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

• 批准号: 10429022
• 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
• 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/10429022
• 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; Exposure to; Female; Fiber; Glutamates; Goals; Hippocampus (Brain); Human; Individual; Knowledge; Lead; Light; 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; base; career development; effective therapy; experience; experimental study; functional plasticity; hippocampal pyramidal neuron; interest; male; multidisciplinary; negative affect; neuroadaptation; neuromechanism; neuronal circuitry; neuronal excitability; neurotransmission; next generation; novel; optogenetics; protective effect; relating to nervous system; response; sex; sexual dimorphism; skills training

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.

项目总结/摘要 除了探索高度相关的科学问题外，K 01的目标还扩展到提供 候选人接受过辅导培训，以协助她过渡到独立调查员。这包括 获得新的，复杂的国家的最先进的技术，以及职业发展与 最终目的是为候选人提供一个多学科的工具包，以研究酒精使用障碍， 增强指导/培训技能，将其专业知识传授给对酒精感兴趣的下一代学员 research.在韦纳博士的指导下，候选人将探索后基底外侧的作用。 酒精依赖男性杏仁核（BLA）对腹侧海马腹侧下托（vSub）的输入 雌性老鼠本项目的具体目标1将侧重于pBLA-vSub的电路和神经适应性 使用经过充分验证的慢性间歇性乙醇暴露（CIE）范例。根据初步 越来越多的证据表明，pBLA在调节情感行为和酒精方面起着核心作用 饮酒相关的行为，我们提出的工作假设，CIE最初增加pBLA-vSub 兴奋性在男性，但不成比例的加强抑制元素，这一电路 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， 和焦虑样行为。这些实验将集中在两个新的抑制性pBLA-vSub 我们已经开始描述的投射，包括来自pBLA的单突触GABA能投射 到vSub神经元上。实验，使用离体光遗传学，和纤维光度学将检查 这些pBLA-vSub回路内的突触和GABA能突触的整合功能可塑性。 为了进一步确定一种新的单突触的BLA内的细胞特性和分布模式， GABA能投射神经元群体的雄性和雌性大鼠，我们将使用FISH RNAScope。额外 然后，化学发生实验将测试突触的CIE依赖性pBLA-vSub适应是否 交流（低兴奋性或高兴奋性）在焦虑样表型中起因果作用， 在退出CIE期间出现。总之，这些发现将大大促进我们对 负责与酒精戒断相关的负性情感症状的神经机制 并可能揭示新的神经基质，以开发更好的治疗酒精使用 disorder.