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.

抽象的 酒精使用障碍 (AUD) 是一种酒精改变广泛神经回路导致的疾病 跨多个行为领域的适应不良行为。尽管这种疾病很普遍且代价高昂， 治疗策略无效，尤其是在预防复发方面。某些人的一个关键特征是 停止饮酒时诱发负面情感状态。在这些人中，饮酒 假设寻求是由负强化所激发的，个体继续 饮酒以避免因禁欲而引发的负面内部状态。虽然过去的研究已经 关注于禁欲如何产生消极情感状态，问题仍然是情感如何产生 干扰会激发行为（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与酒精有关 驱动寻找酒精的相关线索。强化的中心是伏隔核（NAc）。这 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（MSN）在控制动机行为中发挥补充作用4。尽管 之前的工作表明 D1 MSN 具有积极强化作用，我们的数据显示 D2 MSN 对 发出负面强化信号并因果控制避免厌恶刺激的动机的线索。 我们假设戒断慢性酒精后，D2 MSN 会受到酒精相关线索的影响。 间歇性乙醇暴露（CIE；通过蒸气吸入实现），并促使人们寻求酒精。 为了解决这些问题，将使用各种尖端光学方法来记录和记录 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， 将其与 CIE 接触后寻求酒精联系起来。我们将确定 D2 的开发如何应对 与酒精相关的线索是由从 CIE 退出后产生的负面情感状态预测的。 最后，使用膜片钳电生理学和通道视紫红质辅助电路映射，我们将 1) 定义 CIE 如何将谷氨酸驱动改变到由负强化专门激活的 D2 MSN 上 （来自前额皮质、丘脑和基底外侧杏仁核）和 2）使用严重限制的药物 体内束缚（DARTS），以防止通过 NAc 细胞上的 AMPA 受体选择性地进行谷氨酸驱动 被负强化激活并防止酗酒。我们将共同定义这个关键单元如何 控制负强化的人群会驱动对酒精的追求。这种理解将会 对于我们对 AUD 的概念化以及为什么人们在戒断后喝酒至关重要。