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人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。尽管这一过程的现象学已经很好地建立起来，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尚不清楚。海马齿状回的亚颗粒层和嗅觉系统的室下区（SVZ）是神经发生持续的两个脑区。有趣的是，已经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，运动、学习、感觉刺激和抗抑郁药物治疗促进成人神经发生和电路整合，而压力、感觉剥夺和某些神经病理损害突触发生和生存。这些“活动”通过突触前输入传递给新生神经元。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，我们利用工程狂犬病毒（RV）和小鼠遗传学实现了一种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）表达神经元的亚群，这些神经元为新生儿颗粒细胞提供选择性和广泛的输入。已发现CRH影响多种神经调节过程，从可塑性到神经递质功能。此外，CRH信号传导与许多医学和心理状况有关，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，我们发现表达CRH的神经元为新生颗粒细胞提供突触前输入，这代表了一种促进哺乳动物大脑突触形成和电路整合的新机制。为了阐明CRH输入对新生儿颗粒细胞的功能作用，我们提出验证以下假设：来自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新生儿颗粒细胞回路整合和突触形成。最终，我们打算了解成人大脑中突触发生、电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为基于细胞和神经回路的大脑修复寻找新的治疗方法。

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. PUBLIC HEALTH RELEVANCE: The mammalian brain continuously gives rise to newborn neurons throughout adult life, and these neurons integrate into preexisting circuits; however, the molecular and cellular mechanisms underlying this integration process are largely unknown. Towards uncovering these molecular programs, we have used viral transsynaptic tracing to reveal that local Corticotropin-Releasing Hormone (CRH)-expressing neurons provide selective and extensive input onto newborn neurons during periods of synaptogenesis and circuit integration. In the proposed research, we will investigate the detailed molecular, genetic, and electrophysiological mechanisms of how CRH-expressing inputs influence newborn neuron circuit integration in the adult brain with the expectation that our studies will provide valuable insight into conserved plasticity mechanisms by which the mammalian brain continually generates, sculpts, and maintains neural circuits.