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

项目摘要/摘要 除了探索高度相关的科学问题外，K01的目标扩展到提供 候选人接受了指导培训，以促进她向独立调查员的过渡。这包括 获得新的、先进的技术以及职业发展与 最终目标是为候选人提供一个研究酒精使用障碍的多学科工具包 增强辅导/培训技能，将她的专业知识传授给对酒精感兴趣的下一代学员 研究。在韦纳博士的指导下，候选人将探索后基底外侧区的作用 酒精依赖男性杏仁核(BLA)向腹侧海马腹侧下托(VSub)的传入 和雌性老鼠。本项目的具体目标1将集中在pBLA-vSub的回路和神经适应 使用经过充分验证的慢性间歇性酒精暴露(CIE)范例的电路。基于初步的 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 与饮酒行为相关，我们提出了CIE最初增加pBLA-vSub的工作假设 男性的兴奋性，但这种回路中抑制元件的不成比例的加强 最初保护雌性免受这种不适应变化的影响。然而，我们预测，这种保护作用 在更长时间的CIE暴露后丢失或克服，导致类似水平的网络兴奋性 在两性中都有类似焦虑的行为。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 转移到vSub谷氨酸能神经元。实验，使用体外光遗传学，和纤维光度学将检查 这些pBLA-vSub回路中谷氨酸能突触和GABA能突触的整合功能可塑性。 为了进一步建立一个新的单突触的细胞身份和在BLA中的分布模式 对雄性和雌性大鼠的GABA能投射神经元数量，我们将使用FISH RNAScope。其他内容 化学发生实验将测试CIE依赖的pBLA-vSub突触适应 交流(低兴奋性或高兴奋性)在焦虑样表型中起着因果作用 在退出CIE期间出现。总而言之，这些发现将极大地促进我们对 酒精戒断相关负性情感症状的神经机制 并可能为开发更好的酒精治疗方法提供新的神经基质 无序。

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.