Homeostatic Plasticity in the BNST and Drug Abuse

描述（由申请人提供）：终纹床核（BNST）在神经内分泌、自主神经、躯体运动反应的协调和滥用药物的影响中起重要作用。位于BNST背外侧的BNST的囊旁核（jcBNST）接收主要来自BLA后部的密集谷氨酸能投射，然后将gaba能投射发送到杏仁核的内侧中央核（CeAm），这是杏仁核的主要输出核。因此，jbnst神经元整合特性的改变可能导致与药物依赖和戒断相关的情绪失调。我们最近描述了一种长期增强的内源性兴奋性（LTP-IE）的形式，以响应终纹的刺激，终纹在长期停止海洛因、可卡因和酒精的自我给药和长期接受脑室内促肾上腺皮质激素释放因子（CRF）治疗的大鼠中受损。这些结果为药物和酒精滥用的易感性提供了一个新的神经生物学靶点。他们特别提出了一种假设，即jbnst神经元兴奋性的变化可能导致CeAm抑制不足，从而导致后依赖个体长期戒断的负面情感状态。为了验证这一假设，我们提出：1)利用传统电生理方法和动态钳（一种创新的基于计算机的方法，通过近似完整大脑的高电导状态来研究脑切片中神经元的兴奋性）相结合的方法，研究与海洛因依赖相关的jbnst神经元突触和内在特性的变化；2)研究海洛因依赖是否也与CeAm神经元的可塑性变化有关；3)利用动态钳法研究LTP-IE在BLA-jcBNST-CeA回路中的功能意义，以及与阿片依赖相关的jcBNST和CeAm神经元的可塑性变化。最终，了解药物依赖在微电路BLA-jcBNST-CeA中引起的适应性和反适应性变化将使我们能够确定治疗靶点，以恢复正常的神经元兴奋性和回路功能，并对杏仁核输出进行充分的抑制控制。

DESCRIPTION (provided by applicant): The bed nucleus of the stria terminalis (BNST) plays important roles in the coordination of neuroendocrine, autonomic, somatomotor responses and the effects of drugs of abuse. The juxtacapsular nucleus of the BNST (jcBNST) in the dorsolateral BNST receives dense glutamatergic projections primarily from the posterior part of the BLA and, in turn, sends GABAergic projections to the medial central nucleus of the amygdala (CeAm), the main output nucleus of the amygdala. Thus, changes in the integration properties of jcBNST neurons can contribute to the emotional dysregulation associated with drug dependence and withdrawal. We recently described a form of long-term potentiation of the intrinsic excitability (LTP-IE) of neurons of the jcBNST in response to stimulation of the stria terminalis that was impaired during protracted withdrawal from escalated heroin, cocaine, and alcohol self-administration and in rats chronically treated with corticotropin releasing factor (CRF) intracerebroventricularly. These results provide a novel neurobiological target for vulnerability to drug and alcohol abuse. In particular they suggest the hypothesis that changes in the excitability of jcBNST neurons could result in inadequate inhibition of the CeAm, contributing to the negative affective state that characterizes protracted abstinence in post-dependent individuals. To test this hypothesis here we proposed to 1) investigate changes in synaptic and intrinsic properties of jcBNST neurons associated with heroin dependence using a combination of conventional electrophysiological methods and the dynamic clamp, an innovative computer-based method to study neuronal excitability in brain slices by approximating the high-conductance state of the intact brain; 2) to investigate if heroin dependence is also associated with plastic changes in CeAm neurons; 3) to use the dynamic clamp to investigate the functional significance of LTP-IE in the BLA-jcBNST-CeA circuit as well as of the plastic changes in jcBNST and CeAm neurons associated with opiate dependence. Ultimately, knowledge of the adaptive and counter-adaptive changes induced by drug dependence in the microcircuit BLA-jcBNST-CeA will allow us to identify therapeutic targets to restore normal neuronal excitability and circuit functioning with adequate inhibitory control over amygdala output.