Afferent-specific Endocannabinoid Signaling in the Central Amygdala

描述（申请人提供）：中央杏仁核（CeA）是一个关键的脑结结构，整合自主神经、觉醒和感觉信息，对适当的显著刺激启动恐惧和焦虑反应。杏仁核活动将环境压力与易感个体的精神病理状态的发展联系起来，杏仁核功能失调已在许多情感障碍中得到证实，包括重度抑郁症和焦虑障碍，如创伤后应激障碍。因此，了解杏仁核的细胞和突触组织，以及该区域信息加工的调节机制，可以为了解恐惧、焦虑产生和应激反应生理学的调节机制提供重要的见解。此外，了解应激暴露诱导的突触适应可以揭示促进应激相关神经精神疾病发展的新机制。本研究旨在利用光遗传学投影靶向方法阐明CeA的突触组织，以揭示CeA的不同兴奋性输入通过细胞类型特异性靶向对焦虑状态施加差异控制的突触和功能解剖学机制。我们将确定内源性大麻素信号在CeA兴奋性驱动的细胞类型和传入特异性调节中的作用。最后，我们将验证内源性大麻素信号的细胞类型特异性适应抵消应激诱导的与焦虑状态相关的突触重塑的假设。这些研究将提供对CeA突触组织的前所未有的理解，并阐明内源性大麻素信号机制，以传入和细胞类型特异性的方式调节谷氨酸能驱动到CeA神经元。这些研究还揭示了内源性大麻素信号的新突触适应性，这种适应性可能具有旨在使压力诱导的焦虑状态正常化的稳态功能。了解调节CeA功能的突触和分子机制可以最终促进我们对人类情绪和焦虑障碍的病理生理机制的理解。

DESCRIPTION (provided by applicant): The central amygdala (CeA) is a key nodal brain structure that integrates autonomic, arousal, and sensory information to initiate fear and anxiety responses to appropriate salient stimuli. Amygdalar activity links environmental stress to the development of psychopathological states in susceptible individuals, and dysregulation of amygdala function has been demonstrated in numerous affective disorders including major depression, and anxiety disorders such as posttraumatic stress disorder. Thus, understanding the cellular and synaptic organization of the amygdala, and the mechanisms regulating information processing in this region could provide important insights into the mechanisms regulating fear and anxiety generation and stress response physiology. Moreover, understanding the synaptic adaptations induced by stress exposure could reveal novel mechanisms contributing to the development of stress-related neuropsychiatric disorders. Here we aim to elucidate the synaptic organization of the CeA using optogenetic projection-targeting approaches in order to uncover synaptic and functional anatomical mechanisms by which different excitatory inputs to the CeA could exert differential control of anxiety states via cell type-specific targeting. We will determine the role of endogenous cannabinoid signaling in the cell-type- and afferent-specific modulation of excitatory drive to the CeA. Lastly, we will test th hypothesis that cell-type specific adaptations in endogenous cannabinoid signaling counteract stress-induced synaptic remodeling associated with anxiety states. These studies will provide an unprecedented understanding of the synaptic organization of the CeA and elucidate endogenous cannabinoid signaling mechanisms regulating glutamatergic drive to CeA neurons in an afferent and cell type-specific manner. These studies could also reveal novel synaptic adaptations in endocannabinoid signaling that could serve a homeostatic function aimed at normalizing stress-induced anxiety states. Understanding the synaptic and molecular mechanisms regulating CeA function could ultimately advance our understanding of the pathophysiological mechanisms subserving mood and anxiety disorders in humans.