An A8 dopamine-ventral pallidum threat circuit

项目摘要 焦虑症的一个主要特征是对威胁信号的过度恐惧。药物治疗 焦虑症压倒性地靶向弥散调节性多巴胺能系统，但功效有限。 多巴胺是一种弥散性的调节性神经递质，可以调节恐惧。然而，以多巴胺为中心的治疗 焦虑症的治疗方法这项提议将检验A8多巴胺神经元 起源于红核后区的神经元通常通过投射到腹侧苍白球来促进恐惧。 我们已经开发了一种识别程序，其中最小的威胁线索预测10%的人的足部电击。 试验，而一个中性的线索从来没有预测休克。老鼠对最小的威胁线索表现出选择性的适度恐惧， 这使得我们能够通过操纵A8多巴胺活性来观察恐惧夸大或恐惧抑制。目标1将 揭示A8多巴胺双向控制腹侧苍白球对威胁线索和线索引发的恐惧的放电。Th-cre 大鼠将接受双侧A8内输注cre依赖性兴奋性DREADD（hM 3D）、抑制性DREADD （hM 4D）或对照荧光团。所有大鼠将沿纹状体-苍白球轴接受Neuropixels植入物沿着。单个 在最小威胁学习期间，将从腹侧苍白球和额外的纹状体区域记录单位 当A8多巴胺活性是完整的、化学发生性激发的或化学发生性抑制的时。结果将表明 刺激A8多巴胺的hM 3D抑制腹侧苍白球放电并将恐惧夸大到最小 hM 4D抑制A8多巴胺允许腹侧苍白球放电并抑制恐惧至最小威胁。 目标2将恐惧的双向控制与A8多巴胺到腹侧苍白球通路的活动直接联系起来。这- cre大鼠将接受cre依赖性通道视紫红质、盐视紫红质或对照的双侧A8内输注 荧光团。光学套圈将双侧植入腹侧苍白球，允许暂时- A8到腹侧苍白球通路的特定操作。在提示或控制过程中会出现灯光照明 在最小威胁学习过程中。结果将表明，通道视紫红质刺激 A8多巴胺到腹侧苍白球通路将恐惧夸大到最小威胁，而盐视紫红质抑制 A8多巴胺到腹侧苍白球的通路抑制恐惧到最小的威胁。该提案将揭示一个 一种新的多巴胺能通路，通常用于促进恐惧。同时，结果将揭示 选择性抑制A8多巴胺到腹侧苍白球通路作为有效治疗的有希望的靶点 焦虑症

Project Summary A cardinal feature of anxiety disorders is exaggerated fear to cues signaling threat. Pharmacotherapies to treat anxiety disorders overwhelmingly target the diffuse modulatory, serotonergic system, but have limited efficacy. Dopamine is a diffuse, modulatory neurotransmitter known to regulate fear. Yet, dopamine-focused treatments for anxiety disorders are not available. This proposal will test the novel hypothesis that A8 dopamine neurons originating in the retrorubral field normally function to promote fear through projections to the ventral pallidum. We have developed a discrimination procedure in which a minimal threat cue predicts foot shock on 10% of trials, while a neutral cue never predicts shock. Rats show selective, modest fear to the minimal threat cue, allowing us to observe fear exaggeration or fear inhibition via manipulation of A8 dopamine activity. Aim 1 will reveal A8 dopamine bidirectionally controls ventral pallidum firing to a threat cue and cue-elicited fear. Th-cre rats will receive bilateral intra-A8 infusion of a cre-dependent excitatory DREADD (hM3D), inhibitory DREADD (hM4D), or a control fluorophore. All rats will receive Neuropixels implant along a striatum-pallidum axis. Single units will be recorded from the ventral pallidum and additional striatal regions during minimal threat learning when A8 dopamine activity is intact, chemogenetically excited or chemogenetically inhibited. Results will show that hM3D stimulation of A8 dopamine suppresses ventral pallidum firing and exaggerates fear to minimal threat, while hM4D inhibition of A8 dopamine permits ventral pallidum firing and inhibits fear to minimal threat. Aim 2 will directly tie bidirectional control of fear to activity in the A8 dopamine to ventral pallidum pathway. Th- cre rats will receive bilateral, intra-A8 infusion of cre-dependent channelrhodopsin, halorhodopsin, or a control fluorophore. Optical ferrules will be bilaterally implanted over the ventral pallidum, permitting temporally- specific manipulations of the A8 to ventral pallidum pathway. Light illumination will occur during cue or control periods during the minimal threat learning procedure. Results will show that channelrhodopsin stimulation of the A8 dopamine to ventral pallidum pathway exaggerates fear to minimal threat, while halorhodopsin inhibition of the A8 dopamine to ventral pallidum pathway inhibits fear to minimal threat. This proposal will uncover a novel dopaminergic pathway that normally functions to promote fear. Simultaneously, the results will reveal selective inhibition of the A8 dopamine to ventral pallidum pathway as a promising target to effectively treat anxiety disorders.