Dopamine neurons of the ventral tegmental area (VTA) provide essential modulatory signals to the forebrain limbic system and cortex to facilitate learning and motivational processes. Disruptions in dopamine signaling are broadly implicated in mental illness and likely contribute to a spectrum of behavioral dysfunction through distinct cortico-limbic pathways. The heterogeneity of dopamine neurons in the VTA has long been appreciated, but therapeutic strategies targeting the system are still based on a monolithic perspective. Recent advances in mapping the input/output relationships of distinct dopamine pathways have attempted to resolve the basic organization of the VTA, but have yielded little in the way of establishing how specialized subdivisions might be organized. Unraveling the basic anatomical and functional organization of the VTA is essential if precision therapeutics are to be achieved for treating specific behavioral dysfunctions. We hypothesized that the dopamine system in the VTA can be organized based on peptidergic modulation to gate information through specific output pathways. We have mapped the projections of dopamine neurons in the VTA that express distinct neuropeptide receptors and discovered a remarkable specialization of these outputs. Here we propose to establish the basic electrophysiological, anatomical, and behavioral function of these pathways using novel Cre driver mouse lines in combination with advanced techniques in viral-based circuit dissection. We will also establish novel methods for the genetic characterization of these subpopulations. Successful completion of our proposed aims will provide novel insight into the basic organization of the VTA dopamine system and establish a framework for cracking the dopamine code.

Public Health Relevance

Alterations in dopamine function contribute to multiple aspects of mental illness. The manner in which distinct dopamine systems contribute to behavioral dysregulation is poorly understood, but likely contributes to the etiology of many symptom domains of mental illness. We will use advanced genetic techniques to define the specialized organization of the midbrain dopamine system and determine how these subdivisions contribute to behavioral domains relevant to mental illness.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA044315-01A1
Application #
9522328
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Berton, Olivier Roland
Project Start
2018-04-15
Project End
2023-02-28
Budget Start
2018-04-15
Budget End
2019-02-28
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Washington
Department
Pharmacology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195