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Endocannabinoids regulate microglia in developing brain

Award Number: R01DA039062
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2016
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Endocannabinoids regulate microglia in developing brain - Endocannabinoids (EDCs) and the innate immune system are two early signaling systems which independently and together profoundly influence brain development. Critical windows of development are also often sensitive periods for disruption by exogenous stimuli. We have discovered a unique critical period in the neonatal amygdala of the rat during which the innate immune cells of the brain, microglia, actively engulf and kill newborn cells that if left unmolested would have gone on to become astrocytes. Through this mechanism the future density of astrocytes in the amygdala is determined. Most remarkably, the optimal density is lower for males than females in that it is causally responsible for increased neuronal activity many weeks later during epochs of adolescent social play. Equally remarkable, the increased phagocytic activity of microglia in the male amygdala is a direct consequence of a higher EDC tone, which is in turn developmentally programmed by elevated androgens in neonatal males. Changes to either androgen levels or, more importantly, EDC tone, including by exposure to THC, during the critical period permanently alters the neuronal/astrocytic population and playfulness during adolescence. Marijuana use during pregnancy and breastfeeding is prevalent and increasing due to legalization, decriminalization and medicalization but we are largely ignorant of the potential consequences to the fetal and newborn brain. Advances in transcriptomics and adeno-associated virus (AAV) techniques provide new tools for exploration and precision not previously accessible for the rat. A primary goal is a deep mechanistic understanding of endocannabinoid-induced microglia phagocytosis of astrocytic progenitors to illuminate with unprecedented specificity the interaction between immune, neuronal, astrocytic and progenitor cells. An additional goal is to establish a larger framework for understanding development THC exposure that converges on inhibitory neurons in brain regions regulating sex-typic social behaviors. We will achieve these dual ends via the following Specific Aims. Aim 1 will fully characterize the endocannabinoid and innate immune systems of the developing amygdala by high precision cell phenotyping, identification of the source of complement proteins needed for phagocytosis, and transcriptomics to identify genes mediating cell survival. In Aim 2 we will selectively reduce androgen receptor in one cell type at a time to determine the source of the sex difference in endocannabinoid tone and Aim 3 will interrogate the relationship between the effects of THC, EDCs and androgen action with an emphasis on inhibitory neurons across brain regions. Combined, these studies will provide unprecedented clarity in the cellular participants and mechanisms establishing a sex difference in a social circuit and how that process can go awry as a consequence of developmental THC exposure.


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 = $469,533 )
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	001	9	4/21/2025	NON-COMPETING CONTINUATION	$46,953
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	000	9	2/28/2025	NON-COMPETING CONTINUATION	$422,580
														Subtotal = $469,533

Issue Date FY: 2024 ( Subtotal = $469,534 )
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	000	8	2/23/2024	NON-COMPETING CONTINUATION	$422,580
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	001	8	4/26/2024	NON-COMPETING CONTINUATION	$46,954
														Subtotal = $469,534

Issue Date FY: 2023 ( Subtotal = $469,533 )
2023	2023	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	002	7	2/20/2023	NON-COMPETING CONTINUATION	$469,533
2023	2022	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	001	6	12/14/2022	COMPETING CONTINUATION	$219
2023	2020	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	000	5	12/14/2022	NON-COMPETING CONTINUATION	-$219
														Subtotal = $469,533

Issue Date FY: 2022 ( Subtotal = $495,731 )
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	000	6	5/25/2022	COMPETING CONTINUATION	$495,731
														Subtotal = $495,731

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	000	5	3/22/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $347,625 )
2020	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	000	5	1/30/2020	NON-COMPETING CONTINUATION	$347,625
														Subtotal = $347,625

Issue Date FY: 2019 ( Subtotal = $347,625 )
2019	2019	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	000	4	1/31/2019	NON-COMPETING CONTINUATION	$347,625
														Subtotal = $347,625

Issue Date FY: 2018 ( Subtotal = $347,625 )
2018	2018	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	001	3	4/26/2018	NON-COMPETING CONTINUATION	$34,763
2018	2018	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	000	3	1/24/2018	NON-COMPETING CONTINUATION	$312,862
														Subtotal = $347,625

Issue Date FY: 2017 ( Subtotal = $448,050 )
2017	2017	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	002	2	7/24/2017	SUPPLEMENT FOR EXPANSION	$100,425
2017	2017	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	001	2	5/22/2017	NON-COMPETING CONTINUATION	$34,763
2017	2017	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	000	2	1/20/2017	NON-COMPETING CONTINUATION	$312,862
														Subtotal = $448,050

Issue Date FY: 2016 ( Subtotal = $347,344 )
2016	2016	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	000	1	3/21/2016	NEW	$347,344
														Subtotal = $347,344

Grand Total All Awards = $3,742,600

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Endocannabinoids regulate microglia in developing brain

Award Number: R01DA039062

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2016

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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