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Circuit control of motivation to take and seek alcohol

饮酒和寻求酒精动机的电路控制

基本信息

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
项目类别：
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

项目摘要

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.

摘要