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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.

尽管焦虑症患者比其他人更容易患上酒精使用障碍（AUD），健康对照组，负责这种高风险的神经基质知之甚少。这些双重诊断也与两种疾病的症状严重程度和治疗效果差有关结果。本项目的中心目标是采用神经生物学和行为学方法在啮齿类动物模型，以确定神经回路适应，发挥因果作用，促进风险增加的发展 AUD和焦虑症。为此，我们建立了一个啮齿动物青少年社会隔离模型， (aSI)这导致了许多与发展AUD和焦虑症的风险更大相关的行为。相对于在整个青春期（aGH）中分组饲养的大鼠，aSI大鼠表现出焦虑样焦虑增加。行为、新奇反应、冲动和攻击性。aSI大鼠也表现出受损的恐惧灭绝和长期增加自愿乙醇饮用。神经生物学研究表明，促进基底外侧杏仁核（BLA）中的多巴胺能投射神经元的兴奋性增加，这是一个与焦虑样和动机性行为不可或缺的大脑区域，接受来自BLA的密集神经支配。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-分布成两个不同的簇。后轴，并在下游大脑区域形成基本上不重叠的回路。前激活 BLA（aBLA）回路促进厌恶/焦虑发生，而后BLA（pBLA）回路的激活兴奋的奖励/抗焦虑行为。基于这些发现，本项目将检验aSI的假设，改变了这些相反的杏仁核回路之间的兴奋/抑制平衡，导致过度的 aBLA通路内的兴奋性，这些适应不良的变化在“成瘾”中起着因果作用。 aSI促进的“脆弱”表型。待研究的次要假设是aSI促进在雄性和雌性大鼠中出现了类似的适应，但出现的行为表型是性的，二形的其他研究也将寻求确定新的药理学方法，以恢复正常的 aBLA/pBLA兴奋性。总的来说，这个项目将提供关键的新的洞察电路基础对AUD和焦虑症的脆弱性，并可能导致识别新的和急需的治疗患有这些经常合并发生的疾病的个体。相关性（参见说明）：这些研究将采用啮齿动物模型，促进“成瘾脆弱”表型，以确定负责这些行为的特定回路神经适应。研究还将寻求确定新的干预措施来扭转这些不适应的变化。总体而言，这些研究将有助于确定具体的与AUD和共病焦虑障碍相关的神经通路，并可能确定新的为患有这些疾病的人提供治疗。

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。