Mechanisms underlying the reduction in alcohol intake in response to low intensity targeting of the reward circuit

酒精使用障碍（AUD）仍然是美国（US）的一个主要问题，尽管有各种法律，运动， 和预防性努力。到目前为止，酒精是整个生命周期中最常滥用的药物。根据 根据2015年全国药物使用和健康调查的数据，目前有1.38亿酒精使用者， 在美国，几乎一半的饮酒者报告有饮酒问题（酗酒或大量饮酒），15.7 百万澳元报告。已经确定了许多药物靶点，但治疗效果和 由于成本、负面生理效应和需求等因素，禁欲率仍然很低 长期致力于治疗。因此，需要成瘾治疗的新方向。在一个这样 方向，超声技术的最新进展使非侵入性调制深部脑 例如奖励电路。我们提出了一种新的组合低强度聚焦超声（LIFU） 与光声断层扫描（PAT）定位，以修改活动的两个主要组成部分， 奖赏系统、腹侧被盖区和丘脑核。我们的初步工作表明， 当在任一区域每天给药一次时，该方法降低了酒精摄入和偏好。因此在 在拟议的研究中，我们将研究LIFU减少酒精摄入的机制， 这种治疗对大脑的潜在副作用。我们将首先优化我们的协议， 大脑深处奖赏回路的有效性。接下来，我们将评估与以下方面相关的各种行为： 影响和酒精寻求，以确定LIFU发挥其作用的神经过程。 最后，我们将评估LIFU治疗后大脑中的分子效应，以确定那些 神经元的变化，可以解释行为的转变，并确定是否有任何不利影响， 对慢性LIFU治疗后神经元功能的影响。对于这些研究，我们将使用雄性和雌性杂交 高酒精偏好的小鼠，以确定是否有性别依赖性差异的影响， LIFU对酒精寻求，或LIFU的神经元效应。这些研究将提供必要的基础 使用LIFU降低AUD的知识，并将为广泛的进一步研究打开大门 检查其他物质使用障碍，以及在传统上难以治疗的人群中使用LIFU，例如 青少年，或通常与AUD共病的疾病，如睡眠障碍。

Alcohol use disorder (AUD) remains a major issue in the United States (US) despite the various laws, campaigns, and preventative efforts. Alcohol is by far the most commonly-abused drug across the lifespan. According to 2015 data from The National Survey on Drug Use and Health, there are currently 138 million alcohol users in the US, with almost half of drinkers reporting problem drinking (binge or heavy alcohol consumption), and 15.7 million reporting an AUD. A host of pharmaceutical targets have been identified, but treatment efficacy and abstinence rates both remain low due to factors such as cost, negative physiological effects, and requirements of long-term commitment to treatment. Thus, new directions for addiction treatment are needed. In one such direction, recent advances in ultrasound technology have enabled the non-invasive modulation of deep brain systems such as the reward circuit. We propose a novel combination of low intensity focused ultrasound (LIFU) with photoacoustic tomography (PAT) localization to modify the activity of the two primary components of the reward system, the ventral tegmental area and nucleus accumbens. Our preliminary work has demonstrated that this approach reduces alcohol intake and preference when administered once daily in either region. Thus, in the proposed studies, we will examine the mechanisms by which LIFU reduces alcohol intake, the longevity of this effect, and potential side effects of this treatment on the brain. We will first optimize our protocol for maximum efficacy in the deep brain regions of the reward circuit. Next, we will assess a variety of behaviors related to affect and to alcohol-seeking in order to identify the neurological processes on which LIFU is exerting its effects. Finally, we will assess the molecular effects in the brain following LIFU treatment, in order to identify those neuronal changes that may explain the behavioral shifts, and to determine whether there are any adverse effects on neuronal function following chronic LIFU treatment. For these studies, we will use male and female crossed high-alcohol-preferring mice, in order to identify whether there are sex-dependent differences in the effects of LIFU on alcohol-seeking, or in the neuronal effects of LIFU. These studies will provide an essential foundation of knowledge for the use of LIFU to reduce AUD, and will open the door to a wide spectrum of further studies examining other substance use disorders, and use of LIFU in traditionally difficult to treat populations, such as adolescents, or for disorders commonly comorbid with AUD, such as sleep disorders.