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Control of opioid-motivated approach and avoidance behavior by neuronal ensembles in the basolateral amygdala and their projection targets in the nucleus accumbens

Award Number: K01DA054449
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Control of opioid-motivated approach and avoidance behavior by neuronal ensembles in the basolateral amygdala and their projection targets in the nucleus accumbens - Project Summary / Abstract Opioid Use Disorder (OUD) is a chronic, relapsing brain disease characterized by compulsive drug seeking and use, engaging specific neurocircuits. One of the major projection systems implicated in regulating behavior motivated by drugs of abuse including opioids is the basolateral amygdala (BLA) pathway to nucleus accumbens (NAc). However, the BLANAc projection mediates not only approach behavior, as required for drug seeking, but also avoidance responses. This introduces the question as to the mechanisms by which a single excitatory projection system mediates diametrically opposite behaviors. Our preliminary data revealed that morphine (a rewarding opioid agonist) and naloxone (an aversive opioid antagonist) recruit two distinct groups of neurons – neuronal ensembles or engrams – within the same (BLA) brain area. Moreover, selective activation of morphine vs. naloxone reactive BLA axon terminals in the NAc induced opposing conditioned place preference (CPP) and aversion (CPA) respectively. These preliminary data establish a role for two discrete drug-reactive NAc-projecting BLA ensembles each differentially and selectively sensitive to activation by rewarding (morphine) vs. aversive (naloxone) events which elicit the acquisition of approach vs. avoidance behavior. Based on these results, we hypothesize that the expression of CPP and CPA are also mediated by similarly distinct BLANAc ensembles selectively sensitive to morphine vs. naloxone environmental context. In support of this hypothesis, additional preliminary findings confirmed that the expression of morphine CPP and naloxone CPA are accompanied by neuronal activation in both the BLA and NAc. The goal of this proposal is to confirm the function of the morphine vs. naloxone context-reactive BLANAc ensembles for the expression of CPP/CPA, and to establish the brain-wide source of activation innervating these two distinct BLANAc ensembles mediating opposing behaviors. This K01 proposal will, therefore, test the central hypothesis that an environmental context linked to morphine (Aim 1) vs. naloxone (Aim 2) recruits discrete NAc-projecting BLA ensembles, which are activated by excitatory input (Aim 3) from brain areas that process information representing the respective context, thereby engaging discrete BLANAc ensembles to selectively regulate approach vs. avoidance behavior. The training plan, under the primary mentorship of Dr. Friedbert Weiss at Scripps Research, provides a comprehensive research and career development plan for acquiring the necessary experimental and professional skills within a collaborative neuroscience environment. An experienced team of mentors and career advisors will provide training critical for the candidate’s short- and long-term success, including: experiential and didactic learning in study design, execution, and interpretation of behavioral models of drug seeking with a focus on stimuli-responsive activated neurons. Finally, the professional development plan will equip the candidate to lead a laboratory research program investigating the neurobiological control of drug seeking behavior by distinct neuronal ensembles distributed across multiple brain areas comprising behaviorally relevant neurocircuits.


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: 2024 ( Subtotal = $173,275 )
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	3	8/21/2024	NON-COMPETING CONTINUATION	$173,275
														Subtotal = $173,275

Issue Date FY: 2023 ( Subtotal = $173,275 )
2023	2023	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	001	2	8/3/2023	NON-COMPETING CONTINUATION	$173,275
2023	2022	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	1	10/17/2022	NEW	$0
														Subtotal = $173,275

Issue Date FY: 2022 ( Subtotal = $173,275 )
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	1	8/29/2022	NEW	$173,275
														Subtotal = $173,275

Grand Total All Awards = $519,825

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Control of opioid-motivated approach and avoidance behavior by neuronal ensembles in the basolateral amygdala and their projection targets in the nucleus accumbens

Award Number: K01DA054449

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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