WIRELESS IN VIVO OPTICAL CONTROL OF STRESS NEURAL CIRCUITS AND GPCR SIGNALING

描述（由申请人提供）：情感障碍神经科学研究领域的一个主要挑战是确定与压力引起的抑郁、焦虑、成瘾和相关精神疾病的复杂行为有关的关键信号通路和神经回路。在基础神经科学研究中，该领域的一个主要挑战是对动物行为进行建模，以便我们可以有效地预测人类的相关性。行为范式越复杂，神经回路靶向方法越独特，这一挑战就变得越困难。光遗传学领域的最新发展极大地提高了我们对精神疾病的功能神经回路和行为反应的理解，开辟了新的治疗途径。然而，这些技术的一个关键限制是动物被束缚，对离散亚核的访问受到限制，并且同时控制多个输入变得麻烦且具有挑战性。随着材料工程和纳米技术开发了生物工程和神经科学领域融合的潜力，解决这些限制和挑战变得更有可能。我们开发了新型 micro-ILED 生物相容性设备，用于完全无线控制行为，包括社交挫败压力、家庭笼内行为和药物恢复。这些微聚合物装置可用于研究和治疗精神疾病，包括抑郁症、焦虑症和成瘾症。最近的证据表明促肾上腺皮质激素释放因子和强啡肽是关键应激神经肽，参与社交失败压力、社交互动和恢复可卡因寻求。在这项 EUREKA 提案中，我们将新型多模式光遗传学 micro-LED 设备与旨在剖析压力神经回路在情感行为中的作用的特定目标相结合。我们建议：1）通过进一步小型化并向半导体平台添加附加功能来开发和完善微型 ILED 设备 2）剖析社交失败压力和药物寻求恢复中下丘脑和中央杏仁核 CRF 和强啡肽神经回路 3）在无线环境中开发和使用光学 GPCR 信号，以评估 CRF 和强啡肽下游信号传导的激活如何最终影响行为反应，最后 4）评估 CRF 和强啡肽的异质性使用我们的无线多模式 micro-ILED 设备同时输入强啡肽。这项研究将为哺乳动物神经回路深处细胞级半导体器件的集成奠定基础，并将指导未来与精神疾病中选定的神经回路进行接口和相互作用的努力。

DESCRIPTION (provided by applicant): A major challenge in the field of neuroscience research on affective disorders is identifying the critical signaling pathways and neural circuits involved in complex behaviors that underlie stress-induced depression, anxiety, addiction and related psychiatric diseases. In basic neuroscience research, one major challenge in this area is modeling animal behavior such that we can predict human correlates effectively. The more complex the behavioral paradigm, and the more unique the neural circuit targeting approach, the more difficult this challenge becomes. Recent developments in the field of optogenetics have greatly improved our understanding of the functional neural circuits and behavioral responses in psychiatric disease, opening new avenues for treatment. However, one key limitation to these techniques is that animals are tethered, access to discrete subnuclei is limited, and control of multiple inputs simultaneously becomes cumbersome and challenging. As materials engineering and nanotechnology have developed the potential for the field of bioengineering and neuroscience to converge, has become more possible in solving these limitations and challenges. We have developed novel micro-ILED, biocompatible devices for completely wireless control of behavior including social defeat stress, home cage behavior and drug reinstatement. These micropolymeric devices could be used for the study and treatment of psychiatric diseases including depression, anxiety, and addiction. Recent evidence has implicated corticotropin-releasing factor and dynorphin as critical stress neuropeptides involved in social defeat stress, social interaction, and reinstatement of cocaine seeking. In this EUREKA proposal we combine our novel multimodal, optogenetic micro-LED devices with specific aims geared towards dissecting the role of stress neural circuits in affective behavior. We propose to: 1) Develop and refine micro-ILED devices by further miniaturization and adding additional functions to the semiconductor platform 2) to dissect hypothalamic and central amygalar CRF and dynorphin neural circuits in social defeat stress and reinstatement of drug seeking 3) develop and use optical GPCR signaling in a wireless context to assess how activation of downstream signaling for CRF and dynorphin ultimately influence behavioral responses and finally 4) to assess the heterogeneity of CRF and dynorphin inputs simultaneously using our wireless multimodal micro-ILED devices. This research will provide a foundation for the integration of cellular scale semiconductor devices deep within mammalian neural circuits, and will guide future efforts to interface and interact with selected neural circuits in psychiatric diseases.