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Leveraging adolescent plasticity mechanisms to enhance adult frontal dopaminergic circuit function

Award Number: K01DA065706
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Leveraging adolescent plasticity mechanisms to enhance adult frontal dopaminergic circuit function - Abstract My goal is to head an independent research program studying dopaminergic system dysfunction in neurodevelopmental disorders. I have extensive in vivo two-photon microscopy, neural circuit dissection, microglial physiology, and behavioral assay experience. Under my proposed training plan, I will work closely with my co-mentors, Drs. Kuan Wang, Zhigang He, Yi Zuo, and Julie Fudge to broaden and strengthen my research expertise to prepare for full research independence. Dr. Wang is an expert in the developmental plasticity and function of dopaminergic projections to the frontal cortex and in vivo imaging. Dr. He is an expert in sequencing and bioinformatic analyses of transcriptomic changes in microglia in response to CNS milieu disruption. Dr. Zuo is an expert on behavioral assays and circuit plasticity. Dr. Fudge is an expert in the dopaminergic system and psychiatric conditions. Collectively, my mentorship team and experimental plans will provide me with the technical skills and conceptual expertise to become an independent researcher in the fields of dopaminergic development and neuroimmune interactions. The Del Monte Institute of Neuroscience will provide a rich and collaborative training environment with an extensive network of investigators working on neurodevelopmental disorders within the URMC UR-IDDRC. In the Wang Lab, I have explored the mechanisms which drive mesocortical plasticity. Previous published work in the Wang lab established that the mesocortical dopaminergic projections from the ventral tegmental area (VTA) to the frontal cortex undergo activity dependent axonal bouton formation in response to VTA stimulation in adolescents but not adults. However, dopamine receptor 2 (D2R) inhibition paired with stimulation reopens adult plasticity. Interestingly, chemogenetic stimulation of dopaminergic VTA projections during adolescence ameliorates circuit and behavioral deficits in mice with genetic mutations disrupting mesocortical circuit function. My postdoctoral work shows that activity-dependent changes in the adolescent mesocortical circuit increase microglial surveillance of the parenchyma and microglial contacts with axonal boutons and that DR manipulation disrupts these interactions. My immediate goals are to understand the signals which regulate mesocortical dopaminergic plasticity, and to evaluate the therapeutic potential of reopening plasticity after developmental insult. (Aim 1) I will evaluate if microglia are necessary for the reopening of mesocortical plasticity in adult animals. (Aim 2) I will determine if reopening plasticity in adult mice with circuit disruptions from juvenile Δ-9-tetrahydrocannabinol exposure is effective at rescuing both dopaminergic hypofrontality and behavioral deficits. (Aim 3) I will use single-cell sequencing to identify changes in dopaminergic receptor signaling pathways between adolescent and adult animals which close the window of mesocortical plasticity. These experiments will provide a mechanistic understanding of mesocortical plasticity regulation and they will evaluate the therapeutic potential of reopening plasticity in the adult mesocortical circuit.


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: 2026 ( Subtotal = $156,555 )
2026	2026	UNIVERSITY OF ROCHESTER	910 GENESEE ST	ROCHESTER	NY	14611	MONROE	USA	Drug Use and Addiction Research Programs	000	1	4/21/2026	NEW	$156,555
														Subtotal = $156,555

Grand Total All Awards = $156,555

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Leveraging adolescent plasticity mechanisms to enhance adult frontal dopaminergic circuit function

Award Number: K01DA065706

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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