An A8 dopamine-ventral pallidum threat circuit

A8 多巴胺腹侧苍白球威胁回路

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10646630
• 关键词: Anatomy; Anxiety Disorders; Association Learning; Automobile Driving; Behavior; Behavioral; Bilateral; Brain; Brain region; Clinical; Corpus striatum structure; Cues; Diffuse; Discrimination; Dopamine; Fright; Globus Pallidus; Halorhodopsins; Implant; Infusion procedures; Laboratories; Learning; Light; Lighting; Macaca; Mus; Neurons; Neurotransmitters; Optics; Pathway interactions; Pharmacotherapy; Play; Procedures; Process; Prosencephalon; Rattus; Reporting; Research; Resolution; Role; Serotonergic System; Shock; Signal Transduction; Substantia nigra structure; Testing; Ventral Tegmental Area; anatomical tracing; cell type; designer receptors exclusively activated by designer drugs; dopaminergic neuron; fluorophore; foot; novel; therapeutic target; treatment of anxiety disorders

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.

项目摘要 焦虑症的基本特征夸大了提示信号威胁的恐惧。治疗的药物治疗 焦虑症压倒性地针对弥漫性调节性血清素能系统，但功效有限。 多巴胺是一种弥漫性，调节性神经递质，已知可以调节恐惧。然而，以多巴胺为中心的治疗 对于焦虑症，不可用。该建议将检验A8多巴胺神经元的新假设 起源于腹部后场通常起作用，以通过对腹侧粒子的投射来促进恐惧。 我们已经开发了一种歧视程序，其中最小威胁提示预测了10％的脚部冲击 试验，虽然中性提示永远不会预测冲击。老鼠对最小威胁提示表现出选择性，适度的恐惧， 通过操纵A8多巴胺活性，让我们观察到恐惧夸张或恐惧抑制。目标1意志 揭示A8多巴胺双向控制腹侧粒子射击，以威胁提示和提示引起的恐惧。 th-cre 大鼠将接受双侧内部A8输注CRE依赖性兴奋性无神（HM3D），抑制性dreadd （HM4D）或对照荧光团。所有大鼠都将沿纹状体 - 甲状腺轴植入神经蛋白质。单身的 在最小威胁学习期间，将从腹侧粒子和其他纹状体区域记录单元 当A8多巴胺活性完好无损时，化学上激发或化学抑制。结果将显示 A8多巴胺的HM3D刺激抑制了腹侧颗粒剂，并夸大了恐惧至少 威胁，而HM4D对A8多巴胺的抑制允许腹侧粒子射击，并抑制恐惧对最小的威胁。 AIM 2将直接将恐惧的双向控制与A8多巴胺中的活动与腹侧颗粒途径联系起来。 th CRE大鼠将接受双侧，A8在CRE依赖性通道Rhopoptin，卤代紫红质或对照方面接收双边大鼠。 荧光团。光学伪造物将在腹侧粒子上双侧植入，允许在时间上 - A8对腹侧颗粒途径的特定操纵。提示或控制期间将发生光照明 在最小威胁学习程序中的时期。结果将表明刺激通道旋转刺激 A8多巴胺至腹侧颗粒道路夸大了对最小威胁的恐惧 A8多巴胺到腹侧粒细胞途径抑制了恐惧对最小威胁。该提议将发现 新型多巴胺能途径通常起作用以促进恐惧。同时，结果将揭示 选择性抑制A8多巴胺对腹侧钯途径，作为有效治疗的有希望的目标 焦虑症。