Number Of Neural Stem Cells Research Articles

Alteration in peritoneal cells with the chemokine CX3CL1 reverses age-associated impairment of recognition memory.

Cognitive function progressively declines with advancing age. The aging process can be promoted by obesity and attenuated by exercise. Both conditions affect levels of the chemokine CX3CL1 in peripheral tissues; however, its role in cognitive aging is unknown. In the current study, we administered CX3CL1 into the peritoneal cavity of aged mice to investigate its impact on the aging process. In the peritoneal cavity, CX3CL1 not only reversed the age-associated accumulation of cells expressing the senescence marker p16INK4a but also increased peritoneal phagocytic activity, indicating that CX3CL1 affected the phenotypes of peritoneal cells. In the hippocampus of aged mice, intraperitoneal administration of CX3CL1 increased the number of Type-2 neural stem cells and promoted brain-derived neurotrophic factor (BDNF) expression. This treatment, furthermore, improved novel object recognition memory impaired with advancing age. Intraperitoneal transplantation of peritoneal cells from CX3CL1-treated aged mice improved novel object recognition memory in recipient aged mice. It indicates that peritoneal cells have a critical role in the CX3CL1-induced improvement of recognition memory in aged mice. Vagotomy inhibited the CX3CL1-induced increase in BDNF expression, demonstrating that the vagus nerve is involved in the hippocampal BDNF expression induced by intraperitoneal administration of CX3CL1. Thus, our results demonstrate that a novel connection among the peritoneal cells, the vagus nerve, and the hippocampus can reverse the age-associated decline in recognition memory.

Short-Chain Fatty Acids Ameliorate Depressive-like Behaviors of High Fructose-Fed Mice by Rescuing Hippocampal Neurogenesis Decline and Blood-Brain Barrier Damage.

Excessive fructose intake is associated with the increased risk of mental illness, such as depression, but the underlying mechanisms are poorly understood. Our previous study found that high fructose diet (FruD)-fed mice exhibited neuroinflammation, hippocampal neurogenesis decline and blood–brain barrier (BBB) damage, accompanied by the reduction of gut microbiome-derived short-chain fatty acids (SCFAs). Here, we found that chronic stress aggravated these pathological changes and promoted the development of depressive-like behaviors in FruD mice. In detail, the decreased number of newborn neurons, mature neurons and neural stem cells (NSCs) in the hippocampus of FruD mice was worsened by chronic stress. Furthermore, chronic stress exacerbated the damage of BBB integrity with the decreased expression of zonula occludens-1 (ZO-1), claudin-5 and occludin in brain vasculature, overactivated microglia and increased neuroinflammation in FruD mice. These results suggest that high fructose intake combined with chronic stress leads to cumulative negative effects that promote the development of depressive-like behaviors in mice. Of note, SCFAs could rescue hippocampal neurogenesis decline, improve BBB damage and suppress microglia activation and neuroinflammation, thereby ameliorate depressive-like behaviors of FruD mice exposed to chronic stress. These results could be used to develop dietary interventions to prevent depression.

Isoflurane and Sevoflurane Induce Cognitive Impairment in Neonatal Rats by Inhibiting Neural Stem Cell Development Through Microglial Activation, Neuroinflammation, and Suppression of VEGFR2 Signaling Pathway

Inhaled anesthetics are known to induce neurotoxicity in the developing brains of rodents, although the mechanisms are not well understood. The aim of this study was to elucidate the molecular mechanisms underlying anesthetics-induced neurodevelopmental toxicity by VEGF receptor 2 (VEGFR2) through the interaction between microglia and neural stem cells (NSCs) in postnatal day 7 (P7) rats. Cognitive function of P7 rats exposed to isoflurane and sevoflurane were assessed using Morris Water Maze and T maze tests. We also evaluated the expression levels of NSC biomarkers (Nestin and Sox2), microglia biomarker (CD11b or or IBA1), pro-inflammatory cytokines (IL-6 and TNF-α), and VEGFR2 using western blotting and immunohistochemistry in the brains of control and anesthesia-treated rats. We found spatial learning and working memory was impaired 2 weeks after anesthetics exposure in rats. Isoflurane induced stronger and more prolonged neurotoxicity than sevoflurane. However, cognitive functions were recovered 6 weeks after anesthesia. Isoflurane and sevoflurane decreased the levels of Nestin, Sox2, and p-VEGFR2, activated microglia, decreased the number of NSCs and reduced neurogenesis and the proliferation of NSCs, and increased the levels of IL-6, TNF-α, and CD11b. Our results suggested that isoflurane and sevoflurane induced cognitive impairment in rats by inhibiting NSC development and neurogenesis via microglial activation, neuroinflammation, and suppression of VEGFR2 signaling pathway.

Distinguishing between multiple mathematical models of neural stem cell quiescence and activation during age-related neural stem cell decline in neurogenesis

Stem cells are required for tissue maintenance and homeostasis during an organism’s lifetime. Neural stem cells (NSCs) can be in an actively dividing state or in a quiescent state. The balance between stem cell quiescence and cycling activity determines the rate of neurogenesis. With age, more NSCs enter the quiescent state, while the total number of NSCs decreases. Here we reconsider an existing mathematical model of how neural stem cells switch between active and quiescent states from the point of view of control theory by considering the activation rate, self-renewal probability, and division rate as control parameters rather than as pre-defined functions. Our goal is to test whether those modifications to the basic model could explain the observed decline of neural stem cells with age better than Gomerzian time-dependent parameters, and compare the output from different model variants to experimental data from mice using AIC. We find that time-dependent activation rate provides the best fit to the activated cell fraction (ACF) of NSCs over time, but that other model variants with constant parameter values can better fit the total number of NSCs over time. We also consider an alternate model for NSCs with nonlinear feedback from progenitor cells that affect NSC parameters, and compare all models to experimental stem cell and progenitor data. However, all of the feedback models considered provide a worse fit to the experimental data. This suggests that when switching between active and quiescent stem cells is considered, a time-dependent linear model outperforms the integral feedback mechanism considered by other models of stem cell lineages. Fitting progenitor data for both the time varying models and feedback models indicates that four or five intermediate transit amplifying progenitor states are necessary. Our modeling suggests that in order to determine whether an increase in age-related neural stem cell quiescence is determined by a decreasing stem cell activation rate or an increased stem cell depletion rate, additional experiments should be designed to explore whether or not depletion of the stem cell pool is occurring, and that a higher resolution time series for activated cell fraction (ACF) would be best to resolve this issue.

A three-dimensional matrix system containing melatonin and neural stem cells repairs damage from traumatic brain injury in rats.

Brain lesions can cause neural stem cells to activate, proliferate, differentiate, and migrate to the injured area. However, after traumatic brain injury, brain tissue defects and microenvironment changes greatly affect the survival and growth of neural stem cells; the resulting reduction in the number of neural stem cells impedes effective repair of the injured area. Melatonin can promote the survival, proliferation, and differentiation of neural stem cells under adverse conditions such as oxidative stress or hypoxia that can occur after traumatic brain injury. Therefore, we investigated the therapeutic effects of melatonin combined with neural stem cells on traumatic brain injury in rats. First, in vitro studies confirmed that melatonin promoted the survival of neural stem cells deprived of oxygen and glucose. Then, we established a three-dimensional Matrigel-based transplantation system containing melatonin and neural stem cells and then used it to treat traumatic brain injury in rats. We found that treatment with the Matrigel system containing melatonin and neural stem cells decreased brain lesion volume, increased the number of surviving neurons, and improved recovery of neurological function compared with treatment with Matrigel alone, neural stem cells alone, Matrigel and neural stem cells combined, and Matrigel and melatonin combined. Our findings suggest that the three-dimensional Matrigel-based transplantation system containing melatonin and neural stem cells is a potential treatment for traumatic brain injury.

妊娠時低酸素曝露が胎仔脳に与える影響

Maternal hypoxic stress such as threatened abortion at early pregnancy is thought to be a risk factor for onset of children's neurodevelopmental disorder. In fact, we previously demonstrated that maternal stress by rearing at hypoxic condition caused communication deficit and learning disability of rat pups. To clarify the onset mechanism of neurodevelopmental disorder-like phenotype, we conducted immunohistochemical studies by using rat fetal brain. Firstly, TUNEL stain revealed that maternal hypoxic stress didn't induce cell death. Then, immunofluorescent double staining for analyzing proliferation and differentiation of neural stem cells (NSCs) were conducted. NSCs proliferation ability analysis revealed that the rate of Ki67+SOX2+ cells were significantly increased in fetal rat brain received maternal hypoxic stress. In addition, analysis of asymmetric division which means initial step of neurogenesis, by using SOX2 and TBR2 (intermediate progenitor cell marker) double staining, showed that maternal hypoxia induced the increase of the number of NSCs. Furthermore, qPCR results showed that maternal hypoxia reduced astrogliogenesis-related genes and excitatory neurogenesis-related gene expression. This study indicated that maternal hypoxia influenced the function of NSCs and their destination.

Microgravity Significantly Influences Neural Stem Cells Size and Numbers: Implications for Long-term Space Missions

There are two approaches used to study the effects of microgravity on cells -- using simulated microgravity on Earth (sim-µG) or sending cells to space (SPC-µG). We have recently reported that human neural stem cells (NSCs) proliferated seven-times more while in space than Ground Control (GC) NSCs on Earth. Here, using time-lapse microscopy, we determined that in both sim-µG and SPC-µG there are two cell subpopulations distinguished by differences in somatic diameter

A terrifying sound stress inhibits hippocampal neurogenesis in the adult male mice.

Stress impairs hippocampal neurogenesis. The traditional animal model of stress contains a mixture of physical and psychological stress factors. This leads to difficulty in the evaluation of the effect of pure psychological stress on neurogenesis. In this study, we investigated the effect of pure psychological stress on hippocampal neurogenesis. The pure psychological stress model and the mixed stress model were carried out by terrifying sound and restraint, respectively. The open field test showed that restraint treatment improved the general locomotor activity levels, while terrifying sound treatment had opposite effects. Compared with a normal condition, both terrifying sound stimulation and restraint treatment significantly decreased the number of BrdU and Ki-67 and reduced the positive rate of SOX2/GFAP in the hippocampus. These phenomena indicated that pure psychological stress could decrease the number of neural stem cells and inhibit cell proliferation in the hippocampus of a mouse. Furthermore, compared with the restraint treatment, the neurotransmitters including norepinephrine (NE), 5-hydroxytryptamine (5-HT), and gamma-aminobutyric acid (GABA) had not been affected drastically by terrifying sound stimulation. Our results suggest that the terrifying sound stimulation can be considered as a novel and effective pure psychological stress animal model for the further research on the hippocampus.

Neuron-Radial Glial Cell Communication via BMP/Id1 Signaling Is Key to Long-Term Maintenance of the Regenerative Capacity of the Adult Zebrafish Telencephalon.

The central nervous system of adult zebrafish displays an extraordinary neurogenic and regenerative capacity. In the zebrafish adult brain, this regenerative capacity relies on neural stem cells (NSCs) and the careful management of the NSC pool. However, the mechanisms controlling NSC pool maintenance are not yet fully understood. Recently, Bone Morphogenetic Proteins (BMPs) and their downstream effector Id1 (Inhibitor of differentiation 1) were suggested to act as key players in NSC maintenance under constitutive and regenerative conditions. Here, we further investigated the role of BMP/Id1 signaling in these processes, using different genetic and pharmacological approaches. Our data show that BMPs are mainly expressed by neurons in the adult telencephalon, while id1 is expressed in NSCs, suggesting a neuron-NSC communication via the BMP/Id1 signaling axis. Furthermore, manipulation of BMP signaling by conditionally inducing or repressing BMP signaling via heat-shock, lead to an increase or a decrease of id1 expression in the NSCs, respectively. Induction of id1 was followed by an increase in the number of quiescent NSCs, while knocking down id1 expression caused an increase in NSC proliferation. In agreement, genetic ablation of id1 function lead to increased proliferation of NSCs, followed by depletion of the stem cell pool with concomitant failure to heal injuries in repeatedly injured mutant telencephala. Moreover, pharmacological inhibition of BMP and Notch signaling suggests that the two signaling systems cooperate and converge onto the transcriptional regulator her4.1. Interestingly, brain injury lead to a depletion of NSCs in animals lacking BMP/Id1 signaling despite an intact Notch pathway. Taken together, our data demonstrate how neurons feedback on NSC proliferation and that BMP1/Id1 signaling acts as a safeguard of the NSC pool under regenerative conditions.

Electroacupuncture in promoting neural repair after spinal cord injury: Inhibiting the Notch signaling pathway and regulating downstream proteins expression.

Spinal cord injury (SCI) is one of the serious central nervous system injuries and the incidence of SCI continues to increase. Previous studies have indicated that electroacupuncture (EA) is beneficial for promoting recovery after SCI. In the present study, we attempted to evaluate how EA can promote the neural repair in SCI model rats by observing changes in the Notch signaling pathway. Experimental rats were randomly divided into four groups. Each group had its own intervention period: 1 day, 7 days, 14 days, and 28 days, and five randomized subgroups: blank control (B) group, blank electroacupuncture (BE) group, sham operation (S) group, model control (M) group and EA group. Animals in the EA group and the BE group were treated with EA at Dazhui (GV14) and Mingmen (GV4) acupoints for 20 min. After the intervention period, the Basso-Beattie-Bresnahan (BBB) score was used to evaluate the neurological function. We found that BBB score increased in EA-treated groups. Hematoxylin and eosin staining was used to observe pathological changes in the injured spinal cord and the results showed that EA therapy could promote the repair of injured spinal cord tissue. Immunohistochemistry and Western blot methods were used to detect the expression of proteins Delta1, Presenilin1, Hes1, and Hes5 in the injured spinal cord. The results showed that the expression levels of Delta1, Presenilin1, Hes1, and Hes5 increased significantly after SCI and decreased after EA treatment. Our study suggested that the possible mechanism by which EA could benefit the recovery after SCI in rats may include inhibiting the Notch signaling pathway and regulating the downstream proteins expression. In addition, our study can provide reference for selecting acupoints and treatment cycle in the treatment of SCI.

Electromagnetized gold nanoparticles improve neurogenesis and cognition in the aged brain

Adult neurogenesis is the lifelong process by which new neurons are generated in the dentate gyrus. However, adult neurogenesis capacity decreases with age, and this decrease is closely linked to cognitive and memory decline. Our study demonstrated that electromagnetized gold nanoparticles (AuNPs) promote adult hippocampal neurogenesis, thereby improving cognitive function and memory consolidation in aged mice. According to single-cell RNA sequencing data, the numbers of neural stem cells (NSCs) and neural progenitors were significantly increased by electromagnetized AuNPs. Additionally, electromagnetic stimulation resulted in specific activation of the histone acetyltransferase Kat2a, which led to histone H3K9 acetylation in adult NSCs. Moreover, in vivo electromagnetized AuNP stimulation efficiently increased hippocampal neurogenesis in aged and Hutchinson-Gilford progeria mouse brains, thereby alleviating the symptoms of aging. Therefore, our study provides a proof-of-concept for the in vivo stimulation of hippocampal neurogenesis using electromagnetized AuNPs as a promising therapeutic strategy for the treatment of age-related brain diseases.

Active Fraction Combination From Liuwei Dihuang Decoction Improves Adult Hippocampal Neurogenesis and Neurogenic Microenvironment in Cranially Irradiated Mice.

Background: Cranial radiotherapy is clinically used in the treatment of brain tumours; however, the consequent cognitive and emotional dysfunctions seriously impair the life quality of patients. LW-AFC, an active fraction combination extracted from classical traditional Chinese medicine prescription Liuwei Dihuang decoction, can improve cognitive and emotional dysfunctions in many animal models; however, the protective effect of LW-AFC on cranial irradiation–induced cognitive and emotional dysfunctions has not been reported. Recent studies indicate that impairment of adult hippocampal neurogenesis (AHN) and alterations of the neurogenic microenvironment in the hippocampus constitute critical factors in cognitive and emotional dysfunctions following cranial irradiation. Here, our research further investigated the potential protective effects and mechanisms of LW-AFC on cranial irradiation–induced cognitive and emotional dysfunctions in mice. Methods: LW-AFC (1.6 g/kg) was intragastrically administered to mice for 14 days before cranial irradiation (7 Gy γ-ray). AHN was examined by quantifying the number of proliferative neural stem cells and immature neurons in the dorsal and ventral hippocampus. The contextual fear conditioning test, open field test, and tail suspension test were used to assess cognitive and emotional functions in mice. To detect the change of the neurogenic microenvironment, colorimetry and multiplex bead analysis were performed to measure the level of oxidative stress, neurotrophic and growth factors, and inflammation in the hippocampus. Results: LW-AFC exerted beneficial effects on the contextual fear memory, anxiety behaviour, and depression behaviour in irradiated mice. Moreover, LW-AFC increased the number of proliferative neural stem cells and immature neurons in the dorsal hippocampus, displaying a regional specificity of neurogenic response. For the neurogenic microenvironment, LW-AFC significantly increased the contents of superoxide dismutase, glutathione peroxidase, glutathione, and catalase and decreased the content of malondialdehyde in the hippocampus of irradiated mice, accompanied by the increase in brain-derived neurotrophic factor, insulin-like growth factor-1, and interleukin-4 content. Together, LW-AFC improved cognitive and emotional dysfunctions, promoted AHN preferentially in the dorsal hippocampus, and ameliorated disturbance in the neurogenic microenvironment in irradiated mice. Conclusion: LW-AFC ameliorates cranial irradiation–induced cognitive and emotional dysfunctions, and the underlying mechanisms are mediated by promoting AHN in the dorsal hippocampus and improving the neurogenic microenvironment. LW-AFC might be a promising therapeutic agent to treat cognitive and emotional dysfunctions in patients receiving cranial radiotherapy.

Ultrarapid Inflammation of the Olfactory Bulb After Spinal Cord Injury: Protective Effects of the Granulocyte Colony-Stimulating Factor on Early Neurodegeneration in the Brain.

The correlation among olfactory dysfunction, spinal cord injury (SCI), subjective cognitive decline, and neurodegenerative dementia has been established. Impaired olfaction is considered a marker for neurodegeneration. Hence, there is a need to examine if SCI leads to olfactory dysfunction. In this study, the brain tissue of mice with spinal cord hemisection injury was subjected to microarray analysis. The mRNA expression levels of olfactory receptors in the brain began to decline at 8 h post-SCI. SCI promoted neuroinflammation, downregulated the expression of olfactory receptors, decreased the number of neural stem cells (NSCs), and inhibited the production of neurotrophic factors in the olfactory bulbs at 8 h post-SCI. In particular, the SCI group had upregulated mRNA and protein expression levels of glial fibrillary acidic protein (GFAP; a marker of astrocyte reactivation) and pro-inflammatory mediators [IL-1β, IL-6, and Nestin (marker of NSCs)] in the olfactory bulb compared to levels in the sham control group. The mRNA expression levels of olfactory receptors (Olfr1494, Olfr1324, Olfr1241, and Olfr979) and neurotrophic factors [brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), and nerve growth factor (NGF)] were downregulated in the olfactory bulb of the SCI group mice at 8 h post-SCI. The administration of granulocyte colony-stimulating factor (G-CSF) mitigated these SCI-induced pathological changes in the olfactory bulb at 8 h post-SCI. These results indicate that the olfactory bulb is vulnerable to environmental damage even if the lesion is located at sites distant from the brain, such as the spinal cord. Additionally, SCI initiated pathological processes, including inflammatory response, and impaired neurogenesis, at an early stage. The findings of this study will provide a basis for future studies on pathological mechanisms of early neurodegenerative diseases involving the olfactory bulb and enable early clinical drug intervention.

Angiogenin in the Neurogenic Subventricular Zone After Stroke.

Ischemic stroke is a leading cause of death and disability worldwide with effective acute thrombolytic treatments. However, brain repair mechanisms related to spontaneous or rehabilitation-induced recovery are still under investigation, and little is known about the molecules involved. The present study examines the potential role of angiogenin (ANG), a known regulator of cell function and metabolism linked to neurological disorders, focusing in the neurogenic subventricular zone (SVZ). Angiogenin expression was examined in the mouse SVZ and in SVZ-derived neural stem cells (NSCs), which were exposed to exogenous ANG treatment during neurosphere formation as well as in other neuron-like cells (SH-SY5Y). Additionally, male C57Bl/6 mice underwent a distal permanent occlusion of the middle cerebral artery to study endogenous and exercise-induced expression of SVZ-ANG and neuroblast migration. Our results show that SVZ areas are rich in ANG, primarily expressed in DCX+ neuroblasts but not in nestin+NSCs. In vitro, treatment with ANG increased the number of SVZ-derived NSCs forming neurospheres but could not modify SH-SY5Y neurite differentiation. Finally, physical exercise rapidly increased the amount of endogenous ANG in the ipsilateral SVZ niche after ischemia, where DCX-migrating cells increased as part of the post-stroke neurogenesis process. Our findings position for the first time ANG in the SVZ during post-stroke recovery, which could be linked to neurogenesis.

Horse Placental Extract Enhances Neurogenesis in the Presence of Amyloid β.

Human placental extract and animal-derived placental extracts from pigs and horses host a wide range of biological activities. Several placental products are used as medicines, cosmetics, and healthcare substances worldwide. However, the use of placental extracts for neuronal functioning is currently not established because the number of relevant studies is limited. A few previous reports suggested the neuroprotective effect and dendrite genesis effect of placental extract. However, no studies have reported on neurogenesis in placental extracts. Therefore, we aimed to investigate the effects of horse placental extract on neurogenesis, and we examined the protective effect of the extract on the onset of memory disorder. A horse placental extract, JBP-F-02, was used in this study. JBP-F-02 treatment dose-dependently increased the number of neural stem cells and dendrite length under Aβ treatment in primary cultured cortical cells. The oral administration of JBP-F-02 to a 5XFAD mouse model of Alzheimer’s disease at a young age significantly prevented the onset of memory dysfunction. This study suggests that the extract has the potential to prevent dementia.

Evaluation of the Effect of Hyaluronic Acid–Based Biomaterial Enriched With Tenascin-C on the Behavior of the Neural Stem Cells

One of the most important natural extracellular constituents is hyaluronic acid (HA) with the potential to develop a highly organized microenvironment. In the present study, we enriched HA hydrogel with tenascin-C (TN-C) and examined the viability and survival of mouse neural stem cells (NSCs) using different biological assays. Following NSCs isolation and expansion, their phenotype was identified using flow cytometry analysis. Cell survival was measured using MTT assay and DAPI staining after exposure to various concentrations of 50, 100, 200, and 400 nM TN-C. Using acridine orange/ethidium bromide staining, we measured the number of live and necrotic cells after exposure to the combination of HA and TN-C. MTT assay revealed the highest NSCs viability rate in the group exposed to 100 nM TN-C compared to other groups, and a combination of 1% HA + 100 nM TN-C increased the viability of NSCs compared to the HA group after 24 hours. Electron scanning microscopy revealed the higher attachment of these cells to the HA + 100 nM TN-C substrate relative to the HA substrate. Epifluorescence imaging and DAPI staining of loaded cells on HA + 100 nM TN-C substrate significantly increased the number of NSCs per field over 72 hours compared to the HA group (P < 0.05). Live and dead assay revealed that the number of live NSCs significantly increased in the HA + 100 TN-C group compared to HA and control groups. The enrichment of HA substrate with TN-C promoted viability and survival of NSCs and could be applied in neural tissue engineering approaches and regenerative medicine.

Dynamic spatiotemporal coordination of neural stem cell fate decisions occurs through local feedback in the adult vertebrate brain.

SummaryNeural stem cell (NSC) populations persist in the adult vertebrate brain over a lifetime, and their homeostasis is controlled at the population level through unknown mechanisms. Here, we combine dynamic imaging of entire NSC populations in their in vivo niche over several weeks with pharmacological manipulations, mathematical modeling, and spatial statistics and demonstrate that NSCs use spatiotemporally resolved local feedback signals to coordinate their decision to divide in adult zebrafish brains. These involve Notch-mediated short-range inhibition from transient neural progenitors and a dispersion effect from the dividing NSCs themselves exerted with a delay of 9–12 days. Simulations from a stochastic NSC lattice model capturing these interactions demonstrate that these signals are linked by lineage progression and control the spatiotemporal distribution of output neurons. These results highlight how local and temporally delayed interactions occurring between brain germinal cells generate self-propagating dynamics that maintain NSC population homeostasis and coordinate specific spatiotemporal correlations.

3D Image Analysis of the Complete Ventricular-Subventricular Zone Stem Cell Niche Reveals Significant Vasculature Changes and Progenitor Deficits in Males Versus Females with Aging.

SummaryWith age, neural stem cell (NSC) function in the adult ventricular-subventricular zone (V-SVZ) declines, reducing memory and cognitive function in males; however, the impact on females is not well understood. To obtain a global view of how age and sex impact the mouse V-SVZ, we constructed 3D montages after multiplex immunostaining, and used computer-based 3D image analysis to quantify data across the entire niche at 2, 18, and 22 months. We discovered dramatic sex differences in the aging of the V-SVZ niche vasculature, which regulates NSC activity: females showed increased diameter but decreased vessel density with age, while males showed decreased diameter and increased tortuosity and vessel density. Accompanying these vascular changes, males showed significant decline in NSC numbers, progenitor cell proliferation, and more disorganized migrating neuroblast chains with age; however, females did not. By examining the entire 3D niche, we found significant sex differences, with females being relatively spared through very old age.

Coordinated changes in cellular behavior ensure the lifelong maintenance of the hippocampal stem cell population.

SummaryNeural stem cell numbers fall rapidly in the hippocampus of juvenile mice but stabilize during adulthood, ensuring lifelong hippocampal neurogenesis. We show that this stabilization of stem cell numbers in young adults is the result of coordinated changes in stem cell behavior. Although proliferating neural stem cells in juveniles differentiate rapidly, they increasingly return to a resting state of shallow quiescence and progress through additional self-renewing divisions in adulthood. Single-cell transcriptomics, modeling, and label retention analyses indicate that resting cells have a higher activation rate and greater contribution to neurogenesis than dormant cells, which have not left quiescence. These changes in stem cell behavior result from a progressive reduction in expression of the pro-activation protein ASCL1 because of increased post-translational degradation. These cellular mechanisms help reconcile current contradictory models of hippocampal neural stem cell (NSC) dynamics and may contribute to the different rates of decline of hippocampal neurogenesis in mammalian species, including humans.

Integrated Patterning Programs During Drosophila Development Generate the Diversity of Neurons and Control Their Mature Properties.

During the approximately 5 days of Drosophila neurogenesis (late embryogenesis to the beginning of pupation), a limited number of neural stem cells produce approximately 200,000 neurons comprising hundreds of cell types. To build a functional nervous system, neuronal types need to be produced in the proper places, appropriate numbers, and correct times. We discuss how neural stem cells (neuroblasts) obtain so-called area codes for their positions in the nervous system (spatial patterning) and how they keep time to sequentially produce neurons with unique fates (temporal patterning). We focus on specific examples that demonstrate how a relatively simple patterning system (Notch) can be used reiteratively to generate different neuronal types. We also speculate on how different modes of temporal patterning that operate over short versus long time periods might be linked. We end by discussing how specification programs are integrated and lead to the terminal features of different neuronal types.