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: 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
• 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

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.

项目摘要/摘要 除了探索高度相关的科学问题外，该K01的目标还扩展到提供 候选人接受指导的培训，以促进她向独立调查员的过渡。这包括 收购了新的，先进的最先进的技术以及与职业发展 为候选人提供多学科工具包的最终目的，以研究酒精使用障碍和 增强的指导/培训技能，将她的专业知识传递给对酒精感兴趣的下一代受训者 研究。在韦纳博士的指导下，候选人将探索后基底外侧的作用 杏仁核（BLA）输入到酒精依赖性雄性的腹侧海马的腹侧下膜（VSUB） 和雌鼠。该项目的具体目的1将重点放在PBLA-VSUB的电路和神经适应上 使用精心验证的慢性间歇性乙醇暴露（CIE）范式的电路。基于初步 发现和越来越多的证据表明PBLA在介导情感行为和酒精中起着核心作用 与饮酒有关的行为，我们提出了一个工作假设，即CIE最初会增加PBLA-VSUB 男性的兴奋性，但对该电路的抑制元素的增强不成比例 最初保护女性免受这种适应不良的变化。但是，我们预测这种保护作用 在更长的CIE暴露后会丢失或克服，从而导致类似的网络兴奋性水平 和两个性别的焦虑行为。这些实验将集中于两个新型的抑制性PBLA-VSUB 我们已经开始表征的预测，包括PBLA的单突触Gabaergic投影 进入VSUB谷氨酸能神经元。实验，使用离体光遗传学和纤维光度法将检查 这些PBLA-VSUB电路中谷氨酸能和Gabaeregic突触的综合功能可塑性。 进一步建立新单突触的BLA内的细胞身份和分布模式 雄性和雌性大鼠的GABA能投射神经元种群，我们将使用鱼rnascope。额外的 然后，化学发生实验将测试是否依赖CIE的PBLA-VSUB适应突触 沟通（低表现力或过度兴奋）在类似焦虑的表型中起因果作用 从CIE撤离期间出现。这些发现将大大提高我们对 导致与戒酒相关的负面情感症状的神经机制 并有可能阐明新的神经底物，以开发更好的饮酒治疗方法 紊乱。