Regulation Of Adult Hippocampal Neurogenesis Research Articles

Mitochondrial regulation of adult hippocampal neurogenesis: Insights into neurological function and neurodevelopmental disorders

Mitochondria are essential regulators of cellular energy metabolism and play a crucial role in the maintenance and function of neuronal cells. Studies in the last decade have highlighted the importance of mitochondrial dynamics and bioenergetics in adult neurogenesis, a process that significantly influences cognitive function and brain plasticity. In this review, we examine the mechanisms by which mitochondria regulate adult neurogenesis, focusing on the impact of mitochondrial function on the behavior of neural stem/progenitor cells and the maturation and plasticity of newborn neurons in the adult mouse hippocampus. In addition, we explore the link between mitochondrial dysfunction, adult hippocampal neurogenesis and genes associated with cognitive deficits in neurodevelopmental disorders. In particular, we provide insights into how alterations in the transcriptional regulator NR2F1 affect mitochondrial dynamics and may contribute to the pathophysiology of the emerging neurodevelopmental disorder Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS). Understanding how genes involved in embryonic and adult neurogenesis affect mitochondrial function in neurological diseases might open new directions for therapeutic interventions aimed at boosting mitochondrial function during postnatal life.

Disrupted de novo pyrimidine biosynthesis impairs adult hippocampal neurogenesis and cognition in pyridoxine-dependent epilepsy.

Despite seizure control by early high-dose pyridoxine (vitamin B6) treatment, at least 75% of pyridoxine-dependent epilepsy (PDE) patients with ALDH7A1 mutation still suffer from intellectual disability. It points to a need for additional therapeutic interventions for PDE beyond pyridoxine treatment, which provokes us to investigate the mechanisms underlying the impairment of brain hemostasis by ALDH7A1 deficiency. In this study, we show that ALDH7A1-deficient mice with seizure control exhibit altered adult hippocampal neurogenesis and impaired cognitive functions. Mechanistically, ALDH7A1 deficiency leads to the accumulation of toxic lysine catabolism intermediates, α-aminoadipic-δ-semialdehyde and its cyclic form, δ-1-piperideine-6-carboxylate, which in turn impair de novo pyrimidine biosynthesis and inhibit NSC proliferation and differentiation. Notably, supplementation of pyrimidines rescues abnormal neurogenesis and cognitive impairment in ALDH7A1-deficient adult mice. Therefore, our findings not only define the important role of ALDH7A1 in the regulation of adult hippocampal neurogenesis but also provide a potential therapeutic intervention to ameliorate the defective mental capacities in PDE patients with seizure control.

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.

Systematic assessment of microRNA‐132 therapeutic targeting in Alzheimer’s disease using iPSC‐derived neurons and microglia

AbstractBackgroundMapping the mechanistic heterogeneity and multifactorial nature of Alzheimer’s Disease (AD) is a key challenge for therapeutic development and the main reason why network biology and multi‐modal therapies begin to attract attention also in AD research. MiRNA‐targeted therapeutics are particularly suited for such purposes, as they regulate multiple components of several molecular cascades converging on disease‐relevant patho‐phenotypes. MicroRNA‐132 (miR‐132), a potent neuroimmune regulator, has been identified as the most robustly and significantly downregulated microRNA in the brain of AD patients and its deficiency has been functionally linked to amyloid deposition, TAU hyperphosphorylation, neuronal cell death and memory decline, in both human and rodents. Additionally, miR‐132 was recently identified as a potent regulator of adult hippocampal neurogenesis (AHN), exerting multilayered proneurogenic effects in adult neural stem cells and their progeny. Together, these observations suggest that miR‐132‐dependent network‐based gene regulation in human AD brain converges onto biological pathways that can drive disease endophenotypes. Direct miR‐132 infusion in the AD mouse brain can counteract several aspects of pathology, providing a proof‐of‐concept of its therapeutic relevance. Despite the great benefit of the multi‐targeting nature of microRNAs for treating multifactorial diseases such as AD, such approaches also entail the risk of on‐ and off‐ target toxicity, highlighting the importance of systematic genome‐wide targetome profiling. The complex multicellular miR‐132 targetome involved in AHN and the inflammatory response in AD remains elusive, and its mapping is a crucial requirement for therapeutic targeting.MethodIn order to systematically profile the mechanisms underpinning the regulatory effects of miR‐132 in AD, we employed an RNA‐sequencing approach to assess transcriptomic responses to changes in the levels of miR‐132 in AD‐relevant study systems, such as human iPSC‐derived neurons and microglia‐like cells.ResultsWe identify novel miR‐132 targets with putative neuroimmune functions possibly involved in AD pathophysiology.ConclusionOur results shed light on the involvement of miR‐132 in AD and further add to the systematic profiling of miR‐132 targetome, a prerequisite for successful translation of miR‐132 supplementation in AD.

Lactate Improves Long-term Cognitive Impairment Induced By Repeated Neonatal Sevoflurane Exposures Through SIRT1-mediated Regulation of Adult Hippocampal Neurogenesis and Synaptic Plasticity in Male Mice.

Repeated neonatal exposures to sevoflurane induce long-term cognitive impairment that has been reported to have sex-dependent differences. Exercise promotes learning and memory by releasing lactate from the muscle. The study tested the hypothesis that lactate may improve long-term cognitive impairment induced by repeated neonatal exposures to sevoflurane through SIRT1-mediated regulation of adult hippocampal neurogenesis and synaptic plasticity. C57BL/6 mice of both genders were exposed to 3% sevoflurane for 2h daily from postnatal day 6 (P6) to P8. In the intervention experiments, mice received lactate at 1g/kg intraperitoneally once daily from P21 to P41. Behavioral tests including open field (OF), object location (OL), novel object recognition (NOR), and fear conditioning (FC) tests were performed to assess cognitive function. The number of 5-Bromo-2'- deoxyuridine positive (BrdU+) cells and BrdU+/DCX+ (doublecortin) co-labeled cells, expressions of brain-derived neurotrophic factor (BDNF), activity-regulated cytoskeletal-associated protein (Arc), early growth response 1 (Egr-1), SIRT1, PGC-1α and FNDC5, and long-term potentiation (LTP) were evaluated in the hippocampus. Repeated exposures to sevoflurane induced deficits in OL, NOR and contextual FC tests in male but not female mice. Similarly, adult hippocampal neurogenesis, synaptic plasticity-related proteins and hippocampal LTP were impaired after repeated exposures to sevoflurane in male but not female mice, which could rescue by lactate treatment. Our study suggests that repeated neonatal exposures to sevoflurane inhibit adult hippocampal neurogenesis and induce defects of synaptic plasticity in male but not female mice, which may contribute to long-term cognitive impairment. Lactate treatment rescues these abnormalities through activation of SIRT1.

Regulation of adult hippocampal neurogenesis by microglia in the healthy and injured brain

成年脑内终生存在持续性神经发生，该过程受多种内外因素的调节。小胶质细胞是脑内固有的免疫细胞，在维持脑稳态和脑的免疫调节方面有重要作用。越来越多的研究显示，小胶质细胞通过直接与神经元接触和/或释放可溶性因子影响成年海马神经发生。本文综述了在生理状态下小胶质细胞是如何调控成年海马新生神经元的不同阶段，进而调节神经发生；并且综述了在病理状态下，如何通过干预小胶质细胞影响海马神经发生，为应用小胶质细胞促进脑的内源性修复机制提供理论依据。

Microbiota-Gut-Brain Axis Regulation of Adult Hippocampal Neurogenesis.

The birth, maturation, and integration of new neurons in the adult hippocampus regulates specific learning and memory processes, responses to stress, and antidepressant treatment efficacy. This process of adult hippocampal neurogenesis is sensitive to environmental stimuli, including peripheral signals from certain cytokines, hormones, and metabolites, which can promote or hinder the production and survival of new hippocampal neurons. The trillions of microorganisms resident to the gastrointestinal tract, collectively known as the gut microbiota, also demonstrate the ability to modulate adult hippocampal neurogenesis. In doing so, the microbiota-gut-brain axis can influence brain functions regulated by adult hippocampal neurogenesis. Unlike the hippocampus, the gut microbiota is highly accessible to direct interventions, such as prebiotics, probiotics, and antibiotics, and can be manipulated by lifestyle choices including diet. Therefore, understanding the pathways by which the gut microbiota shapes hippocampal neurogenesis may reveal novel targets for non-invasive therapeutics to treat disorders in which alterations in hippocampal neurogenesis have been implicated. This review first outlines the factors which influence both the gut microbiome and adult hippocampal neurogenesis, with cognizance that these effects might happen either independently or due to microbiota-driven mechanisms. We then highlight approaches for investigating the regulation of adult hippocampal neurogenesis by the microbiota-gut-brain axis. Finally, we summarize the current evidence demonstrating the gut microbiota's ability to influence adult hippocampal neurogenesis, including mechanisms driven through immune pathways, microbial metabolites, endocrine signalling, and the nervous system, and postulate implications for these effects in disease onset and treatment.

Ameliorated Neurogenesis Deficits in Dentate Gyrus May Underly the Pronounced Antidepressant Effect of TREK-1 Potassium Channel Blockade in Rats with Depressive-like Behavior.

Depression is considered to be the most common mental disorder and is probed by several studies that chronic mild stress contributes to depression, and fortunately, most antidepressants ameliorate depressive-like behavior accompanied with reversed hippocampal neurogenesis defects. In our present study, we confirmed that different antidepressants repaired the stress-induced neuronal and behavioral deficits by modulating adult hippocampal neurogenesis. Antidepressant treatment restored the adult hippocampal neurodegeneration, which was impaired by chronic unpredicted mild stress displaying decreased proliferation and neuronal differentiation but increased apoptosis of newly formed neurons in dentate gyrus. Notably, sucrose preference ratio significantly correlated with both neuronal differentiation proportion and newborn apoptosis proportion, suggesting a mechanistic relationship between neurogenesis and behavior. Indeed, the neotype TREK-1 potassium channel blocker expressed an earlier and pronounced antidepressant manifestation compared to the traditional selective serotonin-reuptake inhibitors fluoxetine. We therefore conclude that the administration of TREK-1 potassium channel antagonism can reverse the depressive deficits caused by chronic stress quickly via regulation of adult hippocampal neurogenesis.

A Potential Strategy for Treatment of Neurodegenerative Disorders by Regulation of Adult Hippocampal Neurogenesis in Human Brain.

Adult hippocampal neurogenesis is a multistage mechanism that continues throughout the lifespan of human and non-human mammals. These adult-born neurons in the central nervous system (CNS) play a significant role in various hippocampus-dependent processes, including learning, mood regulation, pattern recognition, etc. Reduction of adult hippocampal neurogenesis, caused by multiple factors such as neurological disorders and aging, would impair neuronal proliferation and differentiation and result in memory loss. Accumulating studies have indicated that functional neuron impairment could be restored by promoting adult hippocampal neurogenesis. In this review, we summarized the small molecules that could efficiently promote the process of adult neurogenesis, particularly the agents that have the capacity of crossing the blood-brain barrier (BBB), and showed in vivo efficacy in mammalian brains. This may pave the way for the rational design of drugs to treat human neurodegenerative disorders in the future.

Astrocytes Mediate Cholinergic Regulation of Adult Hippocampal Neurogenesis and Memory Through M1 Muscarinic Receptor

BackgroundIn the neurogenic niches of the adult hippocampus, new functional neurons are continuously generated throughout life, and generation of these neurons has been implicated in learning and memory. Astrocytes, as components of the neurogenic niches, are critical in the regulation of adult hippocampal neurogenesis (AHN). However, little is known about how astrocytes receive and respond to extrinsic cues to regulate AHN. MethodsBy using a transgenic strategy to conditionally delete astrocytic CRHM1 in mice and AAV (adeno-associated virus)–mediated overexpression of astrocytic CHRM1 specifically in the hippocampal dentate gyrus, we systematically investigated the role of astrocytic CHRM1 in the regulation of AHN and the underlying mechanisms using the combined approaches of immunohistochemistry, retrovirus labeling, electrophysiology, primary astrocyte cultures, immunoblotting, and behavioral assays. ResultsWe report that genetic ablation of CHRM1 in astrocytes led to defects in neural stem cell survival, neuronal differentiation, and maturation and integration of newborn neurons in the dentate gyrus. Astrocytic CHRM1-mediated modulation of AHN was mediated by BDNF (brain-derived neurotrophic factor) signaling. Furthermore, CHRM1 ablation in astrocytes impaired contextual fear memory. These impairments in both AHN and memory were rescued by overexpression of astrocytic CHRM1 in the dentate gyrus. ConclusionsOur findings reveal a critical role for astrocytes in mediating cholinergic regulation of AHN and memory through CHRM1.

Wnt Signaling in the Adult Hippocampal Neurogenic Niche.

The subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) is a neurogenic niche of the adult brain that contains neural stem cells (NSCs) able to generate excitatory glutamatergic granule neurons, which integrate into the DG circuit and contribute to hippocampal plasticity, learning, and memory. Thus, endogenous NSCs could be harnessed for therapeutic purposes. In this context, it is critical to characterize the molecular mechanisms controlling the generation and functional integration of adult-born neurons. Adult hippocampal neurogenesis is tightly controlled by both cell-autonomous mechanisms and the interaction with the complex niche microenvironment, which harbors the NSCs and provides the signals to support their maintenance, activation, and differentiation. Among niche-derived factors, Wnt ligands play diverse roles. Wnts are secreted glycoproteins that bind to Frizzled receptors and co-receptors to trigger the Wnt signaling pathway. Here, we summarize the current knowledge about the roles of Wnts in the regulation of adult hippocampal neurogenesis. We discuss the possible contribution of the different niche cells to the regulation of local Wnt signaling activity, and how Wnts derived from different cell types could induce differential effects. Finally, we discuss how the effects of Wnt signaling on hippocampal network activity might contribute to neurogenesis regulation. Although the evidence supports relevant roles for Wnt signaling in adult hippocampal neurogenesis, defining the cellular source and the mechanisms controlling secretion and diffusion of Wnts will be crucial to further understand Wnt signaling regulation of adult NSCs, and eventually, to propose this pathway as a therapeutic target to promote neurogenesis.

Regulation of adult neurogenesis by the endocannabinoid-producing enzyme diacylglycerol lipase alpha (DAGLa)

The endocannabinoid system modulates adult hippocampal neurogenesis by promoting the proliferation and survival of neural stem and progenitor cells (NSPCs). This is demonstrated by the disruption of adult neurogenesis under two experimental conditions: (1) NSPC-specific deletion of cannabinoid receptors and (2) constitutive deletion of the enzyme diacylglycerol lipase alpha (DAGLa) which produces the endocannabinoid 2-arachidonoylglycerol (2-AG). However, the specific cell types producing 2-AG relevant to neurogenesis remain unknown. Here we sought to identify the cellular source of endocannabinoids in the subgranular zone of the dentate gyrus (DG) in hippocampus, an important neurogenic niche. For this purpose, we used two complementary Cre-deleter mouse strains to delete Dagla either in neurons, or in astroglia and NSPCs. Surprisingly, neurogenesis was not altered in mice bearing a deletion of Dagla in neurons (Syn-Dagla KO), although neurons are the main source for the endocannabinoids in the brain. In contrast, a specific inducible deletion of Dagla in NPSCs and astrocytes (GLAST-CreERT2-Dagla KO) resulted in a strongly impaired neurogenesis with a 50% decrease in proliferation of newborn cells. These results identify Dagla in NSPCs in the DG or in astrocytes as a prominent regulator of adult hippocampal neurogenesis. We also show a reduction of Daglb expression in GLAST-CreERT2-Dagla KO mice, which may have contributed to the neurogenesis phenotype.

H3K9 Methyltransferases Suv39h1 and Suv39h2 Control the Differentiation of Neural Progenitor Cells in the Adult Hippocampus.

In the dentate gyrus of the adult hippocampus new neurons are generated from neural precursor cells through different stages including proliferation and differentiation of neural progenitor cells and maturation of newborn neurons. These stages are controlled by the expression of specific transcription factors and epigenetic mechanisms, which together orchestrate the progression of the neurogenic process. However, little is known about the involvement of histone posttranslational modifications, a crucial epigenetic mechanism in embryonic neurogenesis that regulates fate commitment and neuronal differentiation. During embryonic development, the repressive modification trimethylation of histone H3 on lysine 9 (H3K9me3) contributes to the cellular identity of different cell-types. However, the role of this modification and its H3K9 methyltransferases has not been elucidated in adult hippocampal neurogenesis. We determined that during the stages of neurogenesis in the adult mouse dentate gyrus and in cultured adult hippocampal progenitors (AHPs), there was a dynamic change in the expression and distribution of H3K9me3, being enriched at early stages of the neurogenic process. A similar pattern was observed in the hippocampus for the dimethylation of histone H3 on lysine 9 (H3K9me2), another repressive modification. Among H3K9 methyltransferases, the enzymes Suv39h1 and Suv39h2 exhibited high levels of expression at early stages of neurogenesis and their expression decreased upon differentiation. Pharmacological inhibition of these enzymes by chaetocin in AHPs reduced H3K9me3 and concomitantly decreased neuronal differentiation while increasing proliferation. Moreover, Suv39h1 and Suv39h2 knockdown in newborn cells of the adult mouse dentate gyrus by retrovirus-mediated RNA interference impaired neuronal differentiation of progenitor cells. Our results indicate that H3K9me3 and H3K9 methyltransferases Suv39h1 and Suv39h2 are critically involved in the regulation of adult hippocampal neurogenesis by controlling the differentiation of neural progenitor cells.

Ghrelin mediated hippocampal neurogenesis.

The stomach hormone, ghrelin, which is released during food restriction, provides a link between circulating energy state and adaptive brain function. The maintenance of such homeostatic systems is essential for an organism to survive and thrive, and accumulating evidence points to ghrelin being a key regulator of adult hippocampal neurogenesis and memory function. Aberrant neurogenesis is linked to cognitive decline in aging and neurodegeneration. Therefore, identifying endogenous metabolic factors that regulate new adult-born neuron formation is an important objective in understanding the link between nutritional status and CNS function. Here, we review current developments in our understanding of ghrelin's role in regulating neurogenesis and memory function.

Thyroid hormone regulation of adult hippocampal neurogenesis: Putative molecular and cellular mechanisms.

Adult hippocampal neurogenesis is sensitive to perturbations in thyroid hormone signaling, with evidence supporting a key role for thyroid hormone and thyroid hormone receptors (TRs) in the regulation of postmitotic progenitor survival and neuronal differentiation. In this book chapter we summarize the current understanding of the effects of thyroid hormone signaling on adult hippocampal progenitor development, and also critically address the role of TRs in regulation of distinct aspects of stage-specific hippocampal progenitor progression. We highlight actions of thyroid hormone on thyroid hormone responsive target genes, and the implications for hippocampal progenitor regulation. Given the influence of thyroid hormone on both mitochondrial and lipid metabolism, we discuss a putative role for regulation of metabolism in the effects of thyroid hormone on adult hippocampal neurogenesis. Finally, we highlight specific ideas that require detailed experimental investigation, and the need for future studies to obtain a deeper mechanistic insight into the influence of thyroid hormone and TRs in the developmental progression of adult hippocampal progenitors.

Unbiased profiling of miR-132 targetome with implications in adult hippocampal neurogenesis and Alzheimer's disease.

MicroRNA-132 (miR-132), a potent neuroimmune regulator, is robustly downregulated in the brain of Alzheimer's Disease (AD) patients and its deficiency has been functionally linked to amyloid deposition, TAU hyperphosphorylation and memory decline, in both human and rodents. Of note, miR-132 can explain a higher percentage of the observed variance in histopathological AD phenotypes than APOE e4, a major risk factor for AD. This suggests that miR-132-dependent network-based gene regulation in human AD brain converges onto biological pathways that can drive disease endophenotypes. miR-132 regulates several targets in molecular pathways involved in AD pathophysiology, such as memory formation, neuronal morphogenesis, synaptic plasticity, immune homeostasis, neuronal survival and cell death. Recently, we reported miR-132 as a potent regulator of adult hippocampal neurogenesis (AHN) in healthy and AD brain. Direct miR-132 infusion in the AD mouse brain can counteract several aspects of pathology and memory deficits, suggesting its putative therapeutic relevance. microRNA multi-targeting entails the risk of on- and off- target toxicity, highlighting the importance of systematic genome-wide target validation. While specific miR-132 targets with direct implications in amyloid and TAU pathologies have been previously identified, the complex multicellular miR-132 targetome involved in miR-132-dependent regulation of AHN in AD remains elusive. In order to identify the mechanisms underpinning the positive regulatory effects of miR-132 in AHN and in AD in general, we employed a single-cell RNA-sequencing approach to assess miR-132-specific transcriptomic responses in AHN-relevant cells, such as adult neural stem cells in vivo. We identify novel miR-132 targets with putative neuroimmune functions involved in AHN and possibly in AD pathophysiology. Our results shed light on previously unknown molecular regulators of AHN in brain physiology and AD, provide possible novel therapeutic targets, and further add to the systematic profiling of miR-132 targetome, a prerequisite for successful translation of miR-132 supplementation in AD.

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.

Notch3-Dependent Effects on Adult Neurogenesis and Hippocampus-Dependent Learning in a Modified Transgenic Model of CADASIL.

We and others have reported that Notch3 is a regulator of adult hippocampal neurogenesis. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), the most common genetic form of vascular dementia, is caused by mutations in Notch3. The present study intended to investigate whether there is a correlation between altered adult hippocampal neurogenesis and spatial memory performance in CADASIL transgenic mice. To overcome visual disabilities that hampered behavioral testing of the original mice (on an FVB background) we back-crossed the existing TgN3R169C CADASIL mouse model onto the C57BL/6J background. These animals showed an age-dependent increase in the pathognomonic granular osmiophilic material (GOM) deposition in the hippocampus. Analysis in the Morris water maze task at an age of 6 and 12 months revealed deficits in re-learning and perseverance in the CADASIL transgenic mice. Overexpression of Notch3 alone resulted in deficits in the use of spatial strategies and diminished adult neurogenesis in both age groups. The additional CADASIL mutation compensated the effect on strategy usage but not on adult neurogenesis. In brain bank tissue samples from deceased CADASIL patients we found signs of new neurons, as assessed by calretinin immunohistochemistry, but no conclusive quantification was possible. In summary, while our study confirmed the role of Notch3 in adult neurogenesis, we found a specific effect of the CADASIL mutation only on the reversion of the Notch3 effect on behavior, particularly visible at 6 months of age, consistent with a loss of function. The mutation did not revert the Notch3-dependent changes in adult neurogenesis or otherwise affected adult neurogenesis in this model.

Cholinergic regulation of adult hippocampal neurogenesis and hippocampus-dependent functions.

The production and circuit integration of new neurons is one of the defining features of the adult mammalian hippocampus. A wealth of evidence has established that adult hippocampal neurogenesis is exquisitely sensitive to neuronal activity-mediated regulation. How these signals are interpreted and contribute to neurogenesis and hippocampal functions has been a subject of immense interest. In particular, neurotransmitters, in addition to their synaptic roles, have been shown to offer important trophic support. Amongst these, acetylcholine, which has a prominent role in cognition, has been implicated in regulating neurogenesis. In this review, we appraise the evidence linking the contribution of cholinergic signalling to the regulation of adult hippocampal neurogenesis and hippocampus-dependent functions. We discuss open questions that need to be addressed to gain a deeper mechanistic understanding of the role and translational potential of acetylcholine and its receptors in regulating this form of cellular neuroplasticity.

The Dynamic Regulatory Role of miR-132 in Adult Hippocampal Neurogenesis and Neural Stem Cell Development

Introduction: Neurogenesis and neural stem cell development in the adult hippocampus remains an understudied and controversial area of research. These processes are known to be regulated by the dynamic interplay of transcription factors, cell-niche signalling, and recently, microRNAs. microRNA-132 (miR-132) is one example of a miRNA that offers critical insight into neurogenesis and neural stem cell development. The aim of this study was to systematically review the current literature regarding the role of miR-132-mediated post-transcriptional regulation of adult hippocampal neurogenesis (AHN) and neural stem cell (NSC) development. Methods: The literature search consisted of research articles found in PubMed, MEDLINE, Google Scholar, Cochrane, and Scopus databases using combinations of the Medical Subject Headings (MeSH) keywords “micro-RNA 132”, “miR-132”, “adult hippocampal neurogenesis”, and “neural stem cell development” to filter initial results. The study abstracted data in regards to the modalities of miR-132-mediated post-transcriptional regulation and the histophysiological implications associated with AHN and NSC development. Results: miR-132 has been implicated in mediating AHN as well as NSC differentiation and integration into the adult hippocampal dentate gyrus. Knockdown and overexpression of micro-RNA 132 in studies have demonstrated that miR-132 acts as a regulator of several downstream pathways and biochemical targets, including p250-GAP, methyl CpG-binding protein 2, AMPA glutamate receptors, and the RAS/MAPK axon signaling pathway. The fine-tuned modulation of neuronal plasticity associated with miR-132 suggests a role in higher level cognition, learning, and neurodegeneration within the context of Alzheimer’s disease. Discussion: The findings that miR-132 serves as a regulator of AHN and NSC development have significant clinical implications, specifically towards better understanding the pathological basis of neurodegenerative disorders as well as the development of novel miRNA-based therapeutics. Conclusion: The systematic review aggregated key findings on multiple potential biochemical targets and downstream feedback regulation pathways associated with miR-132 expression. Further research is needed to elucidate the mechanism of each pathway and the potential interplay between multiple proteins regulated by miR-132 that are associated with clinical disorders such as Alzheimer’s disease.