Thursday, November 21, 2024 11/21/2024

CELL-TYPE SPECIFIC ROLE OF CIRCADIAN-DEPENDENT TRANSCRIPTION IN FENTANYL-INDUCED SYNAPTIC AND BEHAVIORAL PLASTICITY

Award Number: R01HL150432
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT ABSTRACT Proposal is designed in response to NHLBI/NIDA RFA-HL-19-028 (Sleep and Circadian-Dependent Mechanisms Contributing to Opioid Use Disorder (OUD) and Response to Medication Assisted Treatment (MAT)) as part of the HEAL Initiative. Annual costs attributed to the opioid crisis in the United States have shattered previous estimates. Synthetic opioids like fentanyl have surpassed prescription opioids as the leading cause of death from drug overdose and illicit fentanyl use continues to ride in regions with already high base rates of OUD. Among the most common symptoms experienced by individuals suffering with OUD are severe and persistent sleep and circadian disruptions. These sleep and circadian abnormalities are speculated to foster opioid craving and relapse, although direct evidence is limited. We lack a basic understanding of the mechanisms contributing to opioid dependence and their relationship to sleep and circadian systems. We identified a circadian-dependent mechanism which modulates fentanyl reward-related behaviors potentially via cell-type specific action in a key brain region linked to OUD—the nucleus accumbens (NAc). A majority of the neurons in the NAc are GABAergic medium spiny neurons which predominantly express either dopamine 1 or 2 receptors (D1R-MSNs or D2R-MSNs). These MSN subpopulations exert opposing and sometimes complementary actions on reward-related behaviors, whereby activation of D1R-MSNs drives drug seeking and relapse, while D2R-MSNs attenuate these behaviors. D1R-MSNs are also involved in the regulation of sleep-wake cycles. Our preliminary work suggests the diurnal excitability of NAc D1R-MSNs and their response to fentanyl is directly modulated by the circadian transcription factor NPAS2. We also show NPAS2 impacts sleep-wake cycles, potentially via action in NAc. Findings from human genetics studies indicate variants of NPAS2 are associated with alterations in the diurnal variation of anhedonia and motivation, suggesting links between NPAS2 and the circadian modulation of reward and motivation. We identified a novel role for NPAS2 to regulate fentanyl reward via activity in D1-MSNs of the NAc. We will use a combination of behavioral (i.e., self-administration and sleep polysomnography), slice electrophysiology, and molecular (i.e., cell-type specific RNA-seq) approaches to: Investigate the role of NPAS2 in D1R-MSNs to modulate the behavioral responses to fentanyl (Aim 1); Assess the impact of fentanyl on synaptic plasticity at D1R-MSNs and investigate whether NPAS2 mediates the potentiation of excitatory synapses at specific diurnal phases (Aim 2); Elucidate the cell-type specific NPAS2-dependent transcriptional mechanisms of fentanyl-seeking and relapse behaviors (Aim 3); and, Investigate whether NPAS2 rescue and buprenorphine MAT improve fentanyl-induced sleep disturbances (Aim 4). Our proposal will define the role for circadian-dependent transcriptional mechanisms in key reward circuits of opioid reward and uncover the therapeutic potential of NPAS2 for opioid dependence and relapse. Our studies will provide novel insights into the mechanisms at the intersection of sleep, circadian rhythms, and opioids.


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 = -$35,484 )
2025	2020	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	National Center on Sleep Disorders Research	000	1	10/1/2024	SUPPLEMENT FOR EXPANSION	-$24,242
2025	2019	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	National Center on Sleep Disorders Research	001	2	10/1/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$11,242
														Subtotal = -$35,484

Issue Date FY: 2024 ( Subtotal = -$33,793 )
2024	2019	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	National Center on Sleep Disorders Research	001	3	12/11/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$33,793
2024	2019	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	National Center on Sleep Disorders Research	002	3	3/1/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$33,793
2024	2019	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	National Center on Sleep Disorders Research	000	2	12/11/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$33,793
														Subtotal = -$33,793

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2019	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	National Center on Sleep Disorders Research	000	2	5/22/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$60,184
2023	2019	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	National Center on Sleep Disorders Research	001	3	5/24/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$60,184
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	National Center on Sleep Disorders Research	002	1	4/27/2021	SUPPLEMENT FOR EXPANSION	$0
2021	2020	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	National Center on Sleep Disorders Research	005	1	7/13/2021	SUPPLEMENT FOR EXPANSION	-$388,425
2021	2019	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	National Center on Sleep Disorders Research	003	2	5/26/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,247,712
2021	2019	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	National Center on Sleep Disorders Research	006	2	7/13/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$402,697
2021	2019	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	National Center on Sleep Disorders Research	004	1	7/13/2021	NEW	-$14,272
2021	2019	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	National Center on Sleep Disorders Research	007	2	9/2/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2021	2019	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	National Center on Sleep Disorders Research	001	1	4/27/2021	NEW	-$1,247,712
2021	2019	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	National Center on Sleep Disorders Research	000	1	3/20/2021	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $388,425 )
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	National Center on Sleep Disorders Research	000	1	8/7/2020	SUPPLEMENT FOR EXPANSION	$388,425
														Subtotal = $388,425

Issue Date FY: 2019 ( Subtotal = $1,592,616 )
2019	2019	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	National Center on Sleep Disorders Research	000	1	9/21/2019	NEW	$1,592,616
														Subtotal = $1,592,616

Grand Total All Awards = $1,911,764

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CELL-TYPE SPECIFIC ROLE OF CIRCADIAN-DEPENDENT TRANSCRIPTION IN FENTANYL-INDUCED SYNAPTIC AND BEHAVIORAL PLASTICITY

Award Number: R01HL150432

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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