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Functions and mechanisms of a molecularly defined prefrontal cortex neuron subtype in drug addiction

Award Number: R01DA062669
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 02/28/2031

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Functions and mechanisms of a molecularly defined prefrontal cortex neuron subtype in drug addiction - Functions and mechanisms of a molecularly defined prefrontal cortex neuron subtype in drug addiction Abstract Drug addiction is a chronic, relapsing brain disorder characterized by compulsive drug seeking and use despite harmful consequences. It is an urgent social and health problem contributing to more than 90,000 deaths and incurs a yearly cost of over $700 billion in the United States (see NIDA website). Yet, there is no treatment due to the lack of molecular understanding of addiction pathophysiology. The prefrontal cortex (PFC), a main cortical center regulating reward, is one of the key brain regions that regulate voluntary drug taking. Dysfunction of PFC is well-known in addiction. However, the PFC is also a center for cognitive and executive function. Its tremendous molecular, cellular and anatomical heterogeneity makes it challenging to identify specific neuronal types and circuits modulating addiction that can be selectively targeted. To overcome this problem, we have used single cell RNA sequencing and spatial transcriptomic technique MERFISH and decoded the heterogeneity of the mouse PFC by identifying the molecular composition and anatomical location of all constituent neuronal subtypes. We have also identified a distinct L5 neuron subtype, uniquely marked by the expression of the Pou3f1 gene, that sends specific projections to the midbrain peri-aqueductal gray (PAG) to be responsive to cocaine taking. We further generated a Pou3f1-Cre mouse line, and demonstrated in an intravenous cocaine self-administration (IVSA) mouse model that chemogenetic activation of the Pou3f1+ neurons reduced the drug seeking behavior supporting that the Pou3f1+ neurons play an important role in addiction pathogenesis. To understand the functions and mechanisms of how Pou3f1+ neurons and the PFCàPAG circuit regulate addiction, we have established the following specific aims: 1) To dissect the role of the L5 PFC Pou3f1+ neurons in chronic drug abuse and relapse; 2) To map the downstream circuit of Pou3f1+ neurons that modulate addiction behavior; 3) To identify molecular changes in the Pou3f1+ neurons and the PFC at large, under chronic drug abuse. Completion of the proposed study will not only reveal how the PFC Pou3f1 neuron subtype regulates addiction, but also provide potential targets for therapeutic intervention.


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 = $800,131 )
2026	2026	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	1	4/28/2026	NEW	$800,131
														Subtotal = $800,131

Grand Total All Awards = $800,131

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Functions and mechanisms of a molecularly defined prefrontal cortex neuron subtype in drug addiction

Award Number: R01DA062669

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 02/28/2031

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