Alcohol-induced plasticity within CRF2 microcircuits in distinct amygdala nuclei

描述(由申请人提供)：酒精滥用是美国和世界范围内的一种主要临床疾病。尽管酒精依赖的流行和众所周知的慢性酒精暴露的不良影响，但调节酒精对大脑影响的神经生物学机制仍然不完全清楚。当前和未来研究的挑战是了解神经生物学变化，这些变化影响导致慢性饮酒的动机系统中的耐受性和依赖性。杏仁核是大脑的主要组成部分，参与药物滥用，特别是酒精的激励作用。局部抑制是这一回路的关键元素，也是行为效应的关键组成部分。 急性和慢性酒精消费。许多关于杏仁核回路的研究都集中在恐惧上，并证明了杏仁基底外侧核(BLA)的局部微回路在获得和表达条件性恐惧中起着关键作用(有关综述，请参阅Ehrlich et。Al)。尽管 在恐惧文献中彻底研究这种回路，以及恐惧和酒精依赖之间负相关和习得的行为反应的共同线索，人们对乙醇如何参与和/或改变杏仁核中的特定微回路以产生长期行为影响的了解要少得多。之前在BLA上的研究表明，急性和慢性乙醇改变了兴奋性和抑制性传递，但缺乏研究这些变化如何影响杏仁核回路特定成分的活动。此外，还没有研究使用平行的细胞和整个动物的方法来评估酒精的行为如何整合到整个杏仁核网络功能中。我们小组最近的工作表明，CRF1系统在酒精对中央杏仁核局部回路的影响中发挥了重要作用。这些研究强调了乙醇对CEA内CRF1系统的细胞类型的特异性影响，但CRF1系统如何适应BLA网络仍不清楚。因此，本方案的主要目标是采用细胞电生理、神经解剖学和活体微透析相结合的方法来1)表征BLA两个不同亚区(LA和BM)中的CRF1+和CRF1-神经元，2)在细胞和完整网络水平上检测这些神经元中的时相和紧张性抑制传递以及这种传递对急性乙醇的敏感性，3)确定BLA中CRF1+和CRF1-神经元的局部功能和远程解剖连接，以及4)在细胞和网络水平上确定慢性酒精暴露对这一微电路活动的影响。

DESCRIPTION (provided by applicant): Alcohol abuse represents a major clinical condition in the Unites States and worldwide. Despite the prevalence of alcohol dependence and the well-known adverse effects of chronic alcohol exposure, the neurobiological mechanisms mediating alcohol's effects in the brain are still not fully understood. The challenge of current and future studies is to understand the neurobiological changes that influence tolerance and dependence in motivational systems that lead to chronic drinking. The amygdala is a major component of the brain involved in the motivational effects of drugs of abuse and alcohol in particular. Local inhibition is a key element of this circuitry and a critical component of the behavioral effects of acute and chronic ethanol consumption. Numerous studies on amygdala circuitry have focused on fear and demonstrated a critical role for local microcircuits in the basolateral amygdala (BLA) in the acquisition and expression of conditioned fear (for review, see Ehrlich et. al). Despite the thorough investigation of this circuitry in the fear literature and the common thread of negative association and learned behavioral responses between fear and alcohol dependence, much less is known about how ethanol engages and/or alters specific microcircuits in the amygdala to produce long-lasting behavioral effects. Previous studies in the BLA indicate that acute and chronic ethanol alter excitatory and inhibitory transmission, however studies examining how these changes impact the activity of specific components of amygdala circuitry are lacking. In addition, no studies have employed parallel cellular and whole-animal approaches to assess how the actions of alcohol are integrated into overall amygdala network function. Recent work by our group demonstrated an important role of the CRF1 system in the effects of ethanol on local circuitry in the central amygdala. These studies highlight the cell-type specific effects of ethanol on the CRF1 system within the CeA, however how the CRF1 system fits into the BLA network remains unclear. Thus, the major goals of the current proposal are to employ a combined cellular electrophysiological, neuroanatomical, and in vivo microdialysis approach to 1) characterize CRF1+ and CRF1- neurons in two discrete sub-regions of the BLA, the LA and BM, 2) examine the phasic and tonic inhibitory transmission in these neurons and the sensitivity of that transmission to acute ethanol at both the cellular and intact network level, 3) determine the local functional and long-range anatomical connectivity of CRF1+ and CRF1- neurons in the BLA, and 4) determine the effects of chronic ethanol exposure on the activity of this microcircuitry at a cellular and network level.