Basal ganglia circuit mechanisms for threat coping

应对威胁的基底神经节回路机制

• 批准号: 10727893
• 负责人: Naoshige Uchida
• 金额: $ 67.5万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727893
• 关键词: Acute; Animals; Anxiety Disorders; Area; Basal Ganglia; Behavior; Behavior Control; Behavioral; Brain Stem; Cell Nucleus; Characteristics; Coping Behavior; Corpus striatum structure; Dopamine; Equilibrium; Event; Exhibits; Fiber; Future; Globus Pallidus; Goals; Human; Impairment; Label; Lateral; Lateral Geniculate Body; Learning; Lesion; Mental disorders; Monitor; Monsters; Motivation; Movement; Mus; Neurons; Output; Parvalbumins; Pathway interactions; Phase; Photometry; Play; Post-Traumatic Stress Disorders; Process; Rewards; Role; Sensory; Signal Transduction; Stimulus; Substantia nigra structure; Tail; Testing; Thalamic structure; Time; Visual; Withdrawal; auditory thalamus; avoidance behavior; coping; dopaminergic neuron; experience; insight; molecular marker; neural circuit; neuromechanism; novel; optogenetics; response

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.

项目概要/摘要 在经历灾难性事件之前避免潜在威胁对于生存至关重要，但过度回避 可能会导致适应不良，例如退缩或错过奖励事件。威胁异常—— 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（纹状体后尾部）起着关键作用 （TS），以避免潜在的威胁。这些研究表明 TS 投射的多巴胺神经元 被显着的威胁刺激激活，而动物会避免激活这些神经元。 TS 的作用 使用觅食范式（“怪物任务”）进一步追求威胁规避，其中小鼠 当它们寻找奖励时，会遇到潜在的威胁（移动的怪物）。在这项任务中，虽然小鼠 他们从未经历过身体伤害，他们表现出威胁反应的三个阶段：最初的反应性回避， 逐渐获得主动回避，最终克服威胁以获得奖励。病变部位 TS 投射的多巴胺神经元损害了威胁回避。此外，初步结果表明，在 TS、直接和间接通路（dMSN 和 iMSN）中的中型多棘神经元有助于避免威胁和 分别克服。基于这些观察，该项目的目标是阐明神经网络 TS 和基底神经节相关回路调节疾病进展的机制 威胁应对。目标 1 将检验 TS 中的多巴胺代表威胁预测误差的假设，以及 通过双重运作模式、敏锐和基于学习的行动来规范威胁应对。为此，多巴胺 TS 中的释放将使用光纤光度测定法进行监测或在 Monster 任务期间进行光遗传学操作。 目标 2 将检查多巴胺调节威胁应对的纹状体回路机制。具体的 要测试的假设是（1）dMSN 和 iMSN 之间的平衡决定了行为输出 （避免威胁与克服威胁），并且（2）阶段性多巴胺信号调节这些之间的平衡 对手通过敏锐的和基于学习的机制进行循环。最后，威胁应对可以涉及 至少两个不同的过程：行动选择（选择接近或避免）和/或感觉的变化 处理（调整潜在威胁刺激的显着性）。目标 3 旨在确定路径 参与这些过程的 TS 下游。具体来说，该目标将检验以下假设：(1) dMSN 和 iMSN 活动的整合发生在黑质外侧部 (SNL)，然后 调节回避行为，并且 (2) TS-苍白球-丘脑网状核通路 调节外侧膝状核的感觉表征以应对或克服怪物威胁。 总的来说，这项研究将阐明新型神经回路（TS 和相关基底神经节通路）在 威胁应对、初始反应性回避、主动性回避和克服威胁三个阶段。