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.

项目摘要/摘要 在发生灾难事件之前避免潜在威胁对于生存至关重要，但超级避免 可能导致适应不良的条件，例如戒断或缺失奖励事件。威胁异常 应对可能是精神病患者的基础，包括创伤后应激障碍和焦虑症。 最近的研究表明，纹状体的感觉部分是纹状体的后尾的关键作用 （TS），避免潜在威胁。这些研究表明，TS射击多巴胺神经元是 受到显着威胁刺激的激活，动物避免激活这些神经元。 TS在 使用觅食范式（“怪物任务”）进一步追求避免威胁的威胁 在他们觅食奖励时，出现了潜在的威胁（一个移动的怪物）。在此任务中，尽管老鼠 他们从未遭受过身体伤害，他们暴露了威胁响应的三个阶段：最初的反应性回避， 逐渐获得积极的避免，并最终克服威胁以获得奖励。病变 TS预测多巴胺神经元受损威胁。此外，初步结果表明，在 TS，直接和间接途径（DMSNS和IMSNS）中的中刺神经元促进了避免威胁和 分别克服。基于这些观察，该项目的目的是阐明中立 低音节神经节功能的TS和相关电路以调节的机制来调节的进展 威胁关注。 AIM 1将检验以下假设：TS中的多巴胺代表威胁预测错误和 通过双重功能，急性和基于学习的动作来调节威胁。为此，多巴胺 在怪物任务期间，将使用纤维光度法或可吻合的操纵来监测TS中的释放。 AIM 2将检查多巴胺调节威胁的纹状体电路机制。具体 要测试的假设是（1）DMSN和IMSN之间的平衡确定行为输出 （避免威胁与克服），并且（2）阶段多巴胺信号调节这些之间的平衡 对手通过急性和基于学习的机制循环。最后，威胁要涉及 至少两个不同的过程：选择动作（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）。 AIM 3将旨在识别途径 参与这些过程的TS下游。具体而言，此目标将检验（1）的假设 DMSN和IMSN活动的整合发生在黑质底层（SNL）中，然后 调节回避行为，（2）TS-Globus pallidus-Thalamic网状核途径 调节侧向核中的感觉表示，以参加或克服怪物威胁。 总体而言，这项研究将阐明新型神经回路（TS和相关的巴萨神经节途径）的作用 威胁的三个阶段，最初的反应性避免，主动避免和克服威胁。