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This page shows the most relevant new publications (including preprints) from the last month relating to the genetic control of adult neurogenesis. The manuscripts have been selected by our text mining service and the page is continually updated. Click on the arrows below each item to link out to the source.


Hippocampal neurogenesis Jump to subventricular/subependymal neurogenesis

Zika Virus-Mediated Death of Hippocampal Neurons Is Independent From Maturation State.
Zika virus (ZIKV) infection of pregnant women and diaplazental transmission to the fetus is linked to the congenital syndrome of microcephaly in newborns. This neuropathology is believed to result from significant death of neuronal progenitor cells (NPC). Here, we examined the fate of neurons in the developing hippocampus, a brain structure which houses neuronal populations of different maturation states. For this purpose, we infected hippocampal slice cultures from immunocompetent newborn mice with ZIKV and monitored changes in hippocampal architecture. In neurons of all hippocampal subfields ZIKV was detected by immunofluorescence labeling and electron microscopy. This includes pyramidal neurons that maturate during the embryonic phase. In the dentate gyrus, ZIKV could be found in the Cajal-Retzius (CR) cells which belong to the earliest born cortical neurons, but also in granule cells that are predominantly generated postnatally. Intriguingly, virus particles were also present in the correctly outgrowing mossy fiber axons of juvenile granule cells, suggesting that viral infection does not impair region- and layer-specific formation of this projection. ZIKV infection of hippocampal tissue was accompanied by both a profound astrocyte reaction indicating tissue injury and a microglia response suggesting phagocytotic activity. Furthermore, depending on the viral load and incubation time, we observed extensive overall neuronal loss in the cultured hippocampal slice cultures. Thus, we conclude ZIKV can replicate in various neuronal populations and trigger neuronal death independent of the maturation state of infected cells.
Cell-Biological Requirements for the Generation of Dentate Gyrus Granule Neurons.
The dentate gyrus (DG) receives highly processed information from the associative cortices functionally integrated in the trisynaptic hippocampal circuit, which contributes to the formation of new episodic memories and the spontaneous exploration of novel environments. Remarkably, the DG is the only brain region currently known to have high rates of neurogenesis in adults (Andersen et al., 1966, 1971). The DG is involved in several neurodegenerative disorders, including clinical dementia, schizophrenia, depression, bipolar disorder and temporal lobe epilepsy. The principal neurons of the DG are the granule cells. DG granule cells generated in culture would be an ideal model to investigate their normal development and the causes of the pathologies in which they are involved and as well as possible therapies. Essential to establish such in vitro models is the precise definition of the most important cell-biological requirements for the differentiation of DG granule cells. This requires a deeper understanding of the precise molecular and functional attributes of the DG granule cells in vivo as well as the DG cells derived in vitro. In this review we outline the neuroanatomical, molecular and cell-biological components of the granule cell differentiation pathway, including some growth- and transcription factors essential for their development. We summarize the functional characteristics of DG granule neurons, including the electrophysiological features of immature and mature granule cells and the axonal pathfinding characteristics of DG neurons. Additionally, we discuss landmark studies on the generation of dorsal telencephalic precursors from pluripotent stem cells (PSCs) as well as DG neuron differentiation in culture. Finally, we provide an outlook and comment critical aspects.
Type 2 Neural Progenitor Cell Activation Drives Reactive Neurogenesis after Binge-Like Alcohol Exposure in Adolescent Male Rats.
Excessive alcohol consumption during adolescence remains a significant health concern as alcohol drinking during adolescence increases the likelihood of an alcohol use disorder in adulthood by fourfold. Binge drinking in adolescence is a particular problem as binge-pattern consumption is the biggest predictor of neurodegeneration from alcohol and adolescents are particularly susceptible to the damaging effects of alcohol. The adolescent hippocampus, in particular, is highly susceptible to alcohol-induced structural and functional effects, including volume and neuron loss. However, hippocampal structure and function may recover with abstinence and, like in adults, a reactive burst in hippocampal neurogenesis in abstinence may contribute to that recovery. As the mechanism of this reactive neurogenesis is not known, the current study investigated potential mechanisms of reactive neurogenesis in binge alcohol exposure in adolescent, male rats. In a screen for cell cycle perturbation, a dramatic increase in the number of cells in all phases of the cycle was observed at 7 days following binge ethanol exposure as compared to controls. However, the proportion of cells in each phase was not different between ethanol-exposed rats and controls, indicating that cell cycle dynamics are not responsible for the reactive burst in neurogenesis. Instead, the marked increase in hippocampal proliferation was shown to be due to a twofold increase in proliferating progenitor cells, specifically an increase in cells colabeled with the progenitor cell marker Sox2 and S-phase (proliferation) marker, BrdU, in ethanol-exposed rats. To further characterize the individual subtypes of neural progenitor cells (NPCs) affected by adolescent binge ethanol exposure, a fluorescent quadruple labeling technique was utilized to differentiate type 1, 2a, 2b, and 3 progenitor cells simultaneously. At one week into abstinence, animals in the ethanol exposure groups had an increase in proliferating type 2 (intermediate progenitors) and type 3 (neuroblast) progenitors but not type 1 neural stem cells. These results together suggest that activation of type 2 NPCs out of quiescence is likely the primary mechanism for reactive hippocampal neurogenesis following adolescent alcohol exposure.
Antenatal dexamethasone exposure differentially affects distinct cortical neural progenitor cells and triggers long-term changes in murine cerebral architecture and behavior.
Antenatal administration of synthetic glucocorticoids (sGC) is the standard of care for women at risk for preterm labor before 34 gestational weeks. Despite their widespread use, the type of sGC used and their dose or the dosing regimens are not standardized in the United States of America or worldwide. Several studies have identified neural deficits and the increased risk for cognitive and psychiatric disease later in life for children administered sGC prenatally. However, the precise molecular and cellular targets of GC action in the developing brain remain largely undefined. In this study, we demonstrate that a single dose of glucocorticoid during mid-gestation in mice leads to enhanced proliferation in select cerebral cortical neural stem/progenitor cell populations. These alterations are mediated by dose-dependent changes in the expression of cell cycle inhibitors and in genes that promote cell cycle re-entry. This leads to changes in neuronal number and density in the cerebral cortex at birth, coupled to long-term alterations in neurite complexity in the prefrontal cortex and hippocampus in adolescents, and changes in anxiety and depressive-like behaviors in adults.
Loss of CDKL5 impairs survival and dendritic growth of newborn neurons by altering AKT/GSK-3β signaling.
Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in a neurodevelopmental disorder characterized by early-onset intractable seizures, severe developmental delay, intellectual disability, and Rett's syndrome-like features. Since the physiological functions of CDKL5 still need to be elucidated, in the current study we took advantage of a new Cdkl5 knockout (KO) mouse model in order to shed light on the role of this gene in brain development. We mainly focused on the hippocampal dentate gyrus, a region that largely develops postnatally and plays a key role in learning and memory. Looking at the process of neurogenesis, we found a higher proliferation rate of neural precursors in Cdkl5 KO mice in comparison with wild type mice. However, there was an increase in apoptotic cell death of postmitotic granule neuron precursors, with a reduction in total number of granule cells. Looking at dendritic development, we found that in Cdkl5 KO mice the newly-generated granule cells exhibited a severe dendritic hypotrophy. In parallel, these neurodevelopmental defects were associated with impairment of hippocampus-dependent memory. Looking at the mechanisms whereby CDKL5 exerts its functions, we identified a central role of the AKT/GSK-3β signaling pathway. Overall our findings highlight a critical role of CDKL5 in the fundamental processes of brain development, namely neuronal precursor proliferation, survival and maturation. This evidence lays the basis for a better understanding of the neurological phenotype in patients carrying mutations in the CDKL5 gene.
Neurogenin2 directs granule neuroblast production and amplification while NeuroD1 specifies neuronal fate during hippocampal neurogenesis.
The specification and differentiation of dentate gyrus granule neurons in the hippocampus require temporally and spatially coordinated actions of both intrinsic and extrinsic molecules. The basic helix-loop-helix transcription factor Neurogenin2 (Ngn2) and NeuroD1 are key regulators in these processes. Based on existing classification, we analyzed the molecular events occurring during hippocampal neurogenesis, primarily focusing on juvenile animals. We found that Ngn2 is transiently expressed by late type-2a amplifying progenitors. The Ngn2 progenies mature into hippocampal granule neurons. Interestingly, the loss of Ngn2 at early stages of development leads to a robust reduction in neurogenesis, but does not disturb granule neuron maturation per se. We found that the role of Ngn2 is to maintain progenitors in an undifferentiated state, allowing them to amplify prior to their maturation into granule neurons upon NeuroD1 induction. When we overexpressed Ngn2 and NeuroD1 in vivo, we found NeuroD1 to exhibit a more pronounced neuron-inductive effect, leading to granule neuron commitment, than that displayed by Ngn2. Finally, we observed that all markers expressed during the transcriptional control of hippocampal neurogenesis in rodents are also present in the human hippocampus. Taken together, we demonstrate a critical role of for Ngn2 and NeuroD1 in controlling neuronal commitment and hippocampal granule neuroblast formation, both during embryonic development and in post-natal hippocampal granule neurogenesis.
Lipopolysaccharide-induced Autophagy Increases SOX2-positive Astrocytes While Decreasing Neuronal Differentiation in the Adult Hippocampus.
Inflammation alters the neural stem cell (NSC) lineage from neuronal to astrogliogenesis. However, the underlying mechanism is elusive. Autophagy contributes to the decline in adult hippocampal neurogenesis under E. coli lipopolysaccharide (LPS) stimulation. SRY-box transcription Factor 2 (SOX2) is critical for NSC self-renewal and proliferation. In this study, we investigated the role of SOX2 in induced autophagy and hippocampal adult neurogenesis under LPS stimulation. LPS (5 ng•100 g-1•hour-1 for 7 days) was intraperitoneally infused into male Sprague-Dawley rats (8 weeks old) to induce mild systemic inflammation. Beclin 1 and autophagy protein 12 (Atg12) were significantly upregulated concurrent with decreased numbers of Ki67- and doublecortin (DCX)-positive cells in the dentate gyrus. Synchronically, the levels of phospho(p)-mTOR, the p-mTOR/mTOR ratio, p-P85s6k, and the p-P85s6k/P85s6k ratio were suppressed. In contrast, SOX2 expression was increased. The fluorescence micrographs indicated that the colocalization of Beclin 1 and SOX2 was increased in the subgranular zone (SGZ) of the dentate gyrus. Moreover, increased S100β-positive astrocytes were colocalized with SOX2 in the SGZ. Intracerebroventricular infusion of 3-methyladenine (an autophagy inhibitor) effectively prevented the increases in Beclin 1, Atg12, and SOX2. The SOX2+-Beclin 1+ and SOX2+-S100β+ cells were reduced. The levels of p-mTOR and p-P85s6k were enhanced. Most importantly, the number of DCX-positive cells was preserved. Altogether, these data suggest that LPS induced autophagy to inactivate the mTOR/P85s6k pathway, resulting in a decline in neural differentiation. SOX2 was upregulated to facilitate the NSC lineage, while the autophagy milieu could switch the SOX2-induced NSC lineage from neurogenesis to astrogliogenesis.

Subventricular/subependymal neurogenesis Jump to hippocampal neurogenesis

Mimicking Neural Stem Cell Niche by Biocompatible Substrates.
Neural stem cells (NSCs) participate in the maintenance, repair, and regeneration of the central nervous system. During development, the primary NSCs are distributed along the ventricular zone of the neural tube, while, in adults, NSCs are mainly restricted to the subependymal layer of the subventricular zone of the lateral ventricles and the subgranular zone of the dentate gyrus in the hippocampus. The circumscribed areas where the NSCs are located contain the secreted proteins and extracellular matrix components that conform their niche. The interplay among the niche elements and NSCs determines the balance between stemness and differentiation, quiescence, and proliferation. The understanding of niche characteristics and how they regulate NSCs activity is critical to building in vitro models that include the relevant components of the in vivo niche and to developing neuroregenerative approaches that consider the extracellular environment of NSCs. This review aims to examine both the current knowledge on neurogenic niche and how it is being used to develop biocompatible substrates for the in vitro and in vivo mimicking of extracellular NSCs conditions.
Testosterone-induced adult neurosphere growth is mediated by sexually-dimorphic aromatase expression.
We derived adult neural stem/progenitor cells (NSPCs) from the sub-ventricular zone of male and female mice to examine direct responses to principal sex hormones. In the presence of epidermal growth factor (EGF) and fibroblast growth factor-2 (FGF2) NSPCs of both sexes expressed nestin and sox2, and could be maintained as neurospheres without addition of any sex hormones. The reverse was not observed; neither testosterone (T), 17β-estradiol (E2) nor progesterone (P4) was able to support neurosphere growth in the absence of EGF and FGF2. Ten nanomolar T, E2 or P4 induced nestin(+) cell proliferation within 20 min and enhanced neurosphere growth over 7 days irrespective of sex, which was abolished by Erk inhibition with 20 μM U0126. Maintaining neurospheres with each sex hormone did not affect subsequent neuronal differentiation. However, 10 nM T, E2 or P4 added during differentiation increased βIII tubulin(+) neuron production with E2 being more potent compared to T and P4 in both sexes. Androgen receptor (AR) inhibition with 20 μM flutamide but not aromatase inhibition with 10 μM letrozole reduced basal and T-induced neurosphere growth in females, while only concurrent inhibition of AR and aromatase produced the same effect in males. This sex-specific effect was supported by higher aromatase expression in male neurospheres compared to females measured by Western blot and green fluorescent protein (GFP) reporter. Ten micromolar menadione induced oxidative stress, impaired neurosphere growth and up-regulated aromatase expression in both sexes. However, under oxidative stress letrozole significantly exacerbated impaired neurosphere growth in males only. While both E2 and T could prevent oxidative stress-induced growth reduction in both sexes, the effects of T were dependent on innate aromatase activity. We show for the first time that intrinsic androgen and estrogen signaling may impact the capacity of NSPCs to produce neural progenitors under pathological conditions of oxidative stress.

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