PROJECT 3: Neurobiological basis of negative-reinforcement drinking in female and male mice

项目 3：雌性和雄性小鼠负强化饮酒的神经生物学基础

基本信息

批准号：
10357884
负责人：
Marina R Picciotto
金额：
$ 33.76万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-10 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10357884
关键词：
Acute Affect Agonist Alcohol abuse Alcohol consumption Alcohols Amygdaloid structure Animal Model Anti-Anxiety Agents Antidepressive Agents Anxiety Area Behavior Behavioral Brain Brain Stem Cell physiology Chronic Consumption Data Dependence Development Enzymes Equilibrium Ethanol Ethanol Metabolism Female GABA Agents GABA-A Receptor Grant Guanfacine Hippocampus (Brain)Human Hyperactivity Inflammation Intervention Knock-out Maintenance Measures Mediating Metabolism Microglia Modeling Molecular Molecular Genetics Mus Negative Reinforcements Neurobiology Neuroimmune Neuromodulator Neurons Neurotransmitters Norepinephrine Norepinephrine Receptors Pathway interactions Pharmaceutical Preparations Pharmacology Pilot Projects Predisposition Prefrontal Cortex Public Health Publishing Relapse Rodent Role Sex Differences Side Signal Pathway Signal Transduction Stress Structure Synapses System Therapeutic Time Translating Woman addiction alcohol abuse therapy alcohol behavior alcohol effect alcohol exposure alcohol relapse alcohol use disorder allostasis anxiety-related behavior base biological adaptation to stress brain metabolism catalase cell injury chronic alcohol ingestion density depressive symptoms drinking endophenotype experience gamma-Aminobutyric Acid hypothalamic-pituitary-adrenal axis male men negative affect nerve injury neuroadaptation neurobiological mechanism neurochemistry neuroinflammation neuronal patterning noradrenergic novel postsynaptic preclinical study preference receptor relating to nervous system response restraint stress sex sexual dimorphism stress reactivity synaptic pruning varenicline

项目摘要

The role of Project 3 is to identify and translate the neurobiological mechanisms underlying the ‘dark side of addiction’ studied across Projects 1 and 2. Women have higher stress reactivity and higher rates of depressive symptoms than men that may underlie their increased likelihood of chronic drinking. Since women are particularly sensitive to effects of stress on negative reinforcement drinking (NRD, see Overall Section), a primary aim of Project 3 is to identify mechanisms related to NRD and related treatments. The amygdala is a sexually-dimorphic structure essential for stress reactivity, and both norepinephrine (NE) and GABA signaling are critical for stress-induced behaviors. Based on the established role of GABA and NE in response to both stress and alcohol use, we hypothesize that the increased susceptibility to chronic alcohol use and relapse in women is partly due to sex differences in GABA-NE balance in subregions of the amygdala. We have shown that guanfacine, a NE agonist at α2A receptors, decreases activity of amygdala neurons and induces anxiolytic and antidepressant-like effects, with sex-dependent patterns of neuronal activation. We therefore hypothesize that targeting pre- and postsynaptic NE receptors or activating GABA neurons will counteract NRD, and could have synergistic effects on amygdala neuronal activity and behaviors induced by stress. We further hypothesize that these neuronal mechanisms interact with neuroinflammatory pathways, such as microglial activation, to modify synaptic structure in the brain area, and that targeting these neuroadaptations could alter NRD in a sex-dependent manner. Finally, we know that alcohol metabolism differs in men and women, and have identified a greater effect of decreased brain metabolism of ethanol in female compared to male mice. In Project 3, we will 1) determine whether targeting noradrenergic receptors decrease overall ethanol intake, as well as NRD in female and male mice, 2) determine whether NE manipulations and GABA neuron activity in the amygdala have synergistic effects on NRD in female and male mice using molecular genetics to target specific GABAergic circuit mechanisms, 3) determine the effects of noradrenergic receptors and GABA neuron activity on ethanol-induced microglia alteration and synaptic density in female and male mice, and 4) identify interactions between brain alcohol metabolism and these signaling pathways in NRD. These studies will provide mechanistic data relevant for studies in Projects 1 and 2 to identify brain mechanisms that may modulate stress-related alcohol use in a sex-dependent manner, and to determine how this contributes to sex differences in alcohol-related behaviors.

项目 3 的作用是识别并转化“阴暗面”背后的神经生物学机制项目 1 和项目 2 中研究的成瘾率。女性有更高的压力反应性和更高的成瘾率与男性相比，抑郁症状可能是女性长期饮酒可能性增加的原因。对压力对负强化饮酒的影响特别敏感（NRD，参见总体部分），项目 3 的主要目的是确定与 NRD 和相关治疗相关的机制。对应激反应以及去甲肾上腺素 (NE) 和 GABA 信号传导至关重要的性二态结构根据 GABA 和 NE 在应激反应中的既定作用，它们对于应激诱发的行为至关重要。压力和饮酒，我们勇敢地面对慢性饮酒和复发的易感性增加我们已经证明，女性的性别差异部分是由于杏仁核亚区域 GABA-NE 平衡的性别差异造成的。胍法辛是 α2A 受体的 NE 激动剂，可降低杏仁核神经元的活性并诱导抗焦虑和抗抑郁样作用，具有性别依赖性的神经激活模式。靶向突触前和突触后 NE 受体或激活 GABA 神经元会抵消 NRD，并且可能对杏仁核神经活动和压力引起的行为产生协同作用。此外，这些神经机制与神经炎症途径相互作用，例如小胶质细胞激活，改变大脑区域的突触结构，并针对这些神经适应最后，我们知道男性和女性的酒精代谢有所不同。女性，并且已经发现，与女性相比，女性脑部乙醇代谢下降的影响更大在项目 3 中，我们将 1) 确定针对去甲肾上腺素受体的靶向作用是否总体下降。乙醇摄入量以及雌性和雄性小鼠的 NRD，2) 确定 NE 操作和 GABA 是否分子生物学研究表明，杏仁核中的神经元活动对雌性和雄性小鼠的 NRD 具有协同作用遗传学针对特定的 GABA 能回路机制，3) 确定去甲肾上腺素能受体的作用和 GABA 神经元活性对乙醇诱导的女性和男性小胶质细胞改变和突触密度的影响小鼠，4) 确定脑酒精代谢与 NRD 中这些信号通路之间的相互作用。这些研究将为项目 1 和 2 的研究提供相关的机制数据，以识别大脑可能以性别依赖性方式调节与压力相关的酒精使用的机制，并确定如何这导致了酒精相关行为的性别差异。