Growing evidence suggests that the cognitive symptoms underlying many psychiatric disorders, including addiction, result from a failure to appropriately learn about and/or anticipate potential future events. Indeed, deficits in the prospective consideration of potential rewarding events have been detected in patients diagnosed with addiction, accounting for their inability to limit use despite deleterious consequences. Similar deficits have been identified in patients diagnosed with mental illnesses comorbid with addiction, such as depression, anxiety, and schizophrenia. These mental illnesses are major intractable public health problems in the US, accounting for hundreds of billions of dollars in costs associated with health care, crime, incarceration and law enforcement. Effective approaches to prevent and/or treat these conditions are, therefore, badly needed. The goal of this research is to expose the neural circuits required to learn predictive relationships and to use this information to generate expectations about the future, in order to gain insight into how pathological states arise and determine what can be done to combat them. Addictive substances are thought to hijack the brain systems that normally support adaptive decision making, resulting in maladaptive choices. Adaptive decision making requires accurate prospective consideration of possible future events. Prior encoding of specific stimulus-reward associative memories enables this prospective consideration by allowing the mental simulation (i.e., representation) of possible future rewarding events. Recent studies in rodents and humans have indicated that the basolateral amygdala (BLA) might be a brain region crucial for learning these associations, but precisely how and the neural circuitry through which it achives this function are unknown. The proposed research provides a critical, in-depth, and hypothesis-driven investigation of the contribution of the BLA and its reciprocal connections with the orbitofrontal cortex, a region implicated in decision making, to stimulus-reward encoding and subsequent retrieval of this information to guide adaptive behavior and choice. This will be achieved through a multi-faceted and integrative neural recording and manipulation approach. We will combine projection-specific activity monitoring, tag and capture techniques for manipulation of specific event-activated neuronal ensembles, and behavioral procedures with translational relevance to symptoms of human mental illness to uncover the function of amgydala-cortical loops in adaptive reward-guided behavior and decision making.

Public Health Relevance

The cognitive symptoms underlying many psychiatric disorders, including addiction, result from a failure to appropriately learn about and/or anticipate potential future events. This project will expose the brain circuits vital for encoding and retrieving memories of rewarding events, which will enable future research on how dysfunction in these processes contributes to pathological behavior.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA035443-06A1
Application #
9662594
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Grant, Steven J
Project Start
2019-02-15
Project End
2023-12-31
Budget Start
2019-02-15
Budget End
2019-12-31
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Malvaez, Melissa; Greenfield, Venuz Y; Matheos, Dina P et al. (2018) Habits Are Negatively Regulated by Histone Deacetylase 3 in the Dorsal Striatum. Biol Psychiatry 84:383-392
Wassum, Kate M (2018) Clarifying punishment. Neuropsychopharmacology 43:1633-1634
Malvaez, Melissa; Wassum, Kate M (2018) Regulation of habit formation in the dorsal striatum. Curr Opin Behav Sci 20:67-74
Lichtenberg, Nina T; Wassum, Kate M (2017) Amygdala mu-opioid receptors mediate the motivating influence of cue-triggered reward expectations. Eur J Neurosci 45:381-387
Lichtenberg, Nina T; Pennington, Zachary T; Holley, Sandra M et al. (2017) Basolateral Amygdala to Orbitofrontal Cortex Projections Enable Cue-Triggered Reward Expectations. J Neurosci 37:8374-8384
Wassum, Kate M; Greenfield, Venuz Y; Linker, Kay E et al. (2016) Inflated reward value in early opiate withdrawal. Addict Biol 21:221-33
Aitken, Tara J; Greenfield, Venuz Y; Wassum, Kate M (2016) Nucleus accumbens core dopamine signaling tracks the need-based motivational value of food-paired cues. J Neurochem 136:1026-36
Collins, Anne L; Aitken, Tara J; Greenfield, Venuz Y et al. (2016) Nucleus Accumbens Acetylcholine Receptors Modulate Dopamine and Motivation. Neuropsychopharmacology 41:2830-2838
Collins, Anne L; Greenfield, Venuz Y; Bye, Jeffrey K et al. (2016) Dynamic mesolimbic dopamine signaling during action sequence learning and expectation violation. Sci Rep 6:20231
Wassum, Kate M; Phillips, Paul E M (2015) Probing the neurochemical correlates of motivation and decision making. ACS Chem Neurosci 6:11-3

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