Afferent-specific Endocannabinoid Signaling in the Central Amygdala

描述(申请人提供)：中央杏仁核(CEA)是一个关键的结节脑结构，它整合了自主神经、觉醒和感觉信息，以启动对适当的显著刺激的恐惧和焦虑反应。杏仁核活动将环境应激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被证明，包括严重的抑郁症和焦虑障碍，如创伤后应激障碍。因此，了解杏仁核的细胞和突触组织，以及该区域调节信息处理的机制，可以为调节恐惧和焦虑的产生以及应激反应生理学提供重要的见解。此外，了解应激诱导的突触适应可以揭示导致应激相关神经精神障碍发展的新机制。在这里，我们旨在利用光遗传投射靶向方法阐明CEA的突触组织，以揭示突触和功能解剖学机制，通过这些机制，不同的兴奋性输入可以通过细胞类型特定的靶向对CEA的焦虑状态施加不同的控制。我们将确定内源性大麻素信号在对CEA的兴奋性驱动的细胞类型和传入特异性调制中的作用。最后，我们将检验这一假设，即内源性大麻素信号中的细胞类型特异性适应抵消了与焦虑状态相关的应激诱导的突触重构。这些研究将提供对CEA突触组织的前所未有的了解，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对CEA神经元的谷氨酸驱动。这些研究还可能揭示内源性大麻素信号中新的突触适应，这可能起到旨在使应激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最终可以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.