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

项目摘要/摘要 大脑能够在刺激和它们预测的奖惩之间形成习得的联系， 然后引导适当的行为反应以最大限度地提高存活率。然而，对此的回应 环境刺激在焦虑、抑郁和后遗症等神经疾病中发生严重变化 创伤性应激障碍，导致破坏性的行为后果。了解神经回路 因此，调节习得的联想和动机行为从根本上讲都是至关重要的 科学和人类健康的视角。杏仁核纹状体移行区(AST)有环路连接 这意味着在这些过程中发挥了作用，但这个区域的功能几乎完全未知。这个 这一提议的中心假设是，AST充当杏仁核的平行回路，以调节 联想学习和行为反应。在指导阶段(K99)实验中， 将使用光遗传学、活体电生理学和先进的计算分析来识别 AST中编码刺激信息和特定行为的神经元亚群。这个 独立期(R00)实验将确定来自丘脑、皮质和 杏仁外侧核到AST的活动编码线索信息，并确定这些突触 在联想学习中，向AST神经元的投射得到加强。这项研究的初步数据显示 1)遗传上截然不同的AST神经元群体对预测奖励或 惩罚，以及2)光遗传抑制其中一个种群导致显著减少 条件性恐惧反应。这表明，天冬氨酸转氨酶在行为反应中可能确实起着关键作用 传统上认为是杏仁核引起的。因此，这项提议的成功结果可能会导致重大的 对联想学习背后的电路机制的现有模型进行概念性修订。这项研究将 也为长期悬而未决的问题提供了新的见解，即对 即使在针对杏仁核的双侧功能丧失操作之后，条件性刺激仍然存在。 这不仅将增加我们对动机行为背后的回路的基本知识，而且可能 在行为正常的情况下，也将AST回路确定为神经障碍的重要新靶点 对刺激的反应被打乱。所有拟议的研究都将由费吉尔·米尔斯博士在凯博士的实验室进行 Tye在索尔克生物研究所，该研究所为拟议的实验配备了完整的设备。这个 提案还包括一项全面的培训计划，以促进米尔斯博士的职业发展，并将 让他做好准备，作为一名研究神经回路的独立研究员，指导一个创新的研究项目 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.