Wednesday, April 2, 2025
4/2/2025
Nucleus accumbens circuits for regulating cue-motivated behavior - PROJECT SUMMARY Situational cues that signal reward availability can exert a powerful invigorating influence over reward-seeking behavior. However, this impulse to seek out reward is not always adaptive. To conserve time and effort, cue- motivated reward seeking is regulated by homeostatic and cognitive control processes. There is growing evidence that these processes become dysregulated in a range of neuropsychiatric diseases, including substance use disorder, compulsive overeating, and depression, leading to a drop in healthy reward-seeking activity (e.g., apathy and anhedonia) and/or the development of maladaptive reward seeking (e.g., intense drug and food cravings). Despite their importance to both health and disease, much remains unknown of the neural circuits that regulate adaptive cue-motivated behavior. This project aims to fill this critical gap in knowledge. Based on the recent studies and our strong preliminary findings, we hypothesize that dopamine release is transformed into a motivational message at nucleus accumbens (NAc) terminals by cholinergic activity, and that inputs from the paraventricular thalamus (PVT) and anterior cingulate cortex (ACC) exert opposing regulatory influences over this process to ensure adaptive reward seeking. We will rigorously test this using a multifaceted approach that combines projection- and cell type-specific activity monitoring, neurochemical recordings, projection- and cell type-specific chemogenetic and optogenetic manipulations, and a translationally relevant Pavlovian-to-instrumental transfer assay of cue-motivated behavior. Aim 1 will investigate how cholinergic modulation of NAc dopamine release contributes to homeostatic and cognitive control over cue-motivated reward seeking. We will specifically determine whether cue-elicited NAc dopamine encodes changes in need state and reward probability, how this relates to midbrain dopamine neuron activity, and whether dopamine’s motivational message is locally shaped by cholinergic interneurons acting at β2-containing nicotinic acetylcholine receptors on dopamine terminals. Aim 2 will investigate if projections from PVT to NAc facilitate cue-motivated behavior in line with current needs, and whether it does so by regulating NAc cholinergic and/or dopaminergic activity. Aim 3 will determine if ACC projections to NAc adaptively suppress active reward-seeking behavior when cues signal that an alternative response would be advantageous, and whether this depends on NAc acetylcholine and/or dopamine. Our findings will lead to major advances in knowledge of the specific neural circuits and neurochemical mechanisms responsible for regulating cue-motivated behavior, and will guide future research on how dysfunction in these mechanisms contributes to maladaptive reward seeking in addiction and related disease states.
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