Effect of temozolomide on neurogenesis and anxiety in the adult mouse brain.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e23082-e23082
Author(s):  
Syed Hussaini ◽  
Mihyeon Jang
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Cellular Proliferation ◽  
Radial Glia ◽  
Malignant Gliomas ◽  
Brain Slices ◽  
Adult Brain ◽  
Neuronal Maturation ◽  
Dividing Cells ◽  
Newborn Neurons

e23082 Background: The hippocampus is one of two regions in the adult brain where new neurons are generated well into adulthood. Newborn neurons develop from neural stem cells, and are consequently integrated into the hippocampal circuitry to function in learning and memory. Temozolomide (TMZ) is a commonly used alkylating agent for treatment of malignant gliomas. In this study, we examine the effects of TMZ on adult neurogenesis and cognitive function in the murine model. Methods: Adult male mice (8-week-old) were injected daily with TMZ (25 mg/kg, i.p.) for 2, 2.5 and 3.5 weeks to estimate progenitor proliferation, neuronal maturation and animal behavior respectively. For progenitor proliferation, a single dose of BrdU (50mg/kg, i.p.) was injected at 2 weeks and the mice sacrificed 2 hours later. For maturation analysis, five separate doses of EdU (41.1 mg/kg, i.p.) were injected over five days starting at 2 weeks. Three weeks after first EdU injection mice were sacrificed. Both BrdU and EdU are novel thymidine analogues that label dividing cells. Immunostaining was performed on hippocampal brain slices to label progenitors at different stages of development. For behavioral analysis, daily tests measuring anxiety, memory and motor activity were started at 2 weeks into TMZ administration. Results: TMZ significantly reduced the resident radial glia-like and non-radial glia-like population (MCM2+Nestin+), as well as the overall proliferating progenitor pool (n = 2, p < 0.05). In addition, it significantly reduced the population of Type-3 neuroblasts (EdU+DCX+NeuN-) (n = 4, p < 0.05). During neuronal maturation, immature new neurons (EdU+DCX+NeuN+) and mature new neurons (EdU+DCX-NeuN+) were also reduced by TMZ (n = 4, p < 0.05). These effects of TMZ coincided with specific behavioral deficits. While TMZ had no effect on working memory and locomotor activity, mice that underwent TMZ administration showed significantly increased anxiety on the open field test (n = 7, p < 0.05). Conclusions: Our findings demonstrate TMZ significantly impairs cellular proliferation of neural stem cells and fate-committed neuroblasts, and increases anxiety with sparing of non-hippocampal-dependent memory. TMZ may thus be associated with specific deficits in hippocampal function in the adult brain, providing mechanistic insight into adverse effects that may be observed with TMZ treatment.

scholarly journals Loss of postnatal quiescence of neural stem cells through mTOR activation upon genetic removal of cysteine string protein-α

2019 ◽  
Vol 116 (16) ◽  
pp. 8000-8009 ◽  
Author(s):  
Jose L. Nieto-González ◽  
Leonardo Gómez-Sánchez ◽  
Fabiola Mavillard ◽  
Pedro Linares-Clemente ◽  
María C. Rivero ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Neural Stem Cells ◽  
Neural Stem Cell ◽  
Molecular Mechanisms ◽  
Radial Glia ◽  
Brain Dysfunction ◽  
Mtor Signaling ◽  
Cysteine String Protein ◽  
Newborn Neurons

Neural stem cells continuously generate newborn neurons that integrate into and modify neural circuitry in the adult hippocampus. The molecular mechanisms that regulate or perturb neural stem cell proliferation and differentiation, however, remain poorly understood. Here, we have found that mouse hippocampal radial glia-like (RGL) neural stem cells express the synaptic cochaperone cysteine string protein-α (CSP-α). Remarkably, in CSP-α knockout mice, RGL stem cells lose quiescence postnatally and enter into a high-proliferation regime that increases the production of neural intermediate progenitor cells, thereby exhausting the hippocampal neural stem cell pool. In cell culture, stem cells in hippocampal neurospheres display alterations in proliferation for which hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway is the primary cause of neurogenesis deregulation in the absence of CSP-α. In addition, RGL cells lose quiescence upon specific conditional targeting of CSP-α in adult neural stem cells. Our findings demonstrate an unanticipated cell-autonomic and circuit-independent disruption of postnatal neurogenesis in the absence of CSP-α and highlight a direct or indirect CSP-α/mTOR signaling interaction that may underlie molecular mechanisms of brain dysfunction and neurodegeneration.

scholarly journals A neuronal molecular switch through cell-cell contact that regulates quiescent neural stem cells

2019 ◽  
Vol 5 (2) ◽  
pp. eaav4416 ◽  
Author(s):  
Jian Dong ◽  
Yuan-Bo Pan ◽  
Xin-Rong Wu ◽  
Li-Na He ◽  
Xian-Dong Liu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Granule Cells ◽  
Adult Brain ◽  
Cell Contact ◽  
External Signal ◽  
Neurogenic Niche ◽  
Functional Transition ◽  
Newborn Neurons ◽  
Cell Cell

The quiescence of radial neural stem cells (rNSCs) in adult brain is regulated by environmental stimuli. However, little is known about how the neurogenic niche couples the external signal to regulate activation and transition of quiescent rNSCs. Here, we reveal that long-term excitation of hippocampal dentate granule cells (GCs) upon voluntary running leads to activation of adult rNSCs in the subgranular zone and thereby generation of newborn neurons. Unexpectedly, the role of these excited GC neurons in NSCs depends on direct GC-rNSC interaction in the local niche, which is through down-regulated ephrin-B3, a GC membrane–bound ligand, and attenuated transcellular EphB2 kinase–dependent signaling in the adjacent rNSCs. Furthermore, constitutively active EphB2 kinase sustains the quiescence of rNSCs during running. These findings thus elucidate the physiological significance of GC excitability on adult rNSCs under external environments and indicate a key-lock switch regulation via cell-cell contact for functional transition of rNSCs.

scholarly journals Adult Neurogenesis and the Promise of Adult Neural Stem Cells

2019 ◽  
Vol 13 ◽  
pp. 117906951985687 ◽  
Author(s):  
Hiyaa S Ghosh
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Neural Stem Cells ◽  
Neural Stem Cell ◽  
Adult Neurogenesis ◽  
Therapeutic Potential ◽  
Precursor Cells ◽  
Adult Brain ◽  
Adult Neural Stem Cell ◽  
Dividing Cells

The adult brain, even though largely postmitotic, is now known to have dividing cells that can make both glia and neurons. Of these, the precursor cells that have the potential to make new neurons in the adult brain have attracted great attention from researchers, anticipating their therapeutic potential for neurodegenerative conditions. In this review, I will focus on adult neurogenesis, from the perspective of the overall neurogenic potential in the adult brain, current understanding of the ‘adult neural stem cell’, and the importance of niche as a decisive factor for neurogenesis under homeostasis and pathologic conditions.

scholarly journals Modelling glioblastoma tumour-host cell interactions using adult brain organotypic slice co-culture

2017 ◽  
Author(s):  
Maria Angeles Marques-Torrejon ◽  
Ester Gangoso ◽  
Steven M. Pollard
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Neural Stem Cells ◽  
Neural Stem Cell ◽  
Ex Vivo ◽  
Brain Slices ◽  
Genetically Engineered ◽  
Adult Brain ◽  
Host Interactions ◽  
The Brain

AbstractGlioblastoma (GBM) is an aggressive incurable brain cancer. The cells that fuel the growth of tumours resemble neural stem cells found in the developing and adult mammalian forebrain. These are referred to as GBM stem cells (GSCs). Similar to neural stem cells, GSCs exhibit a variety of phenotypic states: dormant, quiescent, proliferative and differentiating. How environmental cues within the brain influence these distinct states is not well understood. Laboratory models of GBM tumours can be generated using either genetically engineered mouse models, or via intracranial transplantation of cultured tumour initiating cells (mouse or human). Unfortunately, these approaches are expensive, time-consuming, low-throughput and ill-suited for monitoring of live cell behaviours. Here we explored whole adult brain coronal organotypic slices as a complementary strategy to remove the experimental bottleneck. Mouse adult brain slices remain viable in a neural stem cell serum-free basal media for several weeks. GSCs can therefore be easily microinjected into specific anatomical sites ex vivo. We demonstrated distinct responses of engrafted GSCs to different microenvironments in the brain. Within the subependymal zone – one of the adult neural stem cell niches – a subset of injected tumour cells could effectively engraft and respond to endothelial niche signals. GSCs transplanted slices were treated with the anti-mitotic drug temozolomide as proof-of-principle of the utility in modelling responses to existing treatments. Thus, engraftment of mouse or human GSCs onto whole brain coronal organotypic brain slices provides a convenient experimental model for studies of GSC-host interactions and preclinical testing of candidate therapeutic agents.

scholarly journals Neural stem cells: involvement in adult neurogenesis and CNS repair

2008 ◽  
Vol 363 (1500) ◽  
pp. 2111-2122 ◽  
Author(s):  
Hideyuki Okano ◽  
Kazunobu Sawamoto
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Cell Transplantation ◽  
Adult Neurogenesis ◽  
Embryonic Stem ◽  
Adult Brain ◽  
Therapeutic Interventions ◽  
Cell Transplantation Therapy ◽  
Transplantation Therapy

Recent advances in stem cell research, including the selective expansion of neural stem cells (NSCs) in vitro , the induction of particular neural cells from embryonic stem cells in vitro , the identification of NSCs or NSC-like cells in the adult brain and the detection of neurogenesis in the adult brain (adult neurogenesis), have laid the groundwork for the development of novel therapies aimed at inducing regeneration in the damaged central nervous system (CNS). There are two major strategies for inducing regeneration in the damaged CNS: (i) activation of the endogenous regenerative capacity and (ii) cell transplantation therapy. In this review, we summarize the recent findings from our group and others on NSCs, with respect to their role in insult-induced neurogenesis (activation of adult NSCs, proliferation of transit-amplifying cells, migration of neuroblasts and survival and maturation of the newborn neurons), and implications for therapeutic interventions, together with tactics for using cell transplantation therapy to treat the damaged CNS.

Loss of PINK1 leads to metabolic deficits in adult neural stem cells and impedes differentiation of newborn neurons in the mouse hippocampus

2017 ◽  
Vol 31 (7) ◽  
pp. 2839-2853 ◽  
Author(s):  
Sandeep Kumar Agnihotri ◽  
Ruifang Shen ◽  
Jihong Li ◽  
Xu Gao ◽  
Hansruedi Büeler
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Adult Neural Stem Cells ◽  
Mouse Hippocampus ◽  
Newborn Neurons
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