treatment of some neuropsychiatric disorders, including cocaine addiction. However, little information is available as to the mechanisms by which cannabidiol reduces drug use and compulsive seeking. We investigated the role of adult hippocampal neurogenesis in reducing cocaine voluntary intake produced by repeated cannabidiol treatment in mice. Cocaine intake was modelled using the intravenous cocaine self-administration procedure in CD1 male mice. Cannabidiol (20mg/kg) reduced cocaine self-administration behaviour acquisition and total cocaine intake and enhanced adult hippocampal neurogenesis. Our results show that a 6-day repeated temozolomide treatment (25mg/kg/day), a chemotherapy drug that blocks hippocampal neurogenesis, prevented cannabidiol-induced increment in the early stages of neuronal maturation and differentiation, without altering the basal levels of BrdU/NeuN and doublecortin immunostaining. The reduction of total cocaine intake and operant behaviour acquisition observed following cannabidiol exposure was attenuated by temozolomide treatment. Our results also show a similar effect of temozolamide on a cannabidiol-induced improvement of novel object recognition memory, a task influenced by the proneurogenic effects of cannabidiol (10 and 20mg/kg). The anxiolytic effects of cannabidiol (10 and 20mg/kg), however, remained unaffected after its proneurogenic effects decreased. The present study confirms that adult hippocampal neurogenesis is one of the mechanisms by which cannabidiol lowers cocaine reinforcement and demonstrates the functional implication of adult hippocampal neurogenesis in cocaine voluntary consumption in mice. Such findings highlight the possible use of cannabidiol for developing new pharmacotherapies to manage cocaine use disorders.

Increased Axin expression enhances adult hippocampal neurogenesis and exerts an antidepressant effect

Major depressive disorders are emerging health problems that affect millions of people worldwide. However, treatment options and targets for drug development are limited. Impaired adult hippocampal neurogenesis is emerging as a key contributor to the pathology of major depressive disorders. We previously demonstrated that increasing the expression of the multifunctional scaffold protein Axis inhibition protein (Axin) by administration of the small molecule XAV939 enhances embryonic neurogenesis and affects social interaction behaviors. This prompted us to examine whether increasing Axin protein level can enhance adult hippocampal neurogenesis and thus contribute to mood regulation. Here, we report that stabilizing Axin increases adult hippocampal neurogenesis and exerts an antidepressant effect. Specifically, treating adult mice with XAV939 increased the amplification of adult neural progenitor cells and neuron production in the hippocampus under both normal and chronic stress conditions. Furthermore, XAV939 injection in mice ameliorated depression-like behaviors induced by chronic restraint stress. Thus, our study demonstrates that Axin/XAV939 plays an important role in adult hippocampal neurogenesis and provides a potential therapeutic approach for mood-related disorders.

Unique role for dentate gyrus microglia in neuroblast survival and in VEGF-induced activation.

Neurogenic roles of microglia (MG) are thought to include an active role in adult hippocampal neurogenesis in addition to their established roles in pruning surplus dendrites and clearing dead neuroblasts. However, identification of such a role and its delineation in the neurogenic cascade is yet to be established. Using diphtheria toxin-aided MG ablation, we show that MG reduction in the DG-the site where neuronal stem cells (NSCs) reside-is sufficient to impede overall hippocampal neurogenesis due to reduced survival of newly formed neuroblasts. To examine whether MG residing in the hippocampal neurogenic zone are inherently different from MG residing elsewhere in the hippocampus, we compared growth factor responsiveness of DG MG with that of CA1 MG. Strikingly, transgenic induction of the potent neurogenic factor VEGF elicited robust on-site MG expansion and activation exclusively in the DG and despite eliciting a comparable angiogenic response in the CA1 and elsewhere. Temporally, DG-specific MG expansion preceded both angiogenic and neurogenic responses. Remarkably, even partial MG reduction during the process of VEGF-induced neurogenesis led to reducing the number of newly formed neuroblasts to the basal level. Transcriptomic analysis of MG retrieved from the naïve DG and CA1 uncovered a set of genes preferentially expressed in DG MG. Notably the tyrosine kinase Axl is exclusively expressed in naïve and VEGF-induced DG MG and its inhibition prevented neurogenesis augmentation by VEGF. Taken together, findings uncover inherent unique properties of DG MG of supporting both basal- and VEGF-induced adult hippocampal neurogenesis.