Sunday, November 24, 2024
11/24/2024
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.
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