Basolateral amygdala to ventral subiculum network plasticity in alcohol dependent male and female rats

酒精依赖的雄性和雌性大鼠的基底外侧杏仁核到腹侧下托网络的可塑性

基本信息

批准号：
10596654
负责人：
Eva Claudia Bach
金额：
$ 14.26万
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：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10596654
关键词：
Abstinence Affect Affective Alcohol consumption Alcohol dependence Alcohol withdrawal syndrome Amygdaloid structure Anti-Anxiety Agents Anxiety Automobile Driving Behavior Biological Assay Chronic Communication Data Desire for food Development Electrophysiology (science)Elements Equilibrium Experimental Genetics Exposure to Female Fiber Genetic study Glutamates Goals Hippocampus Human Individual Knowledge Measures Mediating Mentors Mentorship Modeling Neurons Optics Pathway interactions Pattern Phenotype Photometry Play Population Proxy Pyramidal Cells Rattus Relapse Research Personnel Rodent Rodent Model Role Signal Transduction Societies Symptoms Synapses Techniques Testing Time Tracer Training United States Withdrawal alcohol abuse therapy alcohol exposure alcohol research alcohol use disorder anxiety-like behavior associated symptom career development effective therapy experience experimental study functional plasticity genetic approach hippocampal pyramidal neuron interest male multidisciplinary negative affect neural neuroadaptation neuromechanism neuronal circuitry neuronal excitability neurotransmission next generation novel optogenetics protective effect response sex sexual dimorphism skills training

项目摘要

Project Summary/Abstract Aside from exploring highly relevant scientific questions, the goal of this K01 extends to providing the candidate with mentored training to facilitate her transition to an independent investigator. This encompasses the acquisition of new, sophisticated state-of-the-art techniques as well as career development with the ultimate aim of providing the candidate with a multidisciplinary toolkit to study alcohol use disorder and enhanced mentoring/training skills to relay her expertise to the next generation of mentees interested in alcohol research. Under the mentorship of Dr. Weiner, the candidate will explore the role of posterior basolateral amygdala (BLA) inputs to the ventral subiculum (vSub) of the ventral hippocampus in alcohol dependent male and female rats. Specific Aim 1 of this project will focus on the circuitry and neuroadaptations of pBLA-vSub circuits using the well-validated chronic intermittent ethanol exposure (CIE) paradigm. Based on preliminary findings and growing evidence that the pBLA plays a central role in mediating affective behavior and alcohol drinking-related behaviors, we advance the working hypothesis that CIE initially increases pBLA-vSub excitability in males but that a disproportionate strengthening of inhibitory elements of this circuitry initially protects females from this maladaptive change. However, we predict that this protective effect is either lost or overcome after a longer CIE exposure, leading to similar levels of network excitability and anxiety-like behavior in both sexes. These experiments will focus on two novel inhibitory pBLA-vSub projections that we have begun to characterize, including a monosynaptic GABAergic projection from the pBLA onto vSub glutamatergic neurons. Experiments, using ex vivo optogenetics, and fiber photometry will examine the integrated functional plasticity of glutamatergic and GABAeregic synapses within these pBLA-vSub circuits. To further establish the cellular identity and distribution pattern within the BLA of a novel monosynaptic GABAergic projection neuron population of male and female rats, we will use FISH RNAScope. Additional chemogenetic experiments will then test whether CIE-dependent pBLA-vSub adaptations of synaptic communication (hypoexcitability or hyperexcitability) play a causal role in the anxiety-like phenotypes that emerge during withdrawal from CIE. Together, these findings will significantly advance our understanding of the neural mechanisms responsible for the negative affective symptoms associated with alcohol withdrawal and potentially shed light on novel neural substrates for the development of better treatments for alcohol use disorder.

项目概要/摘要除了探索高度相关的科学问题之外，K01 的目标还包括提供接受过指导培训的候选人，以促进她过渡为独立调查员。这包括获得新的、先进的、最先进的技术以及职业发展最终目标是为候选人提供一个多学科工具包来研究酒精使用障碍和增强指导/培训技能，将她的专业知识传授给对酒精感兴趣的下一代受训者研究。在Weiner博士的指导下，候选人将探索后基底外侧的作用酒精依赖男性的腹侧海马腹侧下托（vSub）的杏仁核（BLA）输入和雌性老鼠。该项目的具体目标 1 将重点关注 pBLA-vSub 的电路和神经适应使用经过充分验证的慢性间歇性乙醇暴露（CIE）范例的电路。根据初步研究结果和越来越多的证据表明 pBLA 在调节情感行为和酒精方面发挥着核心作用与饮酒相关的行为，我们提出了 CIE 最初增加 pBLA-vSub 的工作假设男性的兴奋性，但该电路的抑制元件的不成比例的加强最初保护女性免受这种适应不良的变化。然而，我们预测这种保护作用在较长时间的 CIE 暴露后，要么丢失，要么克服，导致类似水平的网络兴奋性以及两性的类似焦虑的行为。这些实验将集中于两种新型抑制性 pBLA-vSub 我们已经开始表征的投射，包括 pBLA 的单突触 GABA 能投射到 vSub 谷氨酸能神经元上。使用离体光遗传学和光纤光度测定法的实验将检查这些 pBLA-vSub 电路中谷氨酸能和 GABA 能突触的综合功能可塑性。进一步确定新型单突触 BLA 内的细胞身份和分布模式雄性和雌性大鼠的 GABA 能投影神经元群体，我们将使用 FISH RNAScope。额外的然后化学遗传学实验将测试突触的 CIE 依赖性 pBLA-vSub 适应是否沟通（兴奋性低下或兴奋性过度）在焦虑样表型中起着因果作用，从 CIE 退学期间出现。总之，这些发现将极大地增进我们对与酒精戒断相关的负面情感症状的神经机制并有可能揭示新型神经基质，以开发更好的酒精使用治疗方法紊乱。