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Circadian regulation of dopamine 1 receptor signaling in the Nucleus Accumbens

Award Number: R21MH135207
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/08/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Circadian regulation of dopamine 1 receptor signaling in the Nucleus Accumbens - PROJECT SUMMARY Nucleus Accumbens (NAc) activity is critically important for response to motivated stimuli, including aversive stimuli. However, it is not known how the NAc processes and responds to these stimuli across the 24hrs cycle. We and others have found NAc shows daily changes in neuronal activity which appears to be in phase with circadian-dependent dopamine release from the primary dopamine input to the NAc, the ventral tegmental area (VTA). Therefore, response to motivated stimuli may vary depending on time-of-day. We recently discovered the circadian gene CRYPTOCHROME (CRY) modulates Gs-protein coupled with dopamine 1 (D1) receptor which may alter neuronal activity and excitability of NAc projection neurons. These data suggest circadian regulation of dopamine receptor activity in the NAc has the ability to strongly alter response to dopamine driven by aversive stimuli via the dopamine 1 receptor. We hypothesize that CRY controls circadian NAc activity through modulation of dopamine 1 receptor function. In year 1 of this proposal, we will assess the role of CRY in regulating circadian dopamine 1 receptor function ex vivo and in vivo. We will selective knockdown CRYs in the NAc and assess D1 receptor function by whole-cell patch clamp physiology by monitoring voltage-gated K+ currents ex vivo and by fiber photometry to monitor D1 receptor signal transduction dynamics in vivo. In year 2, we will use ex vivo approaches with selective knockdown of CRYs to assess DA-dependent NAc excitability. We will further determine circadian-dependent VTA dopamine release and NAc neuronal activity changes in response to aversive stimuli in vivo by monitoring calcium signaling with fiber photometry. This study will allow us to dissect mechanistic, circadian regulation of NAc neurophysiological response and dopamine receptor function. The overall aim of this project is to determine the role of CRY in regulating excitability and function of the NAc and how this regulation controls NAc response to aversive stimuli. This proposal will provide translationally relevant information about circadian regulation of basic mechanistic underpinnings of NAc dopamine function and behaviorally relevant, neurobiological response to aversive stimuli. This work will further provide a foundation for understanding how circadian-driven NAc changes underlie susceptibility to mood disorders such as depression.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $158,313 )
2025	2025	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST	COLUMBIA	SC	29208	RICHLAND	USA	Mental Health Research Grants	000	2	12/30/2024	NON-COMPETING CONTINUATION	$158,313
														Subtotal = $158,313

Issue Date FY: 2024 ( Subtotal = $223,500 )
2024	2024	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Mental Health Research Grants	000	1	12/8/2023	NEW	$223,500
														Subtotal = $223,500

Grand Total All Awards = $381,813

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Circadian regulation of dopamine 1 receptor signaling in the Nucleus Accumbens

Award Number: R21MH135207

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/08/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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