Stress-induced alterations in amygdala-LC interactions

描述(由申请人提供)：众所周知，压力是导致精神障碍的病因或恶化的一个因素，并在恢复吸毒行为方面发挥重要作用。这项建议将主要使用麻醉大鼠的电生理记录来检查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被认为是应激反应的中心因素。特别是，LC的去甲肾上腺素能神经元在应激反应的中枢调节中起着重要作用。这些神经元受到许多传入影响的驱动。一组似乎在压力中起主要作用的传入神经与精神障碍和药物滥用复发有关，这是涉及杏仁核的投射。我们建议研究杏仁核对LC神经元活性的调节，以及该系统如何被急性和慢性应激所改变。我们的中心假设是，慢性应激通过对杏仁核通路的影响导致LC神经元反应性的敏化。这项研究将沿着四个具体目标进行：1)检查连接杏仁核基底外侧复合体和LC的投射系统的生理学；2)检查该系统对急性应激源(足部电击)的反应，以及这些反应在慢性冷暴露后是如何改变的；3)评估慢性应激后LC神经元反应性变化的性质；以及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来改变。我们将主要使用活体单个单位和细胞内记录方法来检查系统水平的相互作用，使用体外记录来测量LC神经元活动的持续变化，并在出现特定通路相关问题时解决这些问题。我们将通过测量声惊厥来独立验证慢性冷暴露的行为影响，声惊厥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-蓝斑系统的更好理解将有助于深入了解这些通路中应激诱导的病理生理学如何在一定程度上调节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.