An A8 dopamine-ventral pallidum threat circuit

A8 多巴胺腹侧苍白球威胁回路

基本信息

批准号：
10646630
负责人：
MICHAEL A MCDANNALD
金额：
$ 23.48万
依托单位：
BOSTON COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2025-01-31
项目状态：
未结题

项目摘要

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.

项目概要焦虑症的一个主要特征是夸大对威胁信号的恐惧。药物治疗焦虑症主要针对弥漫性调节、血清素能系统，但疗效有限。多巴胺是一种弥散的调节性神经递质，已知可以调节恐惧。然而，以多巴胺为重点的治疗对于焦虑症不可用。该提案将测试 A8 多巴胺神经元的新假设起源于红后区域的正常功能是通过投射到腹侧苍白球来促进恐惧。我们开发了一种辨别程序，其中最小威胁提示可预测 10% 的人会受到足部电击试验，而中性提示永远不会预测休克。老鼠对最小的威胁信号表现出选择性的、适度的恐惧，使我们能够通过操纵 A8 多巴胺活性来观察恐惧的夸大或恐惧的抑制。目标1将揭示 A8 多巴胺双向控制腹侧苍白球对威胁提示和提示引发的恐惧的放电。 Th-cre 大鼠将接受双侧A8内输注cre依赖性兴奋性DREADD (hM3D)、抑制性DREADD (hM4D)，或对照荧光团。所有大鼠将沿纹状体-苍白球轴接受 Neuropixels 植入。单身的在最小威胁学习期间，将从腹侧苍白球和其他纹状体区域记录单位当 A8 多巴胺活性完整、化学遗传学兴奋或化学遗传学抑制时。结果将显示 hM3D 刺激 A8 多巴胺会抑制腹侧苍白球放电并将恐惧程度降至最低威胁，而 hM4D 对 A8 多巴胺的抑制允许腹侧苍白球放电并将恐惧抑制到最小的威胁。目标 2 将直接将恐惧的双向控制与 A8 多巴胺至腹侧苍白球通路的活动联系起来。钍- cre 大鼠将接受双侧 A8 内输注 cre 依赖性通道视紫红质、盐视紫红质或对照荧光团。光学插芯将被两侧植入腹侧苍白球上，允许暂时- A8 到腹侧苍白球通路的具体操作。提示或控制期间会出现灯光照明最小威胁学习过程期间的时期。结果将表明视紫红质通道刺激 A8 多巴胺到腹侧苍白球的通路将恐惧放大到最小的威胁，而盐视紫红质抑制 A8 多巴胺到腹侧苍白球通路的作用将恐惧抑制到最小程度。该提案将揭示一个一种新的多巴胺能通路，通常会促进恐惧。同时，结果将揭晓选择性抑制 A8 多巴胺至腹侧苍白球通路作为有效治疗的有希望的靶点焦虑症。