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Functional consequences of fetal-alcohol-induced brain growth abnormalities identified with in utero MRI

Award Number: R01AA028769
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Functional consequences of fetal-alcohol-induced brain growth abnormalities identified with in utero MRI - PROJECT SUMMARY Fetal exposure to alcohol leads to a wide range of neurological deficits collectively termed fetal alcohol spectrum disorder (FASD). This prevalent neurodevelopmental disorder currently affects as many as 1-5% of school-aged children in the United States. Existing intervention strategies can improve the quality of life in affected individuals, but early detection is critical for efficacious therapy. In utero MRI has benefited from recent improvements in retrospective motion correction methods in 3D image reconstruction, and is a promising non- invasive technique for identifying abnormal brain development associated with fetal exposure to alcohol. We have recently developed a rhesus macaque model of FASD that resembles human drinking early in gestation, prior to pregnancy awareness, but ceases upon recognition of pregnancy. Abnormal brain growth is apparent at gestation day (G)135 by MRI in fetuses of rhesus macaques that orally self-administered 1.5 g/kg (approximately 6 drinks) daily ethanol over the first 60 days of pregnancy. Compared to controls, ethanol- exposed fetuses possessed brains with smaller cerebellums and less developed white matter fiber systems involved in motor and cognitive function. Ex vivo electrophysiological recordings performed on the G135 fetuses demonstrated that the MRI-identified abnormalities are associated with functional impairments in glutamatergic transmission. The experiments proposed in this application will determine the behavioral consequences of these anatomical and functional abnormalities, and further extend the MRI and electrophysiological characterization of this model of FASD. Twelve rhesus macaques exposed to daily maternal 1.5 g/kg ethanol drinking over the first 60 days of gestation will be compared to 12 control animals. In utero MRI will be performed at G135, and the offspring will be survived to postnatal day (P)180 (approximately 6 months of age). Additional MRI experiments will be performed on P3 and P180. Aim 1 of this proposal will use fetal (G135) and postnatal MRI (P3 and P180) to define the long-term impact of ethanol exposure on brain development. This Aim includes a primary analysis focused on brain structures identified to be different at G135 and whole-brain analysis to define additional brain regions sensitive to fetal ethanol exposure. These results will facilitate data reduction for the combined analyses with other experimental modalities in Aims 2 and 3. Aim 2 will examine impairments in motor behavior due to fetal ethanol exposure and define the underlying neural circuitry. Aim 3 will define the impairments in cognitive function and emotional regulation induced by fetal ethanol exposure and identify the developmental processes and specific brain regions associated with these impairments.


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 = $635,560 )
2025	2025	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Alcohol Research Programs	000	5	4/24/2025	NON-COMPETING CONTINUATION	$635,560
														Subtotal = $635,560

Issue Date FY: 2024 ( Subtotal = $641,513 )
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Alcohol Research Programs	001	4	5/20/2024	NON-COMPETING CONTINUATION	$64,150
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Alcohol Research Programs	000	4	2/8/2024	NON-COMPETING CONTINUATION	$577,363
														Subtotal = $641,513

Issue Date FY: 2023 ( Subtotal = $673,544 )
2023	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Alcohol Research Programs	000	3	2/10/2023	NON-COMPETING CONTINUATION	$673,544
														Subtotal = $673,544

Issue Date FY: 2022 ( Subtotal = $688,779 )
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Alcohol Research Programs	001	2	6/20/2022	NON-COMPETING CONTINUATION	$68,879
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Alcohol Research Programs	000	2	3/11/2022	NON-COMPETING CONTINUATION	$619,900
														Subtotal = $688,779

Issue Date FY: 2021 ( Subtotal = $687,020 )
2021	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Alcohol Research Programs	000	1	4/27/2021	NEW	$687,020
														Subtotal = $687,020

Grand Total All Awards = $3,326,416

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Functional consequences of fetal-alcohol-induced brain growth abnormalities identified with in utero MRI

Award Number: R01AA028769

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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