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压力引起的行为障碍的神经生物学基础。本研究的重点是蓝斑去甲肾上腺素能（LC-NE）系统，在哺乳动物大脑中的主要神经递质系统，并试图了解电路和细胞水平的机制，增加强直活动的LC-NE系统，以及如何这些变化的放电模式有助于应激诱导的行为。LC-NE神经元表现出三种不同的激活模式：低紧张性，高紧张性和阶段性活动，据信在确定响应各种环境挑战的行为灵活性方面具有不同的功能。应激和应激相关的神经肽释放（例如促肾上腺皮质激素释放因子）被认为将LC活性向高紧张性放电模式转变，同时减少相位放电事件，而内源性阿片样物质传递被认为将LC紧张性放电恢复至基线。然而，受体系统和特定的电路，这些活动的变化及其行为的影响是未知的。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紧张活性在介导焦虑样和厌恶行为中的作用。该建议的第一个目的是确定LC-NE系统在驱动这些负性情感行为中的充分性和必要性，并将确定所涉及的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以及随后对行为的影响。所提出的实验将是第一个专门探测内源性LC-NE系统及其CeA神经肽能传入输入模型的压力诱导的焦虑样行为，旨在破译潜在的电路动态介导这些重要的行为反应。这些实验的结果将提供内源性神经肽释放如何调节LC-NE神经元活性以及这些活性变化如何导致焦虑样行为表型的基本理解。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。 以及针对焦虑症和其他神经精神障碍如压力诱发的焦虑症和创伤后应激障碍的行为疗法。

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.