Elucidating the signal transduction pathways regulating CCK-mediated adult hippocampal neurogenesis

 描述(申请人提供)：成人神经发生既涉及正常的神经生物学过程，如学习和记忆，也与其功能障碍的病理状态有关。这一过程由经验和神经活动(依赖活动的成人神经发生)通过局部和远距离连接来调节。然而，缺乏活动依赖的成人神经发生的机制特征不佳，这阻碍了确定成人神经发生是否与学习和记忆等过程有关，或与癫痫和精神分裂症等疾病有关。我已经确认神经肽CCK(CCK)可能是成人神经发生的调节因子。我的初步数据表明，成人神经干细胞表达功能性CCK2受体，表达CCK的神经元的活性可以促进成人神经干细胞和神经前体细胞的增殖。为了进一步研究这些发现，我将利用体内操作、病毒技术和免疫组织化学相结合的方法来激活这些细胞，并确定它们对成年神经干细胞和神经前体细胞的增殖、神经前体细胞和未成熟神经元的存活以及成熟新生神经元的成熟和整合的影响。此外，我还将学习钙成像和电生理学技术，以研究CCK细胞活动如何作用于这些发育中的细胞。最后，我将培训先进的显微技术，以量化这些影响。通过这些技术，我将详尽地描述CCK细胞活动对成人神经发生的这些阶段的影响。了解这一过程也可能导致治疗神经退行性疾病的进展，例如促进移植的神经干细胞的增殖、成熟和整合，以治疗创伤性脑损伤等疾病。了解促进新生神经元增殖、存活和整合的营养信号(如CCK)可以促进这一假定治疗的有效性。综上所述，这项建议将解决神经生物学中的一个基本基本差距，并为人类治疗学提供潜在的翻译发现。

 DESCRIPTION (provided by applicant): Adult neurogenesis is implicated in both normal neurobiological processes such as learning and memory, and in contributing to pathological states in its dysfunction. This process is regulated by experience and neuronal activity (activity-dependent adult neurogenesis) through local and long-distance connections. However, the mechanisms that underly activity-dependent adult neurogenesis are poorly characterized, and this has impeded efforts to determine whether adult neurogenesis is causally linked to linked to processes such as learning and memory, or diseases such as epilepsy and schizophrenia. I have identified the neuropeptide cholecystokinin (CCK) as a putative regulator of adult neurogenesis. My preliminary data suggests adult neural stem cells express functional CCK2 receptors, and that activity of CCK-expressing neurons could promote the proliferation of adult neural stem cells and neural progenitors. In order to further investigate these findings, I will utilize a combination of in vivo manipulations, viral techniques, and immunohistochemistry to activate these cells and determine their influence on the proliferation of adult neural stem cells and neural progenitors, the survival of neural progenitors and immature neurons, and the maturation and integration of maturing newborn neurons. In addition, I will learn calcium imaging and electrophysiology techniques to study how CCK-cell activity acts on these developing cells. Finally, I will train in advanced microscopy techniques in order to quantify these effects. With these techniques, I will exhaustively characterize the influence of CCK-cell activity on these stages of adult neurogenesis. Understanding this process could also lead to advancements in treating neurodegenerative disorders, such as facilitating the the proliferation, maturation, and integration of transplanted neural stem cells in order to treat conditions such as traumatic brain injury. Understanding trophic signals (such as CCK) that promote proliferation, survival, and integration of newborn neurons could advance the effectiveness of this putative therapy. Taken together, this proposal will address a basic fundamental gap in neurobiology, as well as providing potentially translational findings for human therapeutics.