Basal ganglia circuit mechanisms for threat coping

项目总结/摘要 在经历灾难性事件之前避免潜在的威胁对生存至关重要，但过度避免 可能导致适应不良的状况，如退缩或错过奖励活动。在威胁中屈服- 应对可能是精神疾病的基础，包括创伤后应激障碍和焦虑症。 最近的研究表明，纹状体的感觉部分，纹状体的后尾， (TS)以避免潜在的威胁。这些研究表明，TS投射多巴胺神经元是 这些神经元被显著的威胁刺激激活，动物避免激活这些神经元。TS的作用 已经使用觅食范例（“怪物任务”）进一步追求了威胁回避，在该范例中，小鼠被 当他们寻找奖励时，会出现潜在的威胁（移动的怪物）。在这项任务中，虽然老鼠 从未经历过身体伤害，他们表现出三个阶段的威胁反应：最初的反应性回避， 逐渐获得主动回避，并最终克服威胁以获得奖励。病变 TS投射多巴胺神经元损害威胁回避。此外，初步结果表明，在 TS，直接和间接通路中的中型多刺神经元（dMSN和iMSN）有助于避免威胁， 分别克服。在这些观察的基础上，本项目的目标是阐明 TS和基底神经节的相关回路发挥作用以调节 应对威胁目标1将检验TS中的多巴胺代表威胁预测误差的假设， 通过双重运作模式、敏锐行动和基于学习的行动来调节威胁应对。为此，多巴胺 TS中的释放将使用纤维光度法监测或在Monster任务期间进行光遗传学操纵。 目的2将研究多巴胺调节威胁应对的纹状体回路机制。具体 要检验的假设是：（1）dMSN和iMSN之间的平衡决定了行为输出 （威胁回避与克服），以及（2）相位多巴胺信号调节这些之间的平衡 通过急性和学习机制来对抗回路。最后，威胁应对可能涉及 至少有两个不同的过程：动作选择（选择接近或回避）和/或感官变化 处理（调整潜在威胁刺激的显著性）。目标3旨在确定途径 在这些过程中涉及的TS下游。具体而言，这一目标将测试假设（1） dMSN和iMSN活动的整合发生在黑质外侧部（SNL）， 调节回避行为，以及（2）TS-苍白球-丘脑网状核通路 调节外侧膝状体核的感觉表征，以关注或克服怪物威胁。 总之，这项研究将阐明新的神经回路（TS和相关的基底神经节通路）在 威胁应对的三个阶段，最初的反应性回避，主动回避和克服威胁。

Project Summary/Abstract Avoiding potential threats before experiencing disastrous events is critical for survival, yet excessive avoidance may lead to maladaptive conditions such as withdrawal or missing rewarding events. Abnormalities in threat- coping may underlie psychiatric conditions including post-traumatic stress disorder and anxiety disorders. Recent studies have shown a critical role for the sensory part of the striatum, the posterior tail of the striatum (TS), in avoidance of a potential threat. These studies have indicated that TS-projecting dopamine neurons are activated by salient threatening stimuli, and animals avoid activation of these neurons. The role of the TS in threat avoidance has been pursued further using a foraging paradigm (“Monster task”) in which mice are presented with a potential threat (a moving monster) while they forage for a reward. In this task, although mice never experienced physical harm, they exhibited three stages of threat-response: initial reactive avoidance, gradually-acquired proactive avoidance, and eventual overcoming of the threat to obtain reward. Lesions of TS-projecting dopamine neurons impaired threat avoidance. Further, preliminary results indicate that, in the TS, medium spiny neurons in direct and indirect pathways (dMSNs and iMSNs) facilitate threat avoidance and overcoming, respectively. Building on these observations, the goal of this project is to elucidate the neural mechanisms by which TS and associated circuits of the basal ganglia function to regulate progression of threat-coping. Aim 1 will test the hypothesis that dopamine in TS represents threat prediction error and regulates threat-coping by dual modes of functioning, acute and learning-based actions. To this end, dopamine release in TS will be monitored using fiber photometry or manipulated optogenetically during the Monster task. Aim 2 will examine the striatal circuit mechanisms by which dopamine regulates threat-coping. The specific hypotheses to be tested are that (1) the balance between dMSNs and iMSNs determines the behavioral output (threat avoidance vs. overcoming), and that (2) phasic dopamine signals modulate the balance between these opponent circuits through both acute and learning-based mechanisms. Finally, Threat-coping can involve at least two distinct processes: action selection (choosing to approach or avoid) and/or changes in sensory processing (adjusting the salience of a potentially threatening stimulus). Aim 3 will aim to identify pathways downstream of TS which are involved in these processes. Specifically, this aim will test the hypotheses that (1) the integration of dMSN and iMSN activities occurs in the substantia nigra pars lateralis (SNL) which then regulates avoidance behavior, and that (2) the TS-globus pallidus-thalamic reticular nucleus pathway modulates sensory representation in lateral geniculate nucleus to attend or overcome a monster threat. Overall, this study will elucidate a role for novel neural circuits (TS and associated basal ganglia pathways) in three stages of threat-coping, initial reactive avoidance, proactive avoidance, and overcoming of the threat.