Dissecting the contributions of the basolateral amygdala - nucleus accumbens circuit in the addiction-vulnerable phenotype engendered by chronic early life stress

剖析基底外侧杏仁核 - 伏隔核回路在慢性早期生活压力引起的成瘾易感表型中的贡献

• 批准号: 9327188
• 负责人: Sarah Ewin
• 金额: $ 4.4万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9327188
• 关键词: Adolescence; Adolescent; Adult; Alcohol consumption; Alcohol dependence; Alcoholism; Amygdaloid structure; Animal Model; Anxiety; Anxiety Disorders; Appearance; Behavior; Behavioral; Brain; Brain region; Catecholamines; Chronic; Communication; Development; Electrophysiology (science); Elements; Ethanol; Exhibits; Glutamates; Goals; Hippocampus (Brain); Investigation; Lead; Life; Life Stress; Light; Link; Long-Term Depression; Measures; Mental disorders; Modeling; Motivation; N-Methylaspartate; Neurobiology; Neurons; Nucleus Accumbens; Output; Pharmaceutical Preparations; Phenotype; Physiologic pulse; Play; Positioning Attribute; Prefrontal Cortex; Psychological reinforcement; Psychopathology; Rattus; Risk; Risk Factors; Rodent; Role; Self Administration; Signal Transduction; Slice; Social isolation; Synapses; Synaptic Transmission; Synaptic plasticity; Techniques; Testing; Time; Work; addiction; alcohol misuse; alcohol risk; alcohol use disorder; anxiety-like behavior; critical period; drinking; drinking behavior; effective therapy; emotional behavior; experimental study; in vivo; interest; motivated behavior; multidisciplinary; neural circuit; novel; optogenetics; patch clamp; preference; response; stressor; synaptic function; tool; transmission process

PROJECT SUMMARY Much work has been done examining the critical role of chronic early life stress (e.g. adolescent social isolation) on psychiatric disorders and addiction in adulthood. Our lab has developed a model of adolescent social isolation (aSI) which engenders robust increases in a wide range of behaviors that have been linked with increased vulnerability to alcohol addiction, including increases in anxiety-like behaviors and ethanol intake and preference. We have shown that aSI also results in a hyper-excitable basolateral amygdala (BLA), a brain region heavily implicated in anxiety and motivated behaviors. Investigation by other groups suggests that the BLA and nucleus accumbens (NAc) are critical components of a network that regulates reinforcement and reinstatement of drug seeking and drug taking. In fact, modulation of BLA-NAc synapses has recently been shown to bi-directionally regulate motivated behaviors. Moreover, we have shown that the NAc, following aSI, shows disruption in catecholamine signaling. Thus, this proposal, for the first time, will examine the BLA projection to the nucleus accumbens (NAc), in a model of chronic early life stress. Our central hypothesis is that chronic early life stress leads to increased excitability in the BLA-NAc circuit and that this adaptation contributes to the “addiction vulnerable” phenotype engendered by this model. In Aim 1, we will employ electrophysiological and optogenetic techniques to test the hypothesis that aSI strengthens BLA- NAc glutamatergic synaptic function and disrupts addiction-related plasticity. In Aim 2, we will test the hypothesis that aSI disruption of BLA-NAc glutamatergic synapses contributes to the escalation in ethanol intake observed following this chronic early life stressor. We will use chemogenetics to manipulate this circuit, as well as an operant ethanol self-administration task. Collectively, these studies may shed new light on the specific neural circuits through which early life stress heightens risk of alcohol misuse in life and potentially identify novel targets for the development of more effective therapies for alcohol use disorder.

项目总结