Homeostatic Plasticity in the BNST and Drug Abuse

描述（由申请人提供）：终纹床核（BNST）在协调神经内分泌、自主神经、躯体运动反应和滥用药物的影响中起重要作用。背外侧BNST中的BNST的前囊核（jcBNST）主要从BLA的后部接收密集的GABA能投射，并且反过来，将GABA能投射发送到杏仁核的内侧中央核（CeAm），该内侧中央核是杏仁核的主要输出核。因此，jcBNST神经元的整合特性的变化可能有助于与药物依赖和戒断相关的情绪失调。我们最近描述了一种形式的长期增强的内在兴奋性（LTP-IE）的神经元的jcBNST在刺激终纹，这是受损的长期戒断过程中逐步升级的海洛因，可卡因，酒精自我管理和大鼠长期治疗促肾上腺皮质激素释放因子（CRF）脑室内。这些结果为药物和酒精滥用的脆弱性提供了一种新的神经生物学靶点。特别是，他们提出了这样的假设：jcBNST神经元兴奋性的变化可能会导致CeAm的抑制不足，从而导致后依赖个体长期禁欲的负面情感状态。为了验证这一假设，我们提出：1）使用传统的电生理方法和动态钳相结合的方法来研究与海洛因依赖相关的jcBNST神经元的突触和内在特性的变化，动态钳是一种创新的基于计算机的方法，通过近似完整脑的高电导状态来研究脑切片中神经元的兴奋性;（2）探讨海洛因依赖是否也与CeAm神经元的可塑性改变有关; 3）采用动态钳夹技术研究LTP-IE在BLA-jcBNST-1中的功能意义。CeA回路以及与阿片依赖相关的jcBNST和CeAm神经元的可塑性变化。最终，知识的适应性和反适应性变化引起的药物依赖性的微电路BLA-jcBNST-CeA将使我们能够确定治疗目标，以恢复正常的神经元兴奋性和电路功能与足够的抑制控制杏仁核输出。

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.