CORTICOTROPIN RELEASING HORMONE SIGNALING AND NEWBORN NEURON CIRCUIT INTEGRATION

描述(由申请人提供)：哺乳动物大脑中的成年神经发生代表了持续的细胞和结构神经元可塑性的非凡例子。虽然这个过程的现象学已经很好地建立了，但指导新生神经元突触形成、突触维持和电路整合的分子和遗传机制还不是很清楚。显示持续神经发生的两个大脑区域包括海马齿状回的颗粒下层和嗅觉系统的脑室下区(SVZ)。有趣的是，已发现多种形式的神经活动影响新生神经元的增殖、存活和突触形成。例如，锻炼、学习、感觉刺激和抗抑郁药物的治疗促进了成人神经发生和回路整合，而压力、感觉剥夺和某些神经病理损害了突触发生和生存。这些“活动”通过它们的突触前输入系统传递给新生神经元。然而，这些输入的确切类型、数量、来源和性质仍然未知。为了阐明为新生神经元提供突触前输入的细胞类型，我们使用工程狂犬病病毒(RV)和小鼠遗传学实施了跨突触病毒电路追踪方法。我们已经确定了局部促肾上腺皮质激素释放激素(CRH)表达的神经元的一个亚群，它们为新生颗粒细胞提供选择性和广泛的输入。CRH已被发现影响从可塑性到神经递质功能的多种神经调节过程。此外，CRH信号与许多医学和心理疾病有关，从阿尔茨海默病到觉醒、压力、焦虑和抑郁。有趣的是，所有这些状态都被证明会影响成人的神经发生。因此，我们的发现，CRH表达的神经元向新生颗粒细胞提供突触前输入代表了一种促进哺乳动物大脑中突触形成和电路整合的新机制。为了阐明CRH对新生颗粒细胞的功能作用，我们提出了以下假设：促肾上腺皮质激素释放激素表达神经元的突触前输入促进了新生颗粒细胞电路整合和突触形成。最终，我们打算了解成人大脑中突触发生、回路整合和神经元存活的分子和细胞机制。这些知识将使我们能够致力于基于细胞和电路的大脑修复的新的治疗方法。

DESCRIPTION (provided by applicant): Adult neurogenesis in the mammalian brain represents an extraordinary example of continued cellular and structural neuronal plasticity. Although the phenomenology of this process has been well established, the molecular and genetic mechanisms that guide newborn neuron synapse formation, synapse maintenance, and circuit integration are not well understood. Two brain areas that show continued neurogenesis include the subgranular layer of the hippocampal dentate gyrus, and the subventricular zone (SVZ) of the olfactory system. Interestingly, it has been found that multiple forms of neural activity affect the proliferation, survival, and synapse formation of newborn neurons. For example, exercise, learning, sensory stimulation, and treatments with antidepressants promote adult neurogenesis and circuit integration, whereas stress, sensory deprivation, and certain neuropathologies impair synaptogenesis and survival. These "activities" are relayed to newborn neurons via their repertoire of presynaptic inputs. However, the exact types, numbers, origins, and the nature of these inputs remain unknown. To elucidate the cell types that provide presynaptic inputs to newborn neurons, we have implemented a transsynaptic viral circuit tracing approach using engineered Rabies Virus (RV) and mouse genetics. We have identified a subpopulation of local Corticotropin-Releasing Hormone (CRH)-expressing neurons that provide selective and extensive inputs onto newborn granule cells. CRH has been found to influence a variety of neuromodulatory processes ranging from plasticity to neurotransmitter function. Moreover, CRH signaling has been implicated in a number of medical and psychological conditions, ranging from Alzheimer's disease to arousal, stress, anxiety, and depression. Interestingly, all of these states have been shown to influence adult neurogenesis. Thus, our discovery that CRH expressing neurons provide presynaptic inputs onto newborn granule cells represents a novel mechanism to promote synapse formation and circuit integration in the mammalian brain. To elucidate the functional role of CRH inputs onto newborn granule cells, we propose to test the following hypothesis: Presynaptic input from Corticotropin-Releasing Hormone expressing neurons promotes newborn granule cell circuit integration and synapse formation. Ultimately, we intend to understand the molecular and cellular mechanisms underlying synaptogenesis, circuit integration and neuronal survival in the adult brain. This knowledge will allow us to work towards novel therapeutic approaches for cell and circuit-based brain repair.