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

后纹状体投射多巴胺神经元在联想恐惧学习中的作用

• 批准号: 470520017
• 负责人: Dr. Sevil Duvarci
• 金额: --
• 依托单位: Physiologie II: Sinnes- und Neurophysiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/470520017?language=en
• 关键词: Role; Posterior; Striatum; Projecting; Dopamine

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.

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至关重要。特别是，了解哪些刺激可以预测危险的能力对于生存至关重要。 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，其中最初的中性刺激（条件刺激，CS）在与厌恶结果（无条件刺激，US）及时配对后引发恐惧反应。值得注意的是，它的临床意义使恐惧条件反射成为一个深入研究的范式，因为许多证据表明焦虑症，如创伤后应激障碍（PTSD），是由介导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了解焦虑症的病理生理学至关重要，并有助于制定新的治疗策略。联想学习，例如恐惧条件反射，是由预测误差（PE）驱动的，预测误差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 信号来驱动联想奖励学习。重要的是，最近的证据表明，DA 神经元不仅编码奖励的预测错误，还编码厌恶结果的预测错误。纹状体构成DA神经元的主要投射目标；然而，投射到纹状体（特别是纹状体特定亚区域）的 DA 神经元是否参与联想恐惧学习仍然是个谜。最近的研究根据 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独特分区，即纹状体后尾 (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 神经元编码厌恶的 PE 信号，这对于获得联想恐惧学习是必要的。解决这一假设将是该提案的主要目标。为此，我们将进行投影特异性活动依赖性钙记录、时间精确的光遗传学操作以及使用 DA 生物传感器测量 DA 释放。这些数据将首次揭示 pTS 投射 DA 神经元在联想恐惧学习中发挥的关键作用。此外，我们将进一步研究 DA 输入在联想恐惧学习过程中对 pTS 神经元活动的作用，以阐明 DA 如何调节纹状体活动从而实现学习。总而言之，我们期望我们的结果将确定 pTS 投射 DA 神经元的新作用，并且进一步表明独特的中纹状体回路对于联想恐惧学习至关重要。