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The influence of noradrenergic circuitry on prefrontal neuronal ensemble dynamics and cue-induced heroin seeking

Award Number: R01DA051650
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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The influence of noradrenergic circuitry on prefrontal neuronal ensemble dynamics and cue-induced heroin seeking - SUMMARY/ABSTRACT Substance use disorder (SUD) is associated with abnormalities in the dorsomedial prefrontal cortex (dmPFC), a brain region that is activated by drug-predictive cues and contributes to drug seeking. Recent studies show that non-overlapping cell populations within dmPFC, defined by gene expression or projection target, display unique activity profiles during reward seeking. Interestingly, even within these defined cell populations considerable cell- to-cell variability is found suggesting that greater resolution is needed to understand the influence of unique dmPFC neuronal ensembles on behavior. Overall, the influence of unique dmPFC neuronal ensemble activity patterns on drug seeking is unclear. Activity in the dmPFC is highly suppressed following persistent drug use in rodents and humans, in part due to the reduced function of channels that control the intrinsic excitability of dmPFC output neurons. Considering this suppressed excitability, it is surprising that the presentation of drug-associated cues can evoke robust activity in dmPFC of patients with SUD, with that activity being a reliable predictor of future relapse. Thus, a rapid shift in the excitability of dmPFC neurons likely occurs during drug-associated cue exposure, a change that may be controlled by the neuromodulator noradrenaline. In support of this idea, here I show that chemogenetic inhibition of locus coeruleus noradrenergic axons in dmPFC (LC dmPFC) abolishes cue-induced reinstatement of heroin seeking. Furthermore, I confirm that downstream dmPFC excitatory output neurons display bidirectional plasticity following heroin use, becoming hypoactive following heroin self-administration but recovering normal activity during cue-induced relapse. Considering these findings, here I investigate the hypotheses that noradrenergic LC dmPFC neurons become active during the presentation of drug-predictive cues (Aim 1), that noradrenergic activity in dmPFC is critical for cue-induced drug seeking and for amplifying activity in downstream dmPFC neuronal ensembles (Aim 2), and that activity in select dmPFC neuronal ensembles modulates cue-induced drug seeking behavior (Aim 3). Overall, these experiments will characterize the activity dynamics and function of precisely defined dmPFC circuit elements during cue-induced heroin seeking. Findings from these studies are critical for the development of strategies that could normalize dmPFC activity and reduce relapse vulnerability in patients suffering from SUD.


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 = $332,681 )
2025	2025	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Drug Use and Addiction Research Programs	000	5	2/26/2025	NON-COMPETING CONTINUATION	$332,681
														Subtotal = $332,681

Issue Date FY: 2024 ( Subtotal = $369,646 )
2024	2024	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Drug Use and Addiction Research Programs	001	4	4/26/2024	NON-COMPETING CONTINUATION	$36,965
2024	2024	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Drug Use and Addiction Research Programs	000	4	2/27/2024	NON-COMPETING CONTINUATION	$332,681
														Subtotal = $369,646

Issue Date FY: 2023 ( Subtotal = $369,646 )
2023	2023	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Drug Use and Addiction Research Programs	000	3	3/10/2023	NON-COMPETING CONTINUATION	$369,646
														Subtotal = $369,646

Issue Date FY: 2022 ( Subtotal = $369,255 )
2022	2022	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Drug Use and Addiction Research Programs	000	2	2/16/2022	NON-COMPETING CONTINUATION	$332,330
2022	2022	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Drug Use and Addiction Research Programs	001	2	3/29/2022	NON-COMPETING CONTINUATION	$36,925
														Subtotal = $369,255

Issue Date FY: 2021 ( Subtotal = $331,626 )
2021	2021	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Drug Use and Addiction Research Programs	000	1	2/25/2021	NEW	$331,626
														Subtotal = $331,626

Grand Total All Awards = $1,772,854

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The influence of noradrenergic circuitry on prefrontal neuronal ensemble dynamics and cue-induced heroin seeking

Award Number: R01DA051650

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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