Circuit control of motivation to take and seek alcohol

饮酒和寻求酒精动机的电路控制

• 批准号: 10753712
• 负责人: Erin Calipari
• 金额: $ 59.09万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-10 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753712
• 关键词: AMPA Receptors; Abstinence; Acute; Address; Affective; Alcohol consumption; Alcohol withdrawal syndrome; Alcohols; Amygdaloid structure; Animals; Aversive Stimulus; Behavior; Behavioral; Brain; Brain region; Cells; Chronic; Consumption; Cues; Data; Development; Disease; Drug usage; Electrophysiology (science); Endoscopy; Glutamates; Goals; Individual; Inhalation; Learning; Link; Maps; Marble; Measures; Modeling; Motivation; Mus; Negative Reinforcements; Neurons; Nucleus Accumbens; Optics; Pattern; Physiological; Play; Population; Population Control; Positive Reinforcements; Prefrontal Cortex; Prevalence; Psychological reinforcement; Recording of previous events; Research; Resolution; Role; Self Administration; Signal Transduction; Slice; System; Thalamic structure; Withdrawal; Withdrawal Symptom; Work; affective disturbance; alcohol cue; alcohol exposure; alcohol measurement; alcohol prevention; alcohol reinforcement; alcohol response; alcohol seeking behavior; alcohol use disorder; awake; cell type; cost; drinking; feeding; in vivo; maladaptive behavior; mind control; motivated behavior; negative affect; neural; neural circuit; optogenetics; patch clamp; prevent; reinforcer; relapse prevention; treatment strategy; vapor

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.

摘要 酒精使用障碍（AUD）是一种酒精改变广泛神经回路的疾病， 多个行为领域的适应不良行为。尽管这种疾病的流行和成本， 治疗策略无效，特别是在预防复发方面。一些个体的一个关键特征是 当停止饮酒时，诱发消极的情感状态。在这些人中， 而寻求被假设为负强化的动机，在那里，个人继续 饮酒以避免由禁欲引发的负面内部状态。虽然过去的研究 专注于禁欲如何产生消极的情感状态，问题仍然是情感如何影响 干扰激发行为（即负强化）。为此，本提案的目标是 了解控制避免厌恶刺激的动机的回路如何被酒精所吸引， 相关线索来驱动酒精寻求。强化的中心是延髓核（NAc）。的 NAc是一个异质区域，主要由两种不重叠的细胞类型组成：D1和D2培养基 多刺投射神经元（MSNs）在控制动机行为方面发挥补充作用4。而 以前的工作已经暗示了D1 MSN在正强化中，我们的数据显示，D2 MSN响应于 暗示信号负强化和因果控制的动机，以避免厌恶刺激。 我们假设，D2 MSN在从慢性抑郁症中戒断后被酒精相关线索所吸引。 间歇性乙醇暴露（CIE;通过蒸汽吸入实现）和驾驶酒精寻求。 为了解决这些问题，将使用各种尖端的光学方法来记录从和 操纵这些细胞来定义它们对酒精相关线索做出反应的时间模式， 将此与CIE暴露后的酒精寻求联系起来。我们将确定D2的发展如何响应于 酒精相关的线索是预测的负面情感状态，发展超过退出CIE。 最后，使用膜片钳电生理学与通道视紫红质辅助电路映射，我们将1）定义 CIE如何改变D2 MSNs上由负强化特异性激活的神经元驱动力 (from前额叶皮层、丘脑和基底外侧杏仁核）和2）使用药物， 通过NAc细胞上的AMPA受体选择性地阻止多巴胺能驱动 被负强化激活，阻止酒精寻求。我们将一起定义这个关键细胞 控制负强化的人群驱动操作性酒精寻求。这种理解将是 这对我们对AUD的概念化以及为什么个体在戒断后饮酒至关重要。