Electrophysiological ensembles organization during alcohol cue-induced intake and

描述(申请人提供)：环境刺激，如味道，气味和视觉，最喜欢的酒精饮料可以成为突出的线索，增加对酒精的渴望，并导致个人继续饮酒到醉酒的程度(或更远)。在长期戒酒的人中，同样的线索也会导致渴望和复发。由于持续过量饮酒和戒酒后复发都是酒精中毒的特征，了解调节线索诱发的酒精寻求的大脑区域和过程对于制定有效的治疗策略至关重要。 这些酗酒的人。有趣的是，大脑中被称为前额叶皮质(PFC)的区域内的神经活动现在被认为是调节酒精相关线索如何引发渴望、酒精寻求和摄取的关键因素。然而，调节持续过量饮酒和/或渴望和复发的神经活动的确切变化却知之甚少。对于有酗酒遗传风险的人群如何在PFC中表现出异常的神经处理机制，使他们更容易受到与线索相关的渴望的影响，我们也只有非常有限的了解。我们假设，PFC中的神经网络在易受伤害的人群中受到酒精配对线索的影响将比非易受伤害的人群更强烈。我们还假设，在戒酒期间，在遗传脆弱的人群中，PFC神经元网络对重新定位更具抵抗力。这些异常的神经网络过程可能会加剧暗示诱发的渴望，并促使持续过量饮酒，以及在戒酒后复发。我们广泛的、长期的目标是全面了解PFC内的神经元网络(集合)是如何被酒精相关的线索改变的。我们将通过使用最先进的电生理记录和分析清醒行为啮齿动物的大量细胞群的技术来实现这一点，以首次确定酒精配对线索如何引起PFC整体活动的瞬时变化：1)有助于维持酗酒并在灭绝期间被修改，以及2)启动复发样行为。我们将在遗传倾向于过度饮酒的大鼠群体(印第安纳州偏爱酒精的P大鼠)和平均遗传易感性过度饮酒的大鼠群体(Wistar大鼠)中评估这些影响。确定过度饮酒的神经生物学/神经生理学原因和后果，以及遗传易感性对过度饮酒的作用，直接关系到NIAAA的任务。具体地说，拟议的研究将揭示为什么遗传脆弱的人群对酒精的反应不同的神经生物学根源，以及与酒精配对的线索。这将使我们更好地了解酒精为什么以及如何会导致成瘾，并将帮助我们制定预防和治疗过度饮酒的策略。

DESCRIPTION (provided by applicant): Environmental stimuli such as the taste, smell, and sight, of a favorite alcoholic drink can become salient cues that increase craving for alcohol and lead individuals to continue to drink to the point of intoxication (or well beyond). These same cues can also cause craving and relapse in individuals who have abstained from alcohol for long periods of time. Because continued excessive alcohol intake and relapse following abstinence are both hallmarks of alcoholism, understanding the brain regions and processes that regulate cue-evoked alcohol seeking are critical to develop effective treatment strategies for these alcoholic individuals. Interestingly, neural activity within an area of the brain known as th prefrontal cortex (PFC) is now known to be critically involved in regulating how alcohol associated cues elicit craving, alcohol seeking, and intake. However, the exact changes in neural activity that mediate continued excessive alcohol intake and/or craving and relapse are poorly understood. We also have only a very limited understanding of how populations with genetic risk for developing alcoholism might exhibit abnormal neural processing regimes in the PFC, which make them more vulnerable to cue-related craving. We hypothesize that neural networks in the PFC will be more robustly effected by alcohol-paired cues in vulnerable populations than non-vulnerable. We also hypothesize that PFC neuronal networks are more resistant to re-mapping in genetically vulnerable populations during periods of abstinence from alcohol. These abnormal neuronal network processes might contribute to heightened cue-evoked craving and drive both continued excessive alcohol intake, as well as relapse following periods of abstinence. Our broad, long-term objective is to develop a comprehensive understanding of how neuronal networks (ensembles) within the PFC are altered by alcohol associated cues. We will accomplish this by using state-of-the-art electrophysiological recording and analysis techniques of large populations of cells in the awake behaving rodent to determine, for the first time, how instantaneous shifts in PFC ensemble activity evoked by alcohol paired cues: 1) contribute to the maintenance of binge- drinking and are modified during extinction, and 2) initiate relapse-like behavior. We will evaluate these effects in a rat population genetically predisposed to excessive alcohol consumption (Indiana alcohol preferring P rats) and in a rat population with average genetic susceptibility to excessive alcohol consumption (Wistar rats). Determining the neurobiological/neurophysiological causes and consequences of excessive alcohol consumption as well as the role of genetic vulnerability to excessive alcohol intake are directly relevant to the mission of the NIAAA. Specifically, the proposed studies will reveal the neurobiological origins of why genetically vulnerable populations respond to alcohol, and alcohol-paired cues, differently. This will lead us to a better understanding of why and how alcohol can cause addiction and will help us develop strategies to prevent and treat excessive drinking.