Determining the role of amygdalostriatal transition zone circuits in associative learning and motivated behaviors

项目总结/摘要 大脑能够在刺激和它们所预测的奖励或惩罚之间形成习得的联系， 然后引导适当的行为反应以最大化生存。然而，对 环境刺激在神经系统疾病如焦虑、抑郁和产后抑郁中严重改变， 创伤应激障碍，导致破坏性的行为结果。了解神经回路， 因此，中介学习的联想和动机行为是至关重要的，无论是从基本的 科学和人类健康的观点。杏仁核纹状体过渡区（ASt）具有回路连通性 这表明在这些过程中的作用，但该区域的功能几乎完全未知。的 这一提议的中心假设是，ASt作为杏仁核的平行回路， 联想学习和行为反应。在指导阶段（K99）实验中， 光遗传学，体内电生理学和先进的计算分析将用于识别 编码刺激信息和特定行为的ASt神经元亚群。的 独立相（R 00）实验将确定来自丘脑、皮层和 侧杏仁核到ASt活动编码线索信息，并确定是否从这些突触 ASt神经元的投射在联想学习中得到加强。这项研究的初步数据显示， 1)遗传上不同的ASt神经元群体对预测奖励的线索有相反的反应， 惩罚，和2）这些群体之一的光遗传学抑制导致显著减少， 条件性恐惧反应这表明ASt可能确实在行为反应中起着关键作用 传统上被认为是杏仁核。因此，这一建议的成功结果可能导致重大的 对当前的关联学习电路机制模型进行了概念上的修正。这项研究将 也提供了新的见解，长期以来的开放问题，如何显着的行为反应， 即使在针对杏仁核的双侧功能丧失操纵之后，条件刺激仍然持续。 这不仅将增加我们对动机行为背后的电路的基本知识，而且可以 还确定ASt电路作为神经系统疾病的重要新目标，其中正常行为 对刺激的反应被破坏。所有提议的研究将由Fergil米尔斯博士在Kay博士的实验室进行 索尔克生物研究所的Tye说，该研究所为拟议的实验配备了齐全的设备。的 建议书还包括一个全面的培训计划，以促进米尔斯博士的职业发展，并将 准备他直接作为一个独立的研究员研究神经回路创新的研究计划 正常和病理行为的潜在机制。

PROJECT SUMMARY/ABSTRACT The brain is able to form learned associations between stimuli and the rewards or punishments they predict, which then guide appropriate behavioral responses to maximize survival. However, responses to environmental stimuli are severely altered in neurological disorders such as anxiety, depression, and post- traumatic stress disorder, leading to damaging behavioral outcomes. Understanding the neural circuits which mediate learned associations and motivated behavior is therefore of crucial importance both from a basic science and human health perspective. The amygdalostriatal transition zone (ASt) has circuit connectivity which suggests a role in these processes, but the function of this region is almost completely unknown. The central hypothesis of this proposal is that the ASt acts as a parallel circuit to the amygdala to mediate associative learning and behavioral responses. In the mentored phase (K99) experiments, a combination of optogenetics, in vivo electrophysiology and advanced computational analysis will be used to identify subpopulations of neurons in the ASt that encode stimulus information and specific behaviors. The independent phase (R00) experiments will determine the contribution of inputs from the thalamus, cortex and lateral amygdala to ASt activity encoding cue information, and determine whether synapses from these projections onto ASt neurons are strengthened in associative learning. Preliminary data for this study show that 1) genetically distinct populations of ASt neurons have opposing responses to cues predicting rewards or punishments, and 2) optogenetic inhibition of one of these populations results in a striking reduction in conditioned fear responses. This suggests that the ASt may indeed play a critical role in behavioral responses traditionally attributed to the amygdala. A successful outcome of this proposal could therefore result in a major conceptual revision of current models of the circuit mechanisms underlying associative learning. The study will also provide new insight into the long-standing open question of how significant behavioral responses to conditioned stimuli still persist even following bilateral loss-of-function manipulations targeting the amygdala. This will not only increase our fundamental knowledge of the circuits underlying motivated behavior, but could also identify ASt circuits as vital new targets of interest for neurological disorders where normal behavioral responses to stimuli are disrupted. All proposed research will be conducted Dr. Fergil Mills in the lab of Dr. Kay Tye at the Salk Institute for Biological Studies, which is fully equipped for the proposed experiments. The proposal also includes a comprehensive training plan to facilitate Dr. Mills's career development, and will prepare him to direct an innovative research program as an independent investigator studying neural circuit mechanisms underlying normal and pathological behaviors.