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Principal Investigator: Sean Bjorn Ostlund
Organization: UNIVERSITY OF CALIFORNIA-IRVINE
Fiscal Year: 2024
Award: $635,357
Funding agency: National Institute of Mental Health
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.
Terms: <Acetylcholine><Anhedonia><Anterior><Appetite><Assay><Basic Research><Basic Science><Behavior><Behavioral><Binge Eating><Bioassay><Biological Assay><Calcium><Cell Communication and Signaling><Cell Signaling><Characteristics><Connector Neuron><Cues><DA Neuron><Data><Depressed mood><Desire for food><Development><Disease><Disorder><Dopamine><Dopamine neuron><Drops><Drugs><Dysfunction><Ensure><Fiber><Functional disorder><Genetic><Goals><Health><Hydroxytyramine><Intercalary Neuron><Intercalated Neurons><Interneurons><Internuncial Cell><Internuncial Neuron><Intracellular Communication and Signaling><Knowledge><Medication><Mental Depression><Mental disorders><Mental health disorders><Mesencephalon><Methods><Mid-brain><Midbrain><Midbrain structure><Monitor><Motivation><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neuromodulator><Neurons><Nicotinic Acetylcholine Receptors><Nicotinic Receptors><Nucleus Accumbens><Pharmaceutical Preparations><Photometry><Physiopathology><Probability><Process><Psychiatric Disease><Psychiatric Disorder><Regulation><Rewards><Risk><Role><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Source><Structure><Substance Use Disorder><System><Testing><Thalamic structure><Thalamus><Time><Work><addiction><addictive disorder><biological signal transduction><cell type><cholinergic><cingulate cortex><cognitive control><cognitive reappraisal><cognitive regulation><compulsive eating><compulsive feeding><compulsive overeating><cost><depressed><depression><developmental><dopaminergic neuron><drug craving><drug seeking behavior><drug/agent><food craving><innovate><innovation><innovative><maladaptive behavior><mental illness><motivated behavior><neural><neural circuit><neural circuitry><neurochemical><neurochemistry><neurocircuitry><neuronal><neuropsychiatric disease><neuropsychiatric disorder><optogenetics><pathophysiology><prevent><preventing><psychiatric illness><psychological disorder><response><sadness><social role><substance use and disorder><synaptic circuit><synaptic circuitry><thalamic>