Stress-induced alterations in amygdala-LC interactions

描述（由申请人提供）：已知压力是精神疾病的病因或加重的一个因素，并在恢复吸毒行为中起重要作用。本研究主要利用麻醉大鼠的电生理记录来研究急性和慢性应激对杏仁复合体调节蓝斑（LC）的影响。去甲肾上腺素和促肾上腺皮质激素释放激素已被确定为应激反应的中心因子。特别是，已知LC的去甲肾上腺素能神经元在应激反应的中枢介导中具有重要作用。这些神经元受到许多传入影响的驱动。有一组传入神经似乎在压力中起主要作用，因为它与精神疾病和药物滥用复发有关，这是涉及杏仁核的投射。我们建议检查杏仁调节LC神经元的活动，以及如何修改这个系统的急性和慢性应激。我们的中心假设是，慢性应激导致LC神经元的敏感性通过其对杏仁核的影响。这将按照沿着四个具体目标进行：1）检查连接基底外侧杏仁核复合体和LC的投射系统的生理学，2）检查该系统对急性应激的反应（足电击），以及这些反应在慢性冷暴露后如何改变，3）评估慢性应激后LC神经元反应性变化的性质，和4）确定慢性应激后LC反应性的改变是否可以通过选择性阻断这些杏仁核传出而改变。我们将主要使用体内单单位和细胞内记录方法来检查系统水平的相互作用，体外记录用于测量LC神经元活动的持续变化，并解决特定的途径相关的问题，因为它们出现。我们将通过测量声音惊吓来独立验证慢性冷暴露的行为效应，声音惊吓是一种对中央杏仁核和前脑NE系统的操纵敏感的反应。我们希望，对杏仁核-蓝核系统的更好理解将有助于深入了解这些途径中的应激诱导的病理生理学如何在一定程度上介导精神疾病和药物滥用障碍的一些行为症状。

DESCRIPTION (provided by applicant): Stress is known to be a factor in the etiology or exacerbation of psychiatric disorders, and plays an important role in reinstatement of drug-taking behavior. This proposal will use primarily electrophysiological recordings in anesthetized rats to examine the effects of acute and chronic stress on the regulation of the locus coeruleus (LC) by the amygdalar complex. Norepinephrine and corticotropin releasing hormone have been identified as central factors in the response to stress. In particular, the noradrenergic neurons of the LC are known to have a major role in central mediation of stress responses. These neurons are driven by a number of afferent influences. One set of afferents that appears to have a primary role in stress as it relates to psychiatric disorders and relapse to drug abuse are the projections that involve the amygdala. We propose to examine amygdalar regulation of LC neuron activity, and how this system is modified by acute and chronic stress. Our central hypothesis is that chronic stress causes a sensitization of LC neuron responsivity via its effects on amygdalofugal pathways. This will be done along four specific aims: 1) to examine the physiology of projection systems connecting the basolateral amygdala complex with the LC, 2) to examine the response of this system to acute stressors (footshock), and how these responses are modified following chronic cold exposure, 3) to evaluate the nature of the change in LC neuron responsivity following chronic stress, and 4) to determine whether the alteration in LC responsivity following chronic stress can be altered by selective interruption of these amygdalar efferents. We will use primarily in vivo single unit and intracellular recording methods to examine systems-level interactions, with in vitro recordings used to measure persistent changes in LC neuronal activity and to address specific pathway-related questions as they arise. We will independently verify the behavioral effects of chronic cold exposure by measuring acoustic startle, a response that is sensitive to manipulations of the central amygdala and forebrain NE systems. We hope that a better understanding of amygdalar-coerulear systems will lead to insights into how stress-induced pathophysiology in these pathways can, in part, mediate some of the behavioral symptoms of psychiatric disease and drug-abuse disorders.