Circuit control of motivation to take and seek alcohol

摘要 酒精使用障碍(AUD)是一种酒精改变多种神经回路引起的障碍 跨多个行为领域的不适应行为。尽管这种疾病很普遍，成本也很高， 治疗策略无效，尤其是在防止复发方面。某些个体的一个关键特征是 停止饮酒时产生的消极情绪状态。在这些人中，饮酒 而寻求被假设为受到负面强化的激励，在这种情况下，个体继续 饮酒以避免由禁欲引发的消极的内心状态。虽然过去的研究表明 集中在禁欲如何产生负面情感状态上，问题仍然是有多大的情感 干扰会激发行为(即消极强化)。为此，这项提案的目标是 了解控制避免厌恶刺激的动机的回路是如何被酒精和 驱使饮酒的相关线索。位于强化中心的是伏隔核(NAC)。这个 NAC是一个异质性区域，主要由两种不重叠的细胞类型组成：D_1和D_2 棘突投射神经元(MSN)在控制动机行为方面发挥互补作用4。而当 以前的工作已经发现D1MSN参与了阳性强化，我们的数据显示D2MSN对 暗示负面强化的暗示和因果关系控制着避免厌恶刺激的动机。 我们假设D2 MSN在慢性戒断后受到酒精相关线索的影响 间歇性酒精暴露(CIE；通过蒸汽吸入实现)，并驱使寻找酒精。 为了解决这些问题，将使用各种尖端光学方法来记录来自和 操纵这些细胞来定义它们对与酒精相关的线索和 将此与接触CIE后的酗酒行为联系起来。我们将确定D2的发展如何对 酒精相关的线索是通过退出CIE后发展起来的负面情绪状态来预测的。 最后，使用膜片钳电生理学和通道视紫红质辅助的电路映射，我们将1)定义 CIE如何改变负性强化特异性激活的D2MSN上的谷氨酸能驱动 (来自前额叶皮质、丘脑和基底外侧杏仁核)和2)使用受到严重限制的药物 体内拴系(DART)通过NAC细胞上的AMPA受体选择性地阻止谷氨酸能驱动 通过负性强化激活，防止酗酒。我们将共同定义这个关键细胞如何 控制负强化的人群会驱动过度的酒精寻求。这一谅解将是 对于我们对澳元的概念化，以及为什么人们在戒酒后饮酒至关重要。

ABSTRACT Alcohol Use disorder (AUD) is a disorder in which alcohol alters a wide range of neural circuits to cause maladaptive behaviors across several behavioral domains. Despite the prevalence and cost of this disorder, treatment strategies are ineffective, especially in preventing relapse. A key feature in some individuals is the induction of negative affective states when alcohol consumption is ceased. In these individuals, alcohol taking and seeking is hypothesized to be motivated by negative reinforcement, where individuals continue consuming alcohol to avoid negative internal states that are triggered by abstinence. While past research has focused on how abstinence produces negative affective states, the question remains as to how affective disturbances motivate behavior (i.e. negative reinforcement). To this end, the goal of this proposal to understand how circuits that control the motivation to avoid aversive stimuli are engaged by alcohol and associated cues to drive alcohol seeking. At the center of reinforcement is the nucleus accumbens (NAc). The NAc is a heterogeneous region primarily composed of two non-overlapping cell types: D1 and D2 medium spiny projection neurons (MSNs) which play complementary roles in controlling motivated behaviors4. While previous work has implicated D1 MSNs in positive reinforcement, our data show that D2 MSNs respond to cues that signal negative reinforcement and causally control the motivation to avoid aversive stimuli. We hypothesize that D2 MSNs are engaged by alcohol-associated cues following withdrawal from chronic intermittent ethanol exposure (CIE; achieved via vapor inhalation), and drive alcohol seeking. To address these questions, will use a variety of cutting-edge optical approaches to record from and manipulate these cells to define the temporal patterns by which they respond to alcohol associated cues and link this to alcohol seeking following CIE exposure. We will determine how the development of D2 responses to alcohol-associated cues is predicted by the negative affective states that develop over withdrawal from CIE. Finally, using patch clamp electrophysiology with channelrhodopsin assisted circuit mapping we will 1) define how CIE changes glutamatergic drive onto D2 MSNs that are specifically activated by negative reinforcement (from the prefrontal cortex, thalamus, and basolateral amygdala) and 2) use drugs acutely restricted by tethering (DARTS) in vivo to prevent glutamatergic drive selectively through AMPA receptors on NAc cells activated by negative reinforcement and prevent alcohol seeking. Together, we will define how this critical cell population that controls negative reinforcement drives operant alcohol seeking. This understanding will be critical to our conceptualization of AUD and why individuals drink following withdrawal.