Dissecting the role of locus coeruleus circuitry in anxiety-like behaviors

描述（由申请人提供）：本研究的总体目标是更好地了解焦虑和其他应激性行为障碍的神经生物学基础。本研究的重点是蓝斑去肾上腺素能（LC-NE）系统，这是哺乳动物大脑中一个主要的神经递质系统，并试图了解LC-NE系统中强直活性增加的电路和细胞水平机制，以及这些放电模式的变化如何促进应激诱导行为。LC-NE神经元表现出三种不同的激活特征：低强直、高强直和相位活动，据信它们在不同环境挑战下决定行为灵活性方面的功能不同。应激和应激相关的神经肽释放（如促肾上腺皮质激素释放因子）被认为将LC活性转向高强直性放电模式，同时减少相性放电事件，而内源性阿片传递被认为使LC强直性放电恢复到基线。然而，这些活动变化背后的受体系统和特定电路及其行为含义尚不清楚。因此，拟议的研究将使用药理学，光遗传学和电生理学技术来确定这种高滋补活性在介导焦虑样和厌恶行为中的作用。本提案的第一个目标是确定LC-NE系统在驱动这些负面情感行为中的充足性和必要性，并将确定下游肾上腺素能受体系统。第二个目标将确定中央杏仁核（CeA）中含有内源性促肾上腺皮质激素释放因子的特定细胞如何控制这种神经元活动及其对行为的后续影响。这些实验将是第一个专门探讨内源性LC- NE系统及其CeA神经肽能传入输入在应激诱导的焦虑样行为模型中的实验，旨在破译介导这些重要行为反应的潜在电路动力学。这些实验的结果将为内源性神经肽释放如何调节LC-NE神经元的活动以及这些活动的变化如何导致焦虑样行为表型提供基本的理解。了解这个大脑系统的基本功能对于有效的药物治疗至关重要

DESCRIPTION (provided by applicant): The overall goal of this research is to better understand the neurobiological basis of anxiety and other stress- induced behavioral disorders. This research focuses on the locus coeruleus noradrenergic (LC-NE) system, a major neurotransmitter system in the mammalian brain, and seeks to understand the circuit- and cellular-level mechanisms for increased tonic activity in the LC-NE system and how these changes in firing patterns contribute to stress-induced behaviors. LC-NE neurons exhibit three distinct activation profiles: low tonic, high tonic, and phasic activity, believed to function differently in determining behavioral flexibility in response to various environmental challenges. Stress and stress-related neuropeptide release (such as corticotrophin- releasing factor) is thought to shift LC activity towards a high tonic mode of firing while simultaneously decreasing phasic firing events, while endogenous opioid transmission is thought to return LC tonic firing to baseline. However, the receptor systems and specific circuitry that underlie these changes in activity and their behavioral implications are not known. Accordingly, the proposed research will use pharmacological, optogenetic, and electrophysiological techniques to determine the role of this high tonic activity in mediating anxiety-like and aversive behaviors. The first aim of this proposal is to determine the sufficiency and necessity of the LC-NE system in driving these negative affective behaviors and will identify the downstream adrenergic receptor systems involved. The second aim will determine how specific cells in the central amygdala (CeA) containing endogenous corticotrophin-releasing factor control this neuronal activity and the subsequent implications on behavior. The proposed experiments will be the first to specifically probe the endogenous LC- NE system and its CeA neuropeptidergic afferent inputs in models of stress-induced anxiety-like behaviors aimed at deciphering the underlying circuit dynamics that mediate these important behavioral responses. Results from these experiments will provide a basic understanding of how endogenous neuropeptide release modulates LC-NE neuronal activity and how these changes in activity contribute to anxiety-like behavioral phenotypes. Understanding the basic function of this brain system will be critical for effective pharmaceutical and behavioral therapies targeting anxiety and other neuropsychiatric disorders such as stress-induced anxiety and posttraumatic stress disorder.