Proliferation Of Hippocampal Neural Progenitor Cells Research Articles

The metabolic regulator USF-1 is involved in the control of affective behaviour in mice

Epidemiological studies indicate a bidirectional association between metabolic disturbances, including obesity and related pathological states, and mood disorders, most prominently major depression. However, the biological mechanisms mediating the comorbid relationship between the deranged metabolic and mood states remain incompletely understood. Here, we tested the hypothesis that the enhanced activation of brown fat tissue (BAT), known to beneficially regulate obesity and accompanying dysfunctional metabolic states, is also paralleled by an alteration of affective behaviour. We used upstream stimulatory factor 1 (USF-1) knock-out (KO) mice as a genetic model of constitutively activated BAT and positive cardiometabolic traits and found a reduction of depression-like and anxiety-like behaviours associated with USF-1 deficiency. Surgical removal of interscapular BAT did not impact the behavioural phenotype of USF-1 KO mice. Further, the absence of USF-1 did not lead to alterations of adult hippocampal neural progenitor cell proliferation, differentiation, or survival. RNA-seq analysis characterised the molecular signature of USF-1 deficiency in the hippocampus and revealed a significant increase in the expression of several members of the X-linked lymphocyte-regulated (xlr) genes, including xlr3b and xlr4b. Xlr genes are the mouse orthologues of the human FAM9 gene family and are implicated in the regulation of dendritic branching, dendritic spine number and morphology. The transcriptional changes were associated with morphological alterations in hippocampal neurons, manifested in reduced dendritic length and complexity in USF-1 KO mice. Collectively these data suggest that the metabolic regulator USF-1 is involved in the control of affective behaviour in mice and that this modulation of mood states is unrelated to USF-1-dependent BAT activation, but reflected in structural changes in the brain.

MiR-19b is elevated in peripheral blood of schizophrenic patients and attenuates proliferation of hippocampal neural progenitor cells

MicroRNAs (miRNAs) have been investigated in neurodevelopmental and psychiatric disorders including schizophrenia (SZ). Previous studies showed miRNAs dysregulation in postmortem brain tissues and peripheral blood of SZ patients. These suggest that miRNAs may play a role in the pathophysiology of SZ and be a potential biomarker of SZ. Previous studies also showed that miRNAs regulated neurogenesis and that neurogenesis was involved in the pathophysiology of SZ. In addition, a recent study showed that miR-19a and 19b, enriched in neural progenitor cells (NPC) in adult hippocampus, were increased in human NPC derived from induced pluripotent stem cell derived from SZ patients. However, it remains unclear whether the levels of miR-19a and 19b are altered in peripheral blood of SZ patients and how miR-19a and 19b affects neurogenesis. To elucidate them, first we examined the levels of miR-19a and 19b in peripheral blood of SZ patients with quantitative RT-PCR and showed that the level of miR-19b, but not miR-19a, was significantly higher (miR-19a: p = 0.5733, miR-19b: p = 0.0038) in peripheral blood of SZ patients (N = 22) than that of healthy controls (N = 19). Next, we examined the involvement of miR-19b in proliferation and survival of mouse neonatal mice hippocampus-derived NPC with BrdU assay and TUNEL assay. The silencing of miR-19b significantly increased proliferation (N = 5, p = 0.0139), but not survival (N = 5, p = 0.9571), of neonatal mice hippocampus-derived NPC. These results suggest that the level of miR-19b in peripheral blood is a potential biomarker of schizophrenia and that the higher level of miR-19b may increase the vulnerability of SZ via attenuating proliferation of hippocampal NPC.

Agmatine inhibits chronic morphine exposure-induced impairment of hippocampal neural progenitor proliferation in adult rats

Our previous studies have shown that agmatine inhibited opioid dependence, yet the neural mechanism remains unclear. Growing evidence showed that opioids decrease neurogenesis in the adult hippocampal subgranular zone by inhibiting neural progenitor proliferation. However, whether agmatine affects chronic opioid exposure-induced impairment to hippocampal neural progenitor cell proliferation remains unknown. In the present study, we investigated the role of agmatine in hippocampal neural progenitors in morphine dependence rats. We found that chronic administration of morphine for 12 days induced morphine dependence in rats. This treatment not only decreased the proliferation of hippocampal neural progenitors in the granule cell layer, but also decreased the levels of hippocampal cAMP, pCREB and BDNF. However, these alterations can be restored to normal levels by co-treatment of agmatine (10mg/kg, s.c.). In vitro treatment with agmatine (10µM) for two days significantly increased proliferation of the cultured hippocampal neural progenitors. Concurrent treatment of agmatine (10µM) with morphine (10 or 50µM) reversed the supression of morphine-induced neural progenitor proliferation. In conclusion, we found that agmatine abolished chronic morphine-induced decrease in proliferation of hippocampal progenitors in vivo and in vitro, which may be due to the increase in cAMP-CREB-BDNF signaling. The enhancement of agmatine to proliferation of hippocampal progenitors may be one of the important mechanisms involved in the inhibition of morphine dependence by agmatine.

Neuronal NOS Induces Neuronal Differentiation Through a PKCα-Dependent GSK3β Inactivation Pathway in Hippocampal Neural Progenitor Cells.

We investigated the role of neuronal nitric oxide synthase (nNOS) in the neuronal differentiation of neural progenitor cells (NPCs) from hippocampi of E16.5 rat embryos. The production of nitric oxide (NO) and nNOS expression increased markedly during neuronal differentiation as did the expression of neurotrophin-3 (NT3), neurotrophin-4/5 (NT 4/5), and synapsin I. nNOS siRNA or the nNOS inhibitor, 7-nitroindazole (7-NI), decreased expression of the neurotrophins and synapsin I, and suppressed neurite outgrowth. These results suggest that nNOS plays a critical role in neuronal differentiation of hippocampal NPCs. nNOS-mediated neuronal differentiation is controlled by calcineurin since cyclosporin A (CsA), a calcineurin inhibitor, decreased nNOS activation and NO production, and inhibited neurite outgrowth. We found that inactivation of glycogen synthase kinase-3 beta (GSK3β) resulting from activation of protein kinase C alpha (PKCα) is involved in the nNOS-mediated neuronal differentiation. Moreover, lithium chloride (LiCl), a GSK3β inhibitor, increased neuronal differentiation by inhibiting the proliferation of NPCs. Taken together, these results suggest that neuronal differentiation is dependent on calcineurin-mediated activation of nNOS; this induces PKCα-dependent inactivation of GSK3β, which leads to inhibition of the proliferation of hippocampal NPCs.

The mTOR signaling pathway and neuronal stem/progenitor cell proliferation in the hippocampus are altered during the development of absence epilepsy in a genetic animal model.

Hyperactivation of mammalian target of rapamycin (mTOR) signaling pathway occurs after an epileptogenic insult and, its inhibition prevents the development of spontaneous seizures. We have recently demonstrated that mTOR's inhibition by rapamycin (started before seizure onset), permanently reduces the development of spontaneous absence seizures in WAG/Rij rats, an animal model of absence epilepsy; furthermore, mTOR phosphorylation was increased in adult WAG/Rij rats' cortex, but not other brain areas. However, it was not clear whether this hyperphosphorylation was a cause or a consequence of absence seizure. Here, we have addressed this issue by analyzing immunohistochemically: (1) the brain levels of total and phosphorylated mTOR in young (before seizures) and adult WAG/Rij rats; (2) the proliferation of hippocampal neuronal stem/progenitor cells assessed by BrdU analysis at different ages. WAG/Rij rats have higher levels of total mTOR in several brain areas than Wistar rats; phospho-mTOR staining is higher in young WAG/Rij rats than control and adult WAG/Rij rats. Finally, the age-related decline in hippocampal neural progenitor cell proliferation rate was slower in WAG/Rij than Wistar rats. Our results support a role for persistent mTOR activation and consequent change in hippocampal progenitor cell proliferation during the epileptogenic process leading to the development of absence seizures in WAG/Rij rats.

Thyroid hormone contributes to hippocampal neural progenitor cell proliferation in adult 2vo rats

WCN 2013 No: 300 Topic: 3 — Stroke Thyroid hormone contributes to hippocampal neural progenitor cell proliferation in adult 2vo rats L. Ting, B. Chisulo, Q. Wang. Neurology, Nanfang Hospital, Guangzhou, China; Medicine, Kitwe Central Hospital, Kitwe, Zambia Background: Thyroid hormone (TH) plays a critical role in developing the nervous system and regulating proliferation, survival and differentiation of neural progenitor cells. Hypothyroidism decreases the survival and differentiation of adult dentate granule cell progenitors. Objective: To investigate the effects of TH on proliferation of stem cells in the hippocampal subgranular zone (SGZ). Materials andmethods:Weachieved vascular cognitive impairment in animal model by permanent bilateral occlusion of common carotid arteries, set interventions of thyroid hormone treatment, and observe the effect on proliferation of adult dentate granule cell progenitors after chronic cerebral ischemia by immunofluorescence staining method. Rats were administered with T3 (10 mg/30 g·d) for 7 d or a single T3 (10 mg/30 g) after ischemia, and same dose of saline in control animals. Neurogenesis was studied by Bromodeoxyuridine (BrdU) immunohistochemistry in the SGZ. Results: T3 treatment for 7 d after ischemia increased the number of BrdU cells in the SGZ compared to saline (p = 0.005, p b 0.001, respectively). A single T3 injection 10 h before death also enhanced proliferation in SGZ 7d after chronic cerebral ischemia compared to saline (p = 0.015, p b 0.001, respectively). Conclusion: The results suggest that T3 enhance ischemia-induced proliferation of hippocampal in adult rats, and a short T3 influence on mitotic activity suggested T3 may act directly on progenitor cell populations. doi:10.1016/j.jns.2013.07.666 Abstract — WCN 2013 No: 301 Topic: 3 — Stroke The CHA2DS2-VASc score reflects clinical outcomes in NVAF patients with an initial cardioembolic stroke WCN 2013 No: 301 Topic: 3 — Stroke The CHA2DS2-VASc score reflects clinical outcomes in NVAF patients with an initial cardioembolic stroke I. Deguchi, T. Hayashi, Y. Ohe, Y. Kato, T. Fukuoka, H. Maruyama, Y. Horiuchi, H. Sano, Y. Nagamine, N. Tanahashi. Department of Neurology, Saitama Medical University International Medical Center,

Leptin restores adult hippocampal neurogenesis in a chronic unpredictable stress model of depression and reverses glucocorticoid-induced inhibition of GSK-3β/β-catenin signaling

Stress and glucocorticoid stress hormones inhibit neurogenesis, whereas antidepressants increase neurogenesis and block stress-induced decrease of neurogenesis. Our previous studies have shown leptin, an adipocyte-derived hormone with antidepressant-like properties 1, promotes baseline neurogenesis in the adult hippocampus 2. The present study aimed to determine whether leptin is able to restore stress-induced suppression of neurogenesis in a rat chronic unpredictable stress (CUS) model of depression. Chronic treatment with leptin reversed the CUS-induced reduction of hippocampal neurogenesis and depression-like behaviors. Leptin treatment elicited delayed long-lasting antidepressant-like effects in the behavioral despair test, and this effect was blocked by ablation of neurogenesis with X-irradiation. The functional isoform of the leptin receptor, LepRb, and the glucocorticoid receptor (GR) were colocalized in hippocampal neural stem/progenitor cells in vivo and in vitro. Leptin treatment reversed the GR agonist dexamethasone (DEX)-induced reduction of proliferation of cultured neural stem/progenitor cells from adult hippocampus. Further mechanistic analysis revealed that leptin and DEX converged on GSK3β and β-catenin. DEX decreased Ser9 phosphorylation and increased Tyr216 phosphorylation of GSK3β, while leptin increased Ser9 phosphorylation and attenuated the effects of DEX at both Ser9 and Tyr216 phosphorylation sites of GSK3β. Moreover, leptin increased total level and nuclear translocation of β-catenin, a primary substrate of GSK3 β and a key regulator in controlling neural progenitor proliferation, and reversed the inhibitory effects of DEX on β-catenin. Together, our results suggest that adult neurogenesis is involved in the delayed long-lasting antidepressant-like behavioral effects of leptin, and leptin treatment counteracts chronic stress and glucocorticoid-induced suppression of hippocampal neurogenesis via activating the GSK3β/β-catenin signaling pathway.

Hippocampal neural progenitor cell proliferation is more sensitive to estradiol in mouse with an Arg-61 apoE mutation

Hippocampal neural progenitor cell proliferation is more sensitive to estradiol in mouse with an Arg-61 apoE mutation

Sonic Hedgehog Regulates Ischemia/Hypoxia-Induced Neural Progenitor Proliferation

Sonic hedgehog (Shh) protein is required for the maintenance of neural progenitor cells (NPCs) in the embryonic and adult hippocampus. Brain ischemia causes increased proliferation of hippocampal NPCs. We therefore examined whether Shh regulates the increase in proliferation of NPCs after ischemia/hypoxia. Male SV129 mice were exposed to a 20-minute middle cerebral artery occlusion; hippocampi were then analyzed for Shh mRNA and protein expression by real-time polymerase chain reaction, immunoblot, and immunohistochemistry. Primary cell cultures of neurons, astrocytes, and NPCs were exposed to 16 hours of hypoxia (1% O(2)) and analyzed by real-time polymerase chain reaction and immunoblot for Shh expression. Proliferation of NPCs, in vivo and in vitro, was measured by bromodeoxyuridine incorporation. Among the cell types examined in vitro, only NPC and neurons increased Shh mRNA under hypoxic conditions. Furthermore, hypoxia increased proliferation of NPCs and this proliferation was enhanced by the addition of recombinant Shh or blocked by the pathway-specific inhibitor, cyclopamine. Middle cerebral artery occlusion was associated with a transient 2-fold increase in the mRNA encoding both Shh and its transcription factor, Gli1, 0.5 days after ischemia. Within the hippocampus, Shh protein was increased approximately 3-fold 3 and 7 days after ischemia and was observed predominantly within cells in the CA3 and hilar regions. Shh was expressed only in mature neurons. In vivo, cyclopamine suppressed ischemia-induced proliferation of subgranular NPCs. The Shh pathway plays a role in the proliferation of NPCs induced by ischemia/hypoxia and might participate in injury remodeling.

Null Effect of Antidepressants on the Astrocytes-Mediated Proliferation of Hippocampal Progenitor Cells in vitro

BackgroundIt is well known that antidepressants increase neurogenesis in the dentate gyrus of the hippocampus. The increase of neurogenesis might contribute to the behavioral effects of antidepressants. However, the mechanism by which antidepressants increase hippocampal neurogenesis is largely unknown. It has been recently reported that astroglia induce the neurogenesis of the hippocampal neural progenitor cells (NPCs). Therefore, we hypothesized that antidepressants may act on astrocytes, and this in turn induces neurogenesis of NPCs.ResultsTo examine this hypothesis, we used two co-culture systems, i.e., a contact-independent Banker culture and a contact-dependent overlay co-culture. In both of these systems, in comparison with naïve astrocytes, antidepressant-treated astrocytes did not further increase the proliferation of NPCs.ConclusionThese results suggest that astrocytes increase the proliferation of hippocampal NPCs, however, this may not be directly involved in the antidepressant-induced proliferation of NPCs.

Chronically Increased Transforming Growth Factor-β1 Strongly Inhibits Hippocampal Neurogenesis in Aged Mice

There is increasing evidence that hippocampal learning correlates strongly with neurogenesis in the adult brain. Increases in neurogenesis after brain injury also correlate with improved outcomes. With aging the capacity to generate new neurons decreases dramatically, both under normal conditions and after injury. How this decrease occurs is not fully understood, but we hypothesized that transforming growth factor (TGF)-beta1, a cell cycle regulator that rapidly increases after injury and with age, might play a role. We found that chronic overproduction of TGF-beta1 from astrocytes almost completely blocked the generation of new neurons in aged transgenic mice. Even young adult TGF-beta1 mice had 60% fewer immature, doublecortin-positive, hippocampal neurons than wild-type littermate controls. Bromodeoxyuridine labeling of dividing cells in 2-month-old TGF-beta1 mice confirmed this decrease in neuro-genesis and revealed a similar decrease in astrogenesis. Treatment of early neural progenitor cells with TGF-beta1 inhibited their proliferation. This strongly suggests that TGF-beta1 directly affects these cells before their differentiation into neurons and astrocytes. Together, these data show that TGF-beta1 is a potent inhibitor of hippocampal neural progenitor cell proliferation in adult mice and suggest that it plays a key role in limiting injury and age-related neurogenesis.