The hypothalamus acting through the pituitary is important for organismal adaptation to homeostatic challenges. Dysfunction in these systems impairs health, increases addictive behaviors and is a common cause of relapse. Elucidating the molecular cellular mechanisms is therefore critical for understanding, preventing, or treating a variety of associated disorders including substance abuse. The hypothalamic corticotrophin-releasing factor (CRF) and pituitary pro-opiomelanocortin (POMC) neurons are evolutionarily conserved across vertebrates. They control organismal responses to aversive stimuli through regulating circulating neuropeptides and glucocorticoids. However, it remains poorly understood how CRF and POMC neurons are regulated by both external environment and internal neural states. Neuromodulatory systems are involved, but because of the pleiotropic action of most neuromodulatory systems, it has been difficult to understand their role in CRF-POMC regulation in cell type- and gene-specific manners. Dopamine (DA) is a classical neurotransmitter that is best known for its role in signaling reward. Dopamine also plays a critical but poorly understood role in hypothalamic-pituitary regulation in a variety of species including humans, dogs, rats, mice, and fish. Recently, we have uncovered that dopamine (DA) regulates CRF-POMC function in larval zebrafish through both D1 and D2 receptors. This study will employ the transparent and highly accessible larval zebrafish system and advanced molecular genetic technologies to understand the mechanisms by which dopamine regulates CRF-POMC function. This study will unveil new molecular and cellular mechanisms on how DA neurons interact with CRF and POMC neurons to regulate their function. The findings will provide new insights into the development function and evolution of these important neural systems in the context of organismal survival and wellbeing. Equally importantly, this proposal will establish broadly applicable tools for genetically dissecting neuromodulatory systems in complex behaviors.

Public Health Relevance

This project aims to understand how dopamine modulates the hypothalamic-pituitary function in organismal adaptation to homeostatic challenges. Improved mechanistic understandings of this regulation will significantly benefit human health by allowing better preventive measures to be implemented and more effective therapies to be developed for a variety of stress-related disorders, including addiction and depression.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
3R01DA035680-03S1
Application #
9276163
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wu, Da-Yu
Project Start
2013-09-15
Project End
2016-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Wagle, Mahendra; Nguyen, Juliana; Lee, Shinwoo et al. (2017) Heritable natural variation of an anxiety-like behavior in larval zebrafish. J Neurogenet 31:138-148
Huang, Rongchen; Chen, Min; Yang, Leiqing et al. (2017) MicroRNA-133b Negatively Regulates Zebrafish Single Mauthner-Cell Axon Regeneration through Targeting tppp3 in Vivo. Front Mol Neurosci 10:375
Oltrabella, Francesca; Melgoza, Adam; Nguyen, Brian et al. (2017) Role of the endocannabinoid system in vertebrates: Emphasis on the zebrafish model. Dev Growth Differ 59:194-210
Bai, Yiming; Liu, Harrison; Huang, Bo et al. (2016) Identification of environmental stressors and validation of light preference as a measure of anxiety in larval zebrafish. BMC Neurosci 17:63
McGorty, Ryan; Liu, Harrison; Kamiyama, Daichi et al. (2015) Open-top selective plane illumination microscope for conventionally mounted specimens. Opt Express 23:16142-53
Berberoglu, Michael A; Dong, Zhiqiang; Li, Guangnan et al. (2014) Heterogeneously expressed fezf2 patterns gradient Notch activity in balancing the quiescence, proliferation, and differentiation of adult neural stem cells. J Neurosci 34:13911-23