The Role of Posterior Striatum Projecting Dopamine Neurons in Associative Fear Learning

联想学习使动物能够从经验中学习，因此对于在不断变化的环境中做出适应性反应是必不可少的。特别是，学习哪些刺激预示危险的能力对生存至关重要。在实验室中，这种联想学习是使用经典的恐惧条件反射来建模的，即一开始的中性刺激(条件性刺激，CS)在与一个令人厌恶的结果(无条件刺激，美国)配对后，会引发恐惧反应。值得注意的是，它的临床意义使恐惧条件作用成为一个深入研究的范式，因为许多证据表明，焦虑障碍，如创伤后应激障碍(PTSD)，是由调节联想恐惧学习的大脑回路失调引起的。因此，了解恐惧学习背后的神经机制对于更好地理解焦虑症的病理生理学至关重要，并有助于开发新的治疗策略。联想学习，如恐惧条件作用，是由预测错误(PE)驱动的，预测错误充当指导新学习的教学信号。众所周知，多巴胺(DA)神经元编码PE信号来驱动联想奖赏学习。重要的是，最近的证据表明，DA神经元编码预测误差不仅是为了奖励，也是为了厌恶的结果。纹状体是DA神经元的主要投射靶点；然而，投射到纹状体的DA神经元，特别是纹状体的一个特定亚区，是否参与联想恐惧学习仍是个未知数。最近的研究已经根据DA神经元的输入-输出组织确定了一个独特的亚群。这些DA神经元选择性地投射到纹状体的一个不同的细分部分，即纹状体的后部尾部(PTS)，并被新的高强度刺激强烈激活。此外，它们已被证明可以加强威胁规避。然而，这些DA神经元是否是联想恐惧学习所必需的，目前尚不清楚。我们假设，PTS投射的DA神经元编码了一种厌恶的PE信号，这是获得联想恐惧学习所必需的。解决这一假设将是这项提议的主要目标。为此，我们将进行投射特定的活性依赖的钙记录，时间上精确的光遗传操作，以及使用DA生物传感器测量DA释放。这些数据将首次揭示投射PTS的DA神经元在联想恐惧学习中所起的关键作用。此外，我们将进一步研究DA输入在联想恐惧学习中对PTS神经元活动的作用，以阐明DA是如何调节纹状体活动从而使学习得以实现的。综上所述，我们预计我们的结果将为PTS投射的DA神经元确定一个新的角色，并进一步表明一个独特的中纹状体回路对联想恐惧学习至关重要。

Associative learning enables animals to learn from experience, and thus is essential for adaptive responding in an ever-changing environment. In particular, the ability to learn which stimuli predict danger is crucial for survival. In the laboratory, this kind of associative learning is modelled using classical fear conditioning where an initially neutral stimulus (conditioned stimulus, CS) comes to elicit fear responses after being paired in time with an aversive outcome (unconditioned stimulus, US). Notably, its clinical significance has made fear conditioning an intensively studied paradigm since much evidence indicates that anxiety disorders, such as the post-traumatic stress disorder (PTSD), result from dysregulation of brain circuits that mediate associative fear learning. Understanding neural mechanisms underlying fear learning is therefore crucial for a better understanding of the pathophysiology of anxiety disorders and can help develop new treatment strategies. Associative learning, such as fear conditioning, is driven by prediction errors (PE) which act as teaching signals to instruct new learning. It is well-established that dopamine (DA) neurons encode PE signals to drive associative reward learning. Importantly, recent evidence suggests that DA neurons encode prediction errors not only for rewards but also for aversive outcomes. Striatum constitutes the major projection target of DA neurons; however, whether DA neurons that project to the striatum, in particular a specific subregion of the striatum, are involved in associative fear learning has remained elusive. Recent studies have identified a unique subpopulation of DA neurons based on their input-output organization. These DA neurons project selectively to a distinct subdivision of the striatum, the posterior tail of the striatum (pTS), and are activated strongly by novel and high-intensity stimuli. Furthermore, they have been shown to reinforce threat avoidance. However, whether these DA neurons are required for associative fear learning is currently unknown. We hypothesize that pTS-projecting DA neurons encode an aversive PE signal which is necessary for acquisition of associative fear learning. Addressing this hypothesis will be the major goal of this proposal. To this end, we will perform projection-specific activity-dependent calcium recordings, temporally-precise optogenetic manipulations as well as measurement of DA release using a DA biosensor. These data will reveal for the first time the crucial role pTS-projecting DA neurons play in associative fear learning. In addition, we will further investigate the role of DA input on the activity of pTS neurons during associative fear learning to shed light on how DA modulates striatal activity and thus enables learning. Taken together, we expect that our results will identify a novel role for the pTS-projecting DA neurons and furthermore will suggest that a unique mesostriatal circuit is crucial for associative fear learning.