Synaptic Correlates of Vulnerability and Resilience to Alcohol Use Disorder

酒精使用障碍的脆弱性和恢复力的突触相关性

基本信息

批准号：
10617183
负责人：
JEFFREY L WEINER
金额：
$ 34.88万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10617183
关键词：
Adolescence Adolescent Adult Aggressive behavior Alcohol consumption Amygdaloid structure Animal Care and Use Committees Animals Anterior Anti-Anxiety Agents Anxiety Disorders Area Behavior Behavioral Biochemical Brain region Cells Diagnosis Disease Doctor of Medicine Doctor of Philosophy Electrophysiology (science)Equilibrium Evaluation Exhibits Extinction Female Female Adolescents Fright Funding Genetic Glutamates Goals Hippocampus IACUC Impairment Impulsivity Inbred Mouse Individual Instruction Intervention Intervention Studies Male Adolescents Maps Methods Modeling Neural Pathways Neurobiology Neurons Norepinephrine Receptors Nucleus Accumbens Pathway interactions Pharmacological Treatment Pharmacology Pharmacotherapy Phenotype Physiology Play Progress Reports Purinergic P1 Receptors Pyramidal Cells Rattus Research Rewards Risk Rodent Rodent Model Role Severities Social isolation Symptoms Synapses Techniques Testing Treatment outcome Virus addiction alcohol use disorder anxiety-like behavior behavioral phenotyping comorbidity depressive symptoms experimental study genetic approach insight maladaptive behavior male motivated behavior nerve supply neural neural circuit neuroadaptation neurochemistry neurotransmission novel optogenetics pharmacologic resilience sex sexual dimorphism treatment strategy

项目摘要

Although individuals with anxiety disorders are more likely to develop alcohol use disorder (AUD) than healthy controls, the neural substrates responsible for this heightened risk are poorly understood. These dual diagnoses are also associated with greater symptom severity of both disorders and poor treatment outcomes. The central goal of this project is to employ neurobiological and behavioral approaches in rodent models to identify neural circuit adaptations that play a causal role in promoting increased risk of developing AUD and anxiety disorders. To that end, we have established a rodent adolescent social isolation model (aSI) that engenders many behaviors associated with greater risk of developing AUD and anxiety disorders. Relative to rats reared in groups throughout adolescence (aGH), aSI rats exhibit increases in anxiety-like behaviors, novelty responding, impulsivity, and aggression in adulthood. aSI rats also display impaired fear extinction and long-lasting increases in voluntary ethanol drinking. Neurobiological studies revealed that aSI promotes increases in the excitability of glutamatergic projection neurons in the basolateral amygdala (BLA), a brain region integral to anxiety-like and motivated behaviors, as well as increased synaptic activity in areas that receive dense innervation from the BLA. It has also recently been discovered that BLA projection neurons are not homogenous. Rather, these cells are distributed into two distinct clusters along the anterior- posterior axis and form largely non-overlapping circuits in downstream brain regions. Activation of anterior BLA (aBLA) circuits promotes aversion/anxiogenesis whereas activation of posterior BLA (pBLA) circuits elicits rewarding/anxiolytic behaviors. Based on these findings, this project will test the hypothesis that aSI shifts the excitatory/inhibitory balance between these opposing amygdala circuits, leading to excessive excitability within aBLA pathways, and that these maladaptive changes play a causal role in the “addiction vulnerable” phenotypes promoted by aSI. A secondary hypothesis to be investigated is that aSI promotes similar adaptations in male and female rats but that the behavioral phenotypes that emerge are sexually dimorphic. Additional studies will also seek to identify novel pharmacological approaches to restore normal aBLA/pBLA excitability. Collectively, this project will provide critical new insight into the circuitry underlying vulnerability to AUD and anxiety disorders and potentially lead to the identification of novel and much needed treatments for individuals suffering from these frequently co-occurring diseases. RELEVANCE (See instructions): These studies will employ a rodent model that promotes an “addiction vulnerable” phenotype to identify circuit-specific neural adaptations responsible for these behaviors. Studies will also seek to identify novel interventions to reverse these maladaptive changes. Collectively, these studies will help to identify specific neural pathways associated with AUD and comorbid anxiety disorders and potentially identify novel treatments for individuals afflicted with these diseases.

尽管患有焦虑症的人比健康的控制，对这种增加风险的负责的神经底物知之甚少。这些双重诊断也与疾病的症状严重程度更大和治疗不佳有关结果。该项目的核心目标是在啮齿动物中采用神经生物学和行为方法识别神经回路适应的模型，在促进发展风险中起因果关系 aud和焦虑症。为此，我们建立了一个啮齿动物青少年的社会隔离模型（ASI）会导致许多行为与患有AUD和焦虑症的更大风险相关。相对于整个青少年（AGH）饲养的大鼠，ASI大鼠暴露于焦虑状的增加行为，新颖的反应，冲动和成年期。 ASI老鼠还表现出恐惧自愿乙醇饮用的延伸和持久增加。神经生物学研究表明ASI 促进基体杏仁核（BLA）中谷氨酸能投射神经元的兴奋增长大脑区域是焦虑状和成熟行为不可或缺的，以及在区域的突触活动增加从BLA获得密集的神经。最近还发现BLA投影神经元不是同质的。相反，这些细胞沿着前 - 后轴并在下游大脑区域形成很大的非重叠电路。前部的激活 BLA（ABLA）电路促进了厌恶/焦虑生成，而后BLA（PBLA）电路激活引起奖励/抗焦虑行为。基于这些发现，该项目将检验ASI的假设改变这些相反的杏仁核圈之间的兴奋/抑制平衡，导致过多 ABLA途径中的兴奋性，并且这些不良适应性变化在“成瘾 ASI促进的脆弱的”表型。要研究的次要假设是ASI促进男性和雌性大鼠的相似适应双态。其他研究还将寻求确定新型药理方法以恢复正常 ABLA/PBLA兴奋性。总的来说，该项目将为基础电路提供关键的新见解容易患aud和焦虑症的脆弱性，并有可能导致对新颖和急需的识别针对患有这些经常共同出现疾病的人的治疗。相关性（请参阅说明）：这些研究将采用啮齿动物模型，该模型促进“成瘾脆弱”表型来识别电路特异性的中性适应性负责这些行为。研究还将寻求识别新颖干预措施以扭转这些不良适应性变化。总的来说，这些研究将有助于确定具体与AUD和合并焦虑症相关的神经通路，并有可能识别新颖对患有这些疾病的人的治疗。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Optogenetically-induced tonic dopamine release from VTA-nucleus accumbens projections inhibits reward consummatory behaviors.

DOI：
10.1016/j.neuroscience.2016.07.006
发表时间：
2016-10-01
期刊：
Neuroscience
影响因子：
3.3
作者：
Mikhailova MA;Bass CE;Grinevich VP;Chappell AM;Deal AL;Bonin KD;Weiner JL;Gainetdinov RR;Budygin EA
通讯作者：
Budygin EA

Exploring the Neurochemical Basis of Alcohol Addiction-Related Behaviors: Translational Research.

探索酒精成瘾相关行为的神经化学基础：转化研究。