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Amphetamine in adolescence disrupts frontal cortex development

Award Number: R01DA037911
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2015
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Amphetamine in adolescence disrupts frontal cortex development - Adolescence is an age of increased vulnerability to psychopathology, including drug abuse. My work concerns the molecular events underlying the maturation of the medial prefrontal cortex (mPFC) in adolescence and the effect of stimulant drugs on these processes. My ultimate goal is to unravel the molecular factors mediating risk and resilience in adolescence to the deleterious effects of drugs of abuse in males and females. Our work has focused on the impact of amphetamine (AMPH) on the development of the dopamine (DA) innervation to the mPFC. We discovered that DA axons are still growing toward the mPFC across adolescence, remaining particularly susceptible to disruption. This delayed DA axon growth is controlled by the guidance cue receptor DCC, which determines whether, when, and where DA axons stop or continue to grow. Notably, AMPH in early adolescence dysregulates DCC expression and also induces profound changes in mPFC DA synaptic connectivity/function and causes deficits in cognitive control in adulthood. Until very recently all our studies have been focused on male mice only. In addition, we have been investigating only AMPH effects of doses that reach plasma levels equivalent to those seen in recreational drug users. Our recent preliminary data suggest, however, that the vulnerability to the effects of AMPH on mPFC DA development is sex-specific. Also, recently published results show that therapeutic-like doses during this time induce opposite, even beneficial enduring effects. The experiments now proposed are designed to test the following working hypotheses: (a) that the vulnerability to AMPH-induced disruption of mPFC development at particular adolescent time windows is sexually biased, (b) that this dimorphism also impacts detrimental drug effects on adult cognitive processing, (c) that sex-specific control over DCC receptor expression in DA neurons mediates differential drug vulnerability/resilience (d) that these effects are dependent upon recreational- versus therapeutic-like exposure. Methods: To address these questions, we will conduct molecular, anatomical, neurochemical, and behavioral experiments in male and female mice. Our studies will combine dual viral transduction strategies and quantitative neuroanatomical analyses to track DA axon targeting and growth in adolescence. To measure DA function, we will use novel and temporal-sensitive measurements of in vivo DA signaling (dLIght1) in freely moving mice. To identify mechanisms underlying the dimorphic vulnerability to AMPH, we will perform gain- and loss-of-function experiments using neuron optimized CRISPR and Cre-Lox recombination strategies.


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 = $258,140 )
2024	2024	THE ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING	845 ST SHERBROOKE W	MONTREAL	QC			CAN	Drug Use and Addiction Research Programs	000	10	7/23/2024	NON-COMPETING CONTINUATION	$258,140
														Subtotal = $258,140

Issue Date FY: 2023 ( Subtotal = $258,140 )
2023	2023	ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING / MCGILL	845 RUE SHERBROOKE O	MONTREAL	PQ			CAN	Drug Use and Addiction Research Programs	000	9	7/17/2023	NON-COMPETING CONTINUATION	$258,140
														Subtotal = $258,140

Issue Date FY: 2022 ( Subtotal = $258,140 )
2022	2022	ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING / MCGILL	845 RUE SHERBROOKE O	MONTREAL	PQ			CAN	Drug Use and Addiction Research Programs	000	8	7/18/2022	NON-COMPETING CONTINUATION	$258,140
														Subtotal = $258,140

Issue Date FY: 2021 ( Subtotal = $261,477 )
2021	2021	ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING / MCGILL	845 RUE SHERBROOKE O	MONTREAL	PQ			CAN	Drug Use and Addiction Research Programs	001	7	7/30/2021	NON-COMPETING CONTINUATION	$261,477
2021	2019	ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING / MCGILL	845 RUE SHERBROOKE O	MONTREAL	PQ			CAN	Drug Use and Addiction Research Programs	000	5	11/12/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $261,477

Issue Date FY: 2020 ( Subtotal = $300,989 )
2020	2020	ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING / MCGILL	845 RUE SHERBROOKE O	MONTREAL	PQ	H3A 0G4		CAN	Drug Use and Addiction Research Programs	001	6	9/16/2020	COMPETING CONTINUATION	$300,989
2020	2019	ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING / MCGILL	845 RUE SHERBROOKE O	MONTREAL	PQ	H3A 0G4		CAN	Drug Use and Addiction Research Programs	000	5	9/16/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $300,989

Issue Date FY: 2019 ( Subtotal = $216,003 )
2019	2019	ROYAL INSTITUTE FOR ADVANCEMENT OF LEARNING MCGILL	845 SHERBROOKE STREET WEST	MONTREAL	PQ	H3A 0G4		CAN	Drug Use and Addiction Research Programs	000	5	1/28/2019	NON-COMPETING CONTINUATION	$216,003
														Subtotal = $216,003

Issue Date FY: 2018 ( Subtotal = $216,003 )
2018	2018	ROYAL INSTITUTE FOR ADVANCEMENT OF LEARNING MCGILL	845 SHERBROOKE STREET WEST	MONTREAL	PQ	H3A 0G4		CAN	Drug Use and Addiction Research Programs	001	4	4/26/2018	NON-COMPETING CONTINUATION	$21,599
2018	2018	ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING / MCGILL UNIVERSITY	845 RUE SHERBROOKE O BUREAU 318	MONTREAL	PQ	H3A 0G4		CAN	Drug Use and Addiction Research Programs	000	4	1/31/2018	NON-COMPETING CONTINUATION	$194,404
														Subtotal = $216,003

Issue Date FY: 2017 ( Subtotal = $216,003 )
2017	2017	ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING - MCGILL UNIVERSITY	845 SHERBROOKE ST WSUITE 531	MONTREAL	QC	H3A 2T5		CAN	Drug Use and Addiction Research Programs	000	3	1/24/2017	NON-COMPETING CONTINUATION	$194,404
2017	2017	ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING / MCGILL UNIVERSITY	845 RUE SHERBROOKE O BUREAU 318	MONTREAL	PQ	H3A 0G4		CAN	Drug Use and Addiction Research Programs	001	3	5/22/2017	NON-COMPETING CONTINUATION	$21,599
														Subtotal = $216,003

Issue Date FY: 2016 ( Subtotal = $239,867 )
2016	2016	MCGILL UNIVERSITY	361 UNIVERSITY STREET	MONTREAL, QUEBEC				CAN	Drug Use and Addiction Research Programs	000	2	2/8/2016	NON-COMPETING CONTINUATION	$239,867
														Subtotal = $239,867

Issue Date FY: 2015 ( Subtotal = $242,288 )
2015	2015	MCGILL UNIVERSITY	361 UNIVERSITY STREET	MONTREAL, QUEBEC				CAN	Drug Use and Addiction Research Programs	000	1	3/18/2015	NEW	$242,288
														Subtotal = $242,288

Grand Total All Awards = $2,467,050

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Amphetamine in adolescence disrupts frontal cortex development

Award Number: R01DA037911

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2015

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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