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Neural stem cells (NSCs) are multipotent and correct fate determination is crucial to guarantee brain formation and homeostasis. How NSCs are instructed to generate neuronal or glial progeny is not well understood. Here, we addressed how murine adult hippocampal NSC fate is regulated and described how scaffold attachment factor B (SAFB) blocks oligodendrocyte production to enable neuron generation. We found that SAFB prevents NSC expression of the transcription factor nuclear factor I/B (NFIB) by binding to sequences in the Nfib mRNA and enhancing Drosha-dependent cleavage of the transcripts. We show that increasing SAFB expression prevents oligodendrocyte production by multipotent adult NSCs, and conditional deletion of Safb increases NFIB expression and oligodendrocyte formation in the adult hippocampus. Our results provide novel insights into a mechanism that controls Drosha functions for selective regulation of NSC fate by modulating the post-transcriptional destabilization of Nfib mRNA in a lineage-specific manner.

Gut microbiota plays an important role in regulating brain function and adult neurogenesis. Although probiotics have recently been reported as effective against certain psychiatric disorders, the underlying mechanisms remain unclear. In particular, the combination of 3 probiotic strains, Bacillus subtilis TO-A, Enterococcus faecium T-110, and Clostridium butyricum TO-A, hereafter referred to as ProB3, has been reported to potentially alleviate psychiatric symptoms in patients with schizophrenia. Herein, we show that ProB3 promotes adult neurogenesis in mice and restores its dysregulation in germ-free (GF) mice. ProB3 colonization in GF mice enhanced the proliferation of adult neural stem cells compared to specific-pathogen-free and GF mice. Furthermore, ProB3 colonization was sufficient to ameliorate the arrest of newborn neuron maturation and the diminution of quiescent neural stem cells in GF mice. ProB3 colonization in mice increased the levels of several metabolites in the blood, including theanine and 3-hydroxybutyrate, and imidazole peptides, including anserine, which promoted proliferation, neurogenesis, and maturation of newborn neurons in cultured human fetus neural stem cells, as well as mouse adult hippocampal neural stem cells. Collectively, these results indicate that the essential role of the gut microbiota in adult hippocampal neurogenesis can be effectively complemented by the intake of a specific 3-strain probiotic, ProB3, providing novel insights into the brain–gut axis. [ABSTRACT FROM AUTHOR]

In the central nervous system, cell-to-cell interaction is essential for brain plassticity and repair, and its alteration is critically involved in the development of neurodegenerative diseases. Neural stem cells are a plentiful source of biological signals promoting neuroplasticity and the maintenance of cognitive functions. Extracellular vesicles (EVs) represent an additional strategy for cells to release signals in the surrounding cellular environment or to exchange information among both neighboring and distant cells. In the last years, rising attention has been devoted to the ability of stem cell (SC)-derived EVs to counteract inflammatory and degenerative brain disorders taking advantage of their immunomodulatory capacities and regenerative potential. Here, we review the role of adult neurogenesis impairment in the cognitive decline associated with neurodegenerative diseases and describe the beneficial effects of SC-derived EVs on brain plasticity and repair also discussing the advantages of SC-derived EV administration vs SC transplantation in the treatment of neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is one of the major causes of severe neurological disorders and long-term dysfunction in the nervous system. Besides inducing neurodegeneration, TBI alters stem cell activity and neurogenesis within primary neurogenic niches. However, the fate of dividing cells in other brain regions remains unclear despite offering potential targets for therapeutic intervention. Here, we investigated cell division and differentiation in non-neurogenic brain regions during the acute and delayed phases of TBI-induced neurodegeneration. We subjected mice to lateral fluid percussion injury (LFPI) to model TBI and analyzed them 1 or 7 weeks later. To assess cellular proliferation and differentiation, we administered 5-ethinyl-2′-deoxyuridine (EdU) and determined the number and identity of dividing cells 2 h later using markers of neuronal precursors and astro-, micro-, and oligodendroglia. Our results demonstrated a significant proliferative response in several brain regions at one week post-injury that notably diminished by seven weeks, except in the optic tract. In addition to active astro- and microgliosis, we detected oligodendrogenesis in the striatum and optic tract. Furthermore, we observed trauma-induced neurogenesis in the striatum. These findings suggest that subcortical structures, particularly the striatum and optic tract, may possess a potential for self-repair through neuronal regeneration and axon remyelination. [ABSTRACT FROM AUTHOR]

The neuroscience community has largely accepted the notion that functional neurons can be generated from neural stem cells in the adult brain, especially in two brain regions: the subventricular zone of the lateral ventricles and the subgranular zone in the dentate gyrus of the hippocampus. However, impaired neurogenesis has been observed in some neurodegenerative diseases, particularly in Alzheimer's, Parkinson's, and Huntington's diseases, and also in Lewy Body dementia. Therefore, restoration of neurogenic function in neurodegenerative diseases emerges as a potential therapeutic strategy to counteract, or at least delay, disease progression. Considering this, the present study summarizes the different neuronal niches, provides a collection of the therapeutic potential of different pro-neurogenic strategies in pre-clinical and clinical research, providing details about their possible modes of action, to guide future research and clinical practice. [ABSTRACT FROM AUTHOR]

Abstract Adult neurogenesis is a unique cellular process of the ongoing generation of new neurons throughout life, which primarily occurs in the subgranular zone (SGZ) of the dentate gyrus (DG) and the subventricular zone (SVZ) of the lateral ventricle. In the adult DG, newly generated granule cells from neural stem cells (NSCs) integrate into existing neural circuits, significantly contributing to cognitive functions, particularly learning and memory. Recently, more and more studies have shown that rather than being a homogeneous population of identical cells, adult NSCs are composed of multiple subpopulations that differ in their morphology and function. In this study, we provide an overview of the origin, regional characteristics, prototypical morphology, and molecular factors that contribute to NSC heterogeneity. In particular, we discuss the molecular mechanisms underlying the balance between activation and quiescence of NSCs. In summary, this review highlights that deciphering NSC heterogeneity in the adult brain is a challenging but critical step in advancing our understanding of tissue-specific stem cells and the process of neurogenesis in the adult brain.

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.

ObjectiveMethodsResultsConclusionsBrain ischemia is considered an extremely potent stress factor at the cellular and molecular level which may lead to massive neuronal death. Alternatively, short brain ischemia and reperfusion (I/R) can actually stimulate neurogenesis, angiogenesis and peptidergic signaling. There is little known about the potential effect of I/R on brain expression of the novel neuropeptide; phoenixin (PNX) and its receptor GPR173.The study was carried out on adult male Wistar rats divided into seven groups: control, sham operation and 5 ischemic experimental groups across the time course of reperfusion. We examined mRNA and protein expression of GPR173 and neurogenesis markers Musashi-1, doublecortin (DCX), and Sox-2 in the striatum.GPR-173 positive cells were found only in the ischemic hemisphere, where Musashi-1, DCX and Sox-2-positive cells were also observed. Gene expression analysis also showed a significant increase of GPR-173 mRNA level in the I/R striatum in comparison with the control one. Results confirm previous findings suggesting that I/R stimulates adult neurogenesis in the striatum and affects peptidergic signaling in this structure.A very fast occurence of GPR-173 expression revealed in the striatum may potentially be exclusively related to neuroprotective neurochemical changes that occur in this region after I/R. [ABSTRACT FROM AUTHOR]

The neurogenic potential of the brain decreases during ageing, whereas the risk of neurodegenerative diseases and stroke rises. This creates a mismatch between the rate of neuron loss and the brain's capacity for replacement. Adult neurogenesis primarily occurs in the subgranular zone (SGZ) and the ventricular‐subventricular zone (V‐SVZ). Exercise enhances SGZ neurogenesis, and we previously showed that V‐SVZ neurogenesis is induced by exercise via activation of the lactate receptor HCA1. Here, we investigated how high‐intensity interval training (HIIT) and medium‐intensity interval training (MIIT) affect neurogenesis in these niches. Wild‐type (WT) and HCA1 knockout (KO) mice were randomized to sedentary, HIIT or MIIT (n = 5–8 per group) for 3 weeks. In the SGZ, HIIT increased the density of doublecortin (DCX)‐positive cells in WT mice by 85% (5.77±1.76 vs. 3.12±1.54 cells/100 µm, P = 0.013) and KO mice (67% increase; 7.91±2.92 vs. 4.73±1.63 cells/100 µm, P = 0.004). MIIT did not alter the density of DCX‐positive cells in either genotype. HIIT increased the density of Ki‐67‐positive cells only in KO mice (P = 0.038), whereas no differences in nestin‐positive cells were observed. In the V‐SVZ, HIIT increased the density of DCX‐positive cells in WT mice by 155% (117.79±39.72 vs. 46.25±19.96 cells/100 µm, P < 0.001) and MIIT increased the density of DCX‐positive cells by 80% (83.26±39.48 vs. 46.25±19.96 cells/100µm, P = 0.027). No exercise‐induced changes were observed in KO mice. Similar patterns were noted for Ki‐67 positive and DCX/Ki‐67 double‐positive cells in the V‐SVZ. These findings suggest that HIIT enhances neurogenesis more robustly than MIIT in both niches, with HCA1 playing a crucial role in V‐SVZ neurogenesis. Key points: The neurogenic potential of the brain decreases with age, whereas the risk of neurodegenerative diseases and stroke increases, highlighting a mismatch between neuronal loss and replacement capacity.Exercise enhances neurogenesis in both the subgranular zone and the ventricular‐subventricular zone.High‐intensity interval exercise is more effective than medium‐intensity interval exercise at promoting neurogenesis in both the subgranular zone and the ventricular‐subventricular zone of wild‐type mice.The enhancement of neurogenesis in the ventricular‐subventricular zone is dependent on the activation of the HCA1 receptor, as evidenced by the ability of medium‐ and high‐intensity interval exercise to induce neurogenesis in wild‐type mice and the lack of this effect in HCA1 knockout mice.By contrast, neurogenesis in the subgranular zone is independent on the activation of the HCA1 receptor, highlighting that neurogenesis in the two major neurogenic niches are regulated differently. [ABSTRACT FROM AUTHOR]

The discovery of adult‐born granule cells (aDGCs) in the dentate gyrus of the hippocampus has raised questions regarding how they develop, incorporate into the hippocampal circuitry, and contribute to learning and memory. Here, we used patch‐clamp electrophysiology to investigate the intrinsic and synaptic excitability of mouse aDGCs as they matured, enabled by using a tamoxifen‐induced genetic label to birth date the aDGCs at different animal ages. Importantly, we also undertook immunofluorescence studies of the expression of the immediate early gene Egr1 and compared these findings with the electrophysiology data in the same animals. We examined two groups of animals, with aDGC birthdating when the mice were 2 months and at 7–9 months of age. In both groups, cells 4 weeks old had lower thresholds for current‐evoked action potentials than older cells but fired fewer spikes during long current pulses and responded more poorly to synaptic activation. aDGCs born in both 2 and 7–9‐month‐old mice matured in their intrinsic excitability and synaptic properties from 4–12 weeks postgenesis, but this occurred more slowly for the older age animals. Interestingly, this pattern of intrinsic excitability changes did not correlate with the pattern of Egr1 expression. Instead, the development of Egr1 expression was correlated with the frequency of spontaneous excitatory postsynaptic currents. These results suggest that in order for aDGCs to fully participate in hippocampal circuitry, as indicated by Egr1 expression, they must have developed enough synaptic input, in spite of the greater input resistance and reduced firing threshold that characterizes young aDGCs. [ABSTRACT FROM AUTHOR]

The hippocampus is important for social behavior and exhibits unusual structural plasticity in the form of continued production of new granule neurons throughout adulthood, but it is unclear how adult neurogenesis contributes to social interactions. In the present study, we suppressed neurogenesis using a pharmacogenetic mouse model and examined social investigation and aggression in adult male mice to investigate the role of hippocampal adult‐born neurons in the expression of aggressive behavior. In simultaneous choice tests with stimulus mice placed in corrals, mice with complete suppression of adult neurogenesis in adulthood (TK mice) exhibited normal social investigation behaviors, indicating that new neurons are not required for social interest, social memory, or detection of and response to social olfactory signals. However, mice with suppressed neurogenesis displayed decreased offensive and defensive aggression in a resident‐intruder paradigm, and less resistance in a social dominance test, relative to neurogenesis‐intact controls, when paired with weight and strain‐matched (CD‐1) mice. During aggression tests, TK mice were frequently attacked by the CD‐1 intruder mice, which never occurred with WTs, and normal CD‐1 male mice investigated TK mice less than controls when corralled in the social investigation test. Importantly, TK mice showed normal aggression toward prey (crickets) and smaller, nonaggressive (olfactory bulbectomized) C57BL/6J intruders, suggesting that mice lacking adult neurogenesis do not avoid aggressive social interactions if they are much larger than their opponent and will clearly win. Taken together, our findings show that adult hippocampal neurogenesis plays an important role in the instigation of intermale aggression, possibly by weighting a cost–benefit analysis against confrontation in cases where the outcome of the fight is not clear. [ABSTRACT FROM AUTHOR]

Chronic pathological conditions often induce persistent systemic inflammation, contributing to neuroinflammatory diseases like Multiple Sclerosis (MS). MS is known for its autoimmune-mediated damage to myelin, axonal injury, and neuronal loss which drive disability accumulation and disease progression, often manifesting as cognitive impairments. Understanding the involvement of neural stem cells (NSCs) and neural progenitor cells (NPCs) in the remediation of MS through adult neurogenesis (ANG) and gliogenesis—the generation of new neurons and glial cells, respectively is of great importance. Hence, these phenomena, respectively, termed ANG and gliogenesis, involve significant structural and functional changes in neural networks. Thus, the proper integration of these newly generated cells into existing circuits is not only key to understanding the CNS's development but also its remodeling in adulthood and recovery from diseases such as MS. Understanding how MS influences the fate of NSCs/NPCs and their possible neuroprotective role, provides insights into potential therapeutic interventions to alleviate the impact of MS on cognitive function and disease progression. This review explores MS, its pathogenesis, clinical manifestations, and its association with ANG and gliogenesis. It highlights the impact of altered NSCs and NPCs' fate during MS and delves into the potential benefits of its modifications. It also evaluates treatment regimens that influence the fate of NSCS/NPCs to counteract the pathology subsequently. [ABSTRACT FROM AUTHOR]

Stroke is one of the leading causes of chronic disability in humans. It has been proposed that the endogenous neural stem/progenitor cells generate new neurons in the damaged area. Still, the contribution of these cells is negligible because a low number of newborn mature neurons are formed. Tlx conventional knock-out mice, Tlx-CreERT2 mice, and Tlx-overexpressing (Tlx-OE) mice were specifically chosen for their unique genetic characteristics, which were crucial for the experiments. Permanent and transient middle cerebral artery occlusion was used to induce stroke in the mice. Immunostainings for doublecortin and GFP/BrdU/NeuN were performed to study neurogenesis and fate mapping. The rotarod test was performed to assess motor deficits. Here, we show that stroke-induced neurogenesis is dramatically increased with the additional expression of two copies of the nuclear receptor-coding gene tailless (Tlx, also known as Nr2e1), which has been shown to be a master regulator of subventricular zone (SVZ) neural stem cells (NSCs). We show that Tlx expression is upregulated after stroke, and stroke-induced neurogenesis is blocked when Tlx is inactivated. Tlx overexpression in NSCs leads to massive induction of neurogenesis via stroke. More newborn mature neurons are formed in Tlx-overexpressing mice, leading to improved coordination and motor function recovery. Most importantly, we also demonstrate that this process is sustained in aged mice, where stroke-induced neurogenesis is nearly undetectable in wild-type animals. This study provides the first stem cell-specific genetic evidence that endogenous NSCs can be exploited by manipulating their master regulator, Tlx, and thus suggests a novel therapeutic strategy for neuronal repair. [ABSTRACT FROM AUTHOR]

In the brains of adult rodents, the cells arising in the subventricular zone of the lateral ventricles maintain the ability to divide when migrating to the olfactory bulb along the rostral migratory stream (RMS). Dividing cells in the RMS are most frequently revealed through immunohistochemical detection of an exogenous marker of proliferation, 5-Bromo-2-deoxyuridine (BrdU), which incorporates into DNA during the S-phase of mitosis. The more recently recognized antigen Ki-67 (also known as Kiel-67 and MKI67), an endogenous protein expressed in nuclei at all stages of mitosis, is also used for proliferation detection. BrdU and Ki-67 are often used as alternative methods, but they have not previously been compared in the RMS. We analyzed the numbers and distribution of cells labeled either with BrdU or Ki-67 within the RMS of adult rats. The first group of animals received a single i.p. dose of BrdU. In the second group, dividing cells were visualized by Ki-67 immunohistochemistry. Some sections from brains of BrdU-treated rats were also immunostained for Ki-67. Labeled cells were counted in the three anatomical parts of the RMS (vertical arm, elbow and horizontal arm) using a method for unbiased estimation of cell density. The distribution of proliferating cells was similar for both markers. Most BrdU and Ki-67 positive cells were located in the vertical arm and in the elbow, but a caudo-rostral reduction in cell divisions was more evident with Ki-67 labeling. The number of Ki-67 positive cells significantly exceeded the number of BrdU positive cells in all parts of the RMS. Our results indicate that BrdU and Ki-67 are not interchangeable markers for evaluation of proliferative activity in the RMS. [ABSTRACT FROM AUTHOR]

Neural stem cells (NSCs) are progenitor cell populations generating glial cells and neurons and endowed with long-lasting self-renewal and differentiation potential. While some neural progenitors (NPs) in the embryonic nervous system are also long-lived and match this definition, the term NSC classically refers to such progenitor types in the adult. With the discovery of extensive NSC populations in the adult brain of Danio rerio (zebrafish) and of their high neurogenic activity, including for neuronal regeneration, this model organism has become a powerful tool to characterize and mechanistically dissect NSC properties. On these bases, this article will consider NSCs in the adult zebrafish brain, with a focus on its most extensively characterized domain, the telencephalon (notably its dorsal part, the pallium). Whenever necessary, we will also refer to other brain subdivisions, embryonic processes, and the mouse adult brain, whether for comparative purposes or because more information is available in these other systems. [ABSTRACT FROM AUTHOR]

The Izpisua‐Belmonte group identified a cocktail of metabolites that promote partial reprogramming in cultured muscle cells. We tested the effect of brain injection of these metabolites in the dentate gyrus of aged wild‐type mice. The dentate gyrus is a brain region essential for memory function and is extremely vulnerable to aging. A single injection of the cocktail containing four compounds (putrescine, glycine, methionine and threonine) partially reversed brain aging phenotypes and epigenetic alterations in age‐associated genes. Our analysis revealed three levels: chromatin methylation, RNA sequencing, and protein expression. Functional studies complemented the previous ones, showing cognitive improvement. In summary, we report the reversal of various age‐associated epigenetic changes, such as the transcription factor Zic4, and several changes related to cellular rejuvenation in the dentate gyrus (DG). These changes include increased expression of the Sox2 protein. Finally, the increases in the survival of newly generated neurons and the levels of the NMDA receptor subunit GluN2B were accompanied by improvements in both short‐term and long‐term memory performance. Based on these results, we propose the use of these metabolites to explore new strategies for the development of potential treatments for age‐related brain diseases. [ABSTRACT FROM AUTHOR]

Microglia, the resident immune cells of the central nervous system, play a crucial role in regulating adult neurogenesis and contribute significantly to the pathogenesis of Alzheimer's disease (AD). Under physiological conditions, microglia support and modulate neurogenesis through the secretion of neurotrophic factors, phagocytosis of apoptotic cells, and synaptic pruning, thereby promoting the proliferation, differentiation, and survival of neural progenitor cells (NPCs). However, in AD, microglial function becomes dysregulated, leading to chronic neuroinflammation and impaired neurogenesis. This review explores the intricate interplay between microglia and adult neurogenesis in health and AD, synthesizing recent findings to provide a comprehensive overview of the current understanding of microglia-mediated regulation of adult neurogenesis. Furthermore, it highlights the potential of microglia-targeted therapies to modulate neurogenesis and offers insights into potential avenues for developing novel therapeutic interventions. [ABSTRACT FROM AUTHOR]

Modulation of in vivo adult neurogenesis (AN) is an evolving concept in managing neurodegenerative diseases. CDRI‐08, a bacoside‐enriched fraction of Bacopa monnieri, has been demonstrated for its neuroprotective actions, but its effect on AN remains unexplored. This article describes the status of AN by monitoring neuronal stem cells (NSCs) proliferation, differentiation/maturation markers and BDNF–TrkB levels (NSCs signalling players) vs. the level of neurodegeneration and their modulations by CDRI‐08 in the hippocampal dentate gyrus (DG) of male rats with moderate grade hepatic encephalopathy (MoHE). For NSC proliferation, 10 mg/kg b.w. 5‐bromo‐2′‐deoxyuridine (BrdU) was administered i.p. during the last 3 days, and for the NSC differentiation study, it was given during the first 3 days to the control, the MoHE (developed by 100 mg/kg b.w. of thioacetamide i.p. up to 10 days) and to the MoHE male rats co‐treated with 350 mg/kg b.w. CDRI‐08. Compared with the control rats, the hippocampus DG region of MoHE rats showed significant decreases in the number of Nestin+/BrdU+ and SOX2+/BrdU+ (proliferating) and DCX+/BrdU+ and NeuN+/BrdU+ (differentiating) NSCs. This was consistent with a similar decline in BDNF+/TrkB+ NSCs. However, all these NSC marker positive cells were observed to be recovered to their control levels, with a concordant restoration of total cell numbers in the DG of the CDRI‐08‐treated MoHE rats. The findings suggest that the restoration of hippocampal AN by CDRI‐08 is consistent with the recovery of BDNF–TrkB‐expressing NSCs in the MoHE rat model of neurodegeneration. [ABSTRACT FROM AUTHOR]

Introduction: Neurogenesis in the adult brain may play an important role in memory and cognition; however, knowledge of neurogenic markers in the human brain remains limited. We compared the single-nucleus transcriptome of the hippocampus with that of other cortical regions to identify hippocampus-specific neurogenic markers. Methods: We analyzed 26,189 nuclei from four human brains collected within 16 h of death. Clustering and annotation were performed to examine differential expression, gene ontology, and intercellular communication. DCX expression was validated by ddPCR. Results: Immature markers such as DCX, CALB2, NES, SOX2, PAX6, DPYSL3, and TUBB3 were expressed in both hippocampus and prefrontal cortex, with higher levels in the prefrontal cortex. ddPCR confirmed higher expression of DCX in the prefrontal cortex. DCX was involved in both neurogenesis and neuroprotection pathways. Conclusion: Neurogenic markers are not definitive indicators of adult neurogenesis as their roles are more complex than previously understood. [ABSTRACT FROM AUTHOR]

Exercise may prevent or delay aging-related memory loss and neurodegeneration. In rodents, running increases the number of adult-born neurons in the dentate gyrus (DG) of the hippocampus, in association with improved synaptic plasticity and memory function. However, it is unclear whether adult-born neurons remain fully integrated into the hippocampal network during aging and whether long-term running affects their connectivity. To address this issue, we labeled proliferating DG neural progenitor cells with retrovirus expressing the avian TVA receptor in two-month-old sedentary and running male C57Bl/6 mice. More than six months later, we injected EnvA-pseudotyped rabies virus into the DG as a monosynaptic retrograde tracer, to selectively infect TVA expressing old new neurons. We identified and quantified the direct afferent inputs to these adult-born neurons within the hippocampus and (sub)cortical areas. Here, we show that long-term running substantially modifies the network of the neurons generated in young adult mice, upon middle-age. Exercise increases input from hippocampal interneurons onto old adult-born neurons, which may play a role in reducing aging-related hippocampal hyperexcitability. In addition, running prevents the loss of adult-born neuron innervation from perirhinal cortex, and increases input from subiculum and entorhinal cortex, brain areas that are essential for contextual and spatial memory. Thus, long-term running maintains the wiring of old new neurons, born during early adulthood, within a network that is important for memory function during aging.

Domestic strains of canaries (Serinus canaria) variably respond to photoperiod changes and apparently stay in breeding state for extended periods. Fife Fancy canaries are supposed to be similar to the native species living at 27–39° north where photoperiod significantly changes across the year. Our birds showed reproductive cycles when exposed to light regimes mimicking the annual cycle of photoperiod. However after 6 months in short days (SD: 8L:16D), males developed large testes, as observed by X‐ray tomography, and intense singing. Switching to long days (LD: 16L:8D) did not further increase song rate nor testes size but increased song duration, number of syllables per song, and trill occurrence frequency. No sign of regression was observed after 12 weeks in LD but return to SD produced a rapid decrease in testes size and singing activity below values in birds maintained throughout in SD. Fife Fancy thus does not seem to develop absolute but only relative refractoriness. The relatively high singing activity expressed by SD‐photosensitive males does not seem to depend on high testosterone (T) concentrations. Singing did not correlate with plasma testosterone (T). Treatment with ATD + Flutamide only marginally decreased song rate and did not affect song quality nor song control nuclei volume. These birds are either supersensitive to low T levels or their reproductive physiology is activated by other mechanisms. Neurogenesis is increased by T and by LD but the function of new neurons incorporated in HVC is poorly understood. We developed a procedure based on X‐ray focal irradiation to deplete neural progenitors adjacent to HVC and study the functional consequences. The decrease in neurogenesis increased the variability of T‐induced songs in females and decreased their bandwidth. Neurogenesis in HVC thus plays a role in song production and X‐ray focal irradiation represents an excellent tool to analyze adult neurogenesis. [ABSTRACT FROM AUTHOR]

The subventricular zone (SVZ) is one of the neurogenic regions of the adult mammalian brain. Neural stem cells (NSCs) in the SVZ have certain key features: they express glial fibrillary acidic protein (GFAP), proliferate slowly, have a radial glia–like (RG‐L) morphology, and are in contact with the cerebrospinal fluid (CSF). NSCs have been isolated by FACS to analyse them, but their morphology has not been systematically examined. To address this knowledge gap, we sparsely labelled RG‐L cells in the SVZ of neonatal mice by introducing via electroporation a plasmid expressing fluorescent protein under the control of the GFAP promoter. We then classified RG‐L cells into three types (RG‐L1, 2, and 3) based on their morphologies. RG‐L1 cells had a basal process with some branches and numerous fine processes. RG‐L2 cells had a basal process, but fewer branches and fine processes than RG‐L1 cells. RG‐L3 cells had one basal process that was almost free of branches and fine processes. Importantly, regardless of the cell type, about half of their somata resided on the basal side of the SVZ. Based on changes in their proportions during postnatal development and their expression of GFAP and cell proliferation markers at the adult stage, we speculated that NSCs change their morphologies during development/maturation and not all NSCs must always be in the apical SVZ or in contact with the CSF. Our results indicate that in addition to expression of markers for NSCs, the morphology is a critical feature to identify NSCs. [ABSTRACT FROM AUTHOR]

Neuronal apoptosis is a mechanism used to clear the cells of oxidative stress or DNA damage and refine the final number of neurons for a functional neuronal circuit. The tumor suppressor protein p53 is a key regulator of the cell cycle and serves as a checkpoint for eliminating neurons with high DNA damage, hyperproliferative signals or cellular stress. During development, p53 is largely expressed in progenitor cells. In the adult brain, p53 expression is restricted to the neurogenic niches where it regulates cell proliferation and self-renewal. To investigate the functional consequences of p53 deletion in the cortex and hippocampus, we generated a conditional mutant mouse (p53-cKO) in which p53 is deleted from pallial progenitors and their derivatives. Surprisingly, we did not find any significant change in the number of neurons in the mutant cortex or CA region of the hippocampus compared with control mice. However, p53-cKO mice exhibit more proliferative cells in the subgranular zone of the dentate gyrus and more granule cells in the granular cell layer. Glutamatergic synapses in the CA3 region are more numerous in p53-cKO mice compared with control littermates, which correlates with overexcitability and higher epileptic susceptibility in the mutant mice. [ABSTRACT FROM AUTHOR]

Adult neural stem cells (NSCs) in the hippocampal dentate gyrus continuously proliferate and generate new neurons throughout life. Although various functions of organelles are closely related to the regulation of adult neurogenesis, the role of endoplasmic reticulum (ER)-related molecules in this process remains largely unexplored. Here we show that Derlin-1, an ER-associated degradation component, spatiotemporally maintains adult hippocampal neurogenesis through a mechanism distinct from its established role as an ER quality controller. Derlin-1 deficiency in the mouse central nervous system leads to the ectopic localization of newborn neurons and impairs NSC transition from active to quiescent states, resulting in early depletion of hippocampal NSCs. As a result, Derlin-1-deficient mice exhibit phenotypes of increased seizure susceptibility and cognitive dysfunction. Reduced Stat5b expression is responsible for adult neurogenesis defects in Derlin-1-deficient NSCs. Inhibition of histone deacetylase activity effectively induces Stat5b expression and restores abnormal adult neurogenesis, resulting in improved seizure susceptibility and cognitive dysfunction in Derlin-1-deficient mice. Our findings indicate that the Derlin-1-Stat5b axis is indispensable for the homeostasis of adult hippocampal neurogenesis. Synopsis: Derlin-1, an endoplasmic reticulum (ER)-associated degradation component, regulates seizure susceptibility and cognitive function through Stat5b-mediated maintenance of adult neurogenesis, and this function is distinct from its role in ER quality control. Derlin-1 is essential for the appropriate localization of newborn neurons and the transition of neural stem cells from active to quiescent states. Mice with a loss of Derlin-1 in the central nervous system exhibit increased seizure susceptibility and cognitive dysfunction. Derlin-1 maintains adult neurogenesis homeostasis through the regulation of Stat5b expression. Histone deacetylase inhibition effectively induces Stat5b expression and restores abnormal adult neurogenesis. Derlin-1, an endoplasmic reticulum (ER)-associated degradation component, regulates seizure susceptibility and cognitive function through Stat5b-mediated maintenance of adult neurogenesis, and this function is distinct from its role in ER quality control. [ABSTRACT FROM AUTHOR]

Young immature granule cells (imGCs) appear via adult neurogenesis in the hippocampal dentate gyrus (DG). In comparison to mature GCs (mGCs) (born during development), the imGCs exhibit two competing distinct properties such as high excitability (increasing activation degree) and low excitatory innervation (reducing activation degree). We develop a spiking neural network for the DG, incorporating both the mGCs and the imGCs. The mGCs are well known to perform "pattern separation" (i.e., a process of transforming similar input patterns into less similar output patterns) to facilitate pattern storage in the hippocampal CA3. In this paper, we investigate the effect of the young imGCs on pattern separation of the mGCs. The pattern separation efficacy (PSE) of the mGCs is found to vary through competition between high excitability and low excitatory innervation of the imGCs. Their PSE becomes enhanced (worsened) when the effect of high excitability is higher (lower) than the effect of low excitatory innervation. In contrast to the mGCs, the imGCs are found to perform "pattern integration" (i.e., making association between dissimilar patterns). Finally, we speculate that memory resolution in the hippocampal CA3 might be optimally maximized via mixed cooperative encoding through pattern separation and pattern integration. [ABSTRACT FROM AUTHOR]

In adult songbirds, new neurons are born in large numbers in the proliferative ventricular zone in the telencephalon and migrate to the adjacent song control region HVC (acronym used as proper name) [A. Reiner et al., J. Comp. Neurol. 473, 377-414 (2004)]. Many of these new neurons send long axonal projections to the robust nucleus of the arcopallium (RA). The HVC-RA circuit is essential for producing stereotyped learned song. The function of adult neurogenesis in this circuit has not been clear. A previous study suggested that it is important for the production of well-structured songs [R. E. Cohen, M. Macedo-Lima, K. E. Miller, E. A. Brenowitz, J. Neurosci. 36, 8947-8956 (2016)]. We tested this hypothesis by infusing the neuroblast migration inhibitor cyclopamine into HVC of male Gambel's white-crowned sparrows (Zonotrichia leucophrys gambelii) to block seasonal regeneration of the HVC-RA circuit. Decreasing the number of new neurons in HVC prevented both the increase in spontaneous electrical activity of RA neurons and the improved structure of songs that would normally occur as sparrows enter breeding condition. These results show that the incorporation of new neurons into the adult HVC is necessary for the recovery of both electrical activity and song behavior in breeding birds and demonstrate the value of the bird song system as a model for investigating adult neurogenesis at the level of long projection neural circuits. [ABSTRACT FROM AUTHOR]

The brain's neuroreparative capacity after injuries such as ischemic stroke is partly contained in the brain's neurogenic niches, primarily the subventricular zone (SVZ), which lies in close contact with the cerebrospinal fluid (CSF) produced by the choroid plexus (ChP). Despite the wide range of their proposed functions, the ChP/CSF remain among the most understudied compartments of the central nervous system (CNS). Here, we report a mouse genetic tool (the ROSA26iDTR mouse line) for noninvasive, specific, and temporally controllable ablation of CSF-producing ChP epithelial cells to assess the roles of the ChP and CSF in brain homeostasis and injury. Using this model, we demonstrate that ChP ablation causes rapid and permanent CSF volume loss in both aged and young adult brains, accompanied by disruption of ependymal cilia bundles. Surprisingly, ChP ablation did not result in overt neurological deficits at 1 mo postablation. However, we observed a pronounced decrease in the pool of SVZ neuroblasts (NBs) following ChP ablation, which occurs due to their enhanced migration into the olfactory bulb. In the middle cerebral artery occlusion model of ischemic stroke, NB migration into the lesion site was also reduced in the CSF-depleted mice. Thus, our study establishes an important role of ChP/CSF in regulating the regenerative capacity of the adult brain under normal conditions and after ischemic stroke. [ABSTRACT FROM AUTHOR]

Exercise can induce beneficial improvements in cognition. However, the effects of different modes and intensities of exercise have yet to be explored in detail. This study aimed to identify the effects of different exercise modes (aerobic and resistance) and intensities (low and high) on cognitive performance, adult hippocampal neurogenesis and synaptic plasticity in mice. A total of 40 C57BL/6J mice were randomised into 5 groups (n = 8 mice per group): control, low-intensity aerobic exercise, high-intensity aerobic exercise, low-intensity resistance exercise, and high-intensity resistance exercise. The aerobic exercise groups underwent treadmill training, while the resistance exercise groups underwent ladder climbing training. At the end of the exercise period, cognitive performance was assessed by the Y-maze and Barnes maze. In addition, adult hippocampal neurogenesis was evaluated immunohistochemically by 5-bromo-2'-deoxyuridine (BrdU)/ neuronal nuclei (NeuN) co-labeling. The levels of synaptic plasticity-related proteins in the hippocampus, including synaptophysin (SYP) and postsynaptic density protein 95 (PSD-95), were analyzed by western blotting. Our results showed no significant differences in cognitive performance among the groups. However, high-intensity aerobic exercise significantly increased hippocampal adult neurogenesis relative to the control. A trend towards increased adult neurogenesis was observed in the low-intensity aerobic group compared to the control group. No significant changes in synaptic plasticity were observed among all groups. Our results indicate that high-intensity aerobic exercise may be the most potent stimulator of adult hippocampal neurogenesis. [ABSTRACT FROM AUTHOR]

Impaired mitochondrial function is a hallmark of aging and a major contributor to neurodegenerative diseases. We have shown that disrupted mitochondrial dynamics typically found in aging alters the fate of neural stem cells (NSCs) leading to impairments in learning and memory. At present, little is known regarding the mechanisms by which neural stem and progenitor cells survive and adapt to mitochondrial dysfunction. Using Opa1‐inducible knockout as a model of aging and neurodegeneration, we identify a decline in neurogenesis due to impaired stem cell activation and progenitor proliferation, which can be rescued by the mitigation of oxidative stress through hypoxia. Through sc‐RNA‐seq, we identify the ATF4 pathway as a critical mechanism underlying cellular adaptation to metabolic stress. ATF4 knockdown in Opa1‐deficient NSCs accelerates cell death, while the increased expression of ATF4 enhances proliferation and survival. Using a Slc7a11 mutant, an ATF4 target, we show that ATF4‐mediated glutathione production plays a critical role in maintaining NSC survival and function under stress conditions. Together, we show that the activation of the integrated stress response (ISR) pathway enables NSCs to adapt to metabolic stress due to mitochondrial dysfunction and metabolic stress and may serve as a therapeutic target to enhance NSC survival and function in aging and neurodegeneration. [ABSTRACT FROM AUTHOR]

The lateral wall of the mouse subventricular zone harbors neural stem cells (NSC, B cells) which generate proliferating transient-amplifying progenitors (TAP, C cells) that ultimately give rise to neuroblasts (NB, A cells). Molecular profiling at the single-cell level struggles to distinguish these different cell types. Here, we combined transcriptome analyses of FACS-sorted cells and single-cell RNAseq to demonstrate the existence of an abundant, clonogenic and multipotent population of immature neuroblasts (iNB cells) at the transition between TAP and migrating NB (mNB). iNB are reversibly engaged in neuronal differentiation. Indeed, they keep molecular features of both undifferentiated progenitors, plasticity and unexpected regenerative properties. Strikingly, they undergo important progressive molecular switches, including changes in the expression of splicing regulators leading to their differentiation in mNB subdividing them into two subtypes, iNB1 and iNB2. Due to their plastic properties, iNB could represent a new target for regenerative therapy of brain damage.

Chronic pathological conditions often induce persistent systemic inflammation, contributing to neuroinflammatory diseases like Multiple Sclerosis (MS). MS is known for its autoimmune-mediated damage to myelin, axonal injury, and neuronal loss which drive disability accumulation and disease progression, often manifesting as cognitive impairments. Understanding the involvement of neural stem cells (NSCs) and neural progenitor cells (NPCs) in the remediation of MS through adult neurogenesis (ANG) and gliogenesis—the generation of new neurons and glial cells, respectively is of great importance. Hence, these phenomena, respectively, termed ANG and gliogenesis, involve significant structural and functional changes in neural networks. Thus, the proper integration of these newly generated cells into existing circuits is not only key to understanding the CNS’s development but also its remodeling in adulthood and recovery from diseases such as MS. Understanding how MS influences the fate of NSCs/NPCs and their possible neuroprotective role, provides insights into potential therapeutic interventions to alleviate the impact of MS on cognitive function and disease progression. This review explores MS, its pathogenesis, clinical manifestations, and its association with ANG and gliogenesis. It highlights the impact of altered NSCs and NPCs’ fate during MS and delves into the potential benefits of its modifications. It also evaluates treatment regimens that influence the fate of NSCS/NPCs to counteract the pathology subsequently.

Introduction: Ectopic expression of transcription factor-mediated in vivo neuronal reprogramming provides promising strategy to compensate for neuronal loss, while its further clinical application may be hindered by delivery and safety concerns. As a novel and attractive alternative, small molecules may offer a non-viral and non-integrative chemical approach for reprogramming cell fates. Recent definitive evidences have shown that small molecules can convert non-neuronal cells into neurons in vitro. However, whether small molecules alone can induce neuronal reprogramming in vivo remains largely unknown. Objectives: To identify chemical compounds that can induce in vivo neuronal reprogramming in the adult spinal cord. Methods: Immunocytochemistry, immunohistochemistry, qRT-PCR and fate-mapping are performed to analyze the role of small molecules in reprogramming astrocytes into neuronal cells in vitro and in vivo. Results: By screening, we identify a chemical cocktail with only two chemical compounds that can directly and rapidly reprogram cultured astrocytes into neuronal cells. Importantly, this chemical cocktail can also successfully trigger neuronal reprogramming in the injured adult spinal cord without introducing exogenous genetic factors. These chemically induced cells showed typical neuronal morphologies and neuron-specific marker expression and could become mature and survive for more than 12 months. Lineage tracing indicated that the chemical compound-converted neuronal cells mainly originated from post-injury spinal reactive astrocytes. Conclusion: Our proof-of-principle study demonstrates that in vivo glia-to-neuron conversion can be manipulated in a chemical compound-based manner. Albeit our current chemical cocktail has a low reprogramming efficiency, it will bring in vivo cell fate reprogramming closer to clinical application in brain and spinal cord repair. Future studies should focus on further refining our chemical cocktail and reprogramming approach to boost the reprogramming efficiency.

Abstract In the injured brain, new neurons produced from endogenous neural stem cells form chains and migrate to injured areas and contribute to the regeneration of lost neurons. However, this endogenous regenerative capacity of the brain has not yet been leveraged for the treatment of brain injury. Here, we show that in healthy brain chains of migrating new neurons maintain unexpectedly large non-adherent areas between neighboring cells, allowing for efficient migration. In instances of brain injury, neuraminidase reduces polysialic acid levels, which negatively regulates adhesion, leading to increased cell–cell adhesion and reduced migration efficiency. The administration of zanamivir, a neuraminidase inhibitor used for influenza treatment, promotes neuronal migration toward damaged regions, fosters neuronal regeneration, and facilitates functional recovery. Together, these findings shed light on a new mechanism governing efficient neuronal migration in the adult brain under physiological conditions, pinpoint the disruption of this mechanism during brain injury, and propose a promising therapeutic avenue for brain injury through drug repositioning.

Contrary to humans, adult hippocampal neurogenesis in rodents is not controversial. And in the last three decades, multiple studies in rodents have deemed adult neurogenesis essential for most hippocampal functions. The functional relevance of new neurons relies on their distinct physiological properties during their maturation before they become indistinguishable from mature granule cells. Most functional studies have used very young animals with robust neurogenesis. However, this trait declines dramatically with age, questioning its functional relevance in aging animals, a caveat that has been mentioned repeatedly, but rarely analyzed quantitatively. In this meta-analysis, we use data from published studies to determine the critical functional window of new neurons and to model their numbers across age in both mice and rats. Our model shows that new neurons with distinct functional profile represent about 3% of the total granule cells in young adult 3-month-old rodents, and their number decline following a power function to reach less than 1% in middle aged animals and less than 0.5% in old mice and rats. These low ratios pose an important logical and computational caveat to the proposed essential role of new neurons in the dentate gyrus, particularly in middle aged and old animals, a factor that needs to be adequately addressed when defining the relevance of adult neurogenesis in hippocampal function. [ABSTRACT FROM AUTHOR]