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Mechanisms and treatments of learning deficits in Fetal Alcohol Spectrum Disorders

Award Number: R01AA026272
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: 01/25/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Mechanisms and treatments of learning deficits in Fetal Alcohol Spectrum Disorders - Prenatal alcohol (ethanol) exposure (PAE) significantly impacts cognitive and behavioral abilities of the offspring. These conditions are defined as Fetal Alcohol Spectrum Disorders (FASD). Early intervention of such abnormalities is imperative for optimal outcomes; however, specific therapeutic targets and effective treatments are yet unavailable. The goal of this project is to elucidate the mechanisms underlying the long-term impacts of prenatal alcohol exposure and find effective treatments for the symptoms caused by such impacts in FASD. We have recently shown that the activation of heat shock signaling, which protects young neurons in the alcohol-exposed embryonic brain, can instead cause neuronal migration delay when it is hyperactivated. Our preliminary analysis has identified novel, long-term changes in gene expression associated with this prenatal hyperactivation of heat shock signaling, at the single-cell level within the brains of adolescent mice. These mice show gross and fine motor skills impairment, one of the earliest problems in FASD patients noticed by caregivers. Some of these changes were negatively correlated with the motor learning ability of these mice, and remarkably, reverting one of such altered factors, increased Kcnn2 (a calcium-activated potassium channel) function, improved the motor learning deficits. In addition, preliminary data suggested that overexpression of Kcnn2 in the motor cortex alone can cause motor learning defects. Based on these findings and preliminary data, we hypothesize that epigenetic changes associated with acute high-level activation of heat shock signaling in the fetal brain by PAE are involved in motor learning defects in later life. To test this hypothesis, we will first define the postnatal epigenetic traits specifically associated with the prenatal acute activation of heat shock signaling in the motor cortex of PAE mice, which display motor learning deficits (Aim 1). By investigating the specific effects of Kcnn2 overexpression in untreated mice and those of Kcnn2 knockdown in PAE mice, we will then define how increased Kcnn2 expression contributes to the learning deficits of PAE mice (Aim 2). We also test whether reverting the increased Kcnn2 function can be a novel therapeutic target to improve the deficits (Aim 3). Our multidisciplinary team puts our expertise to achieve these aims, by employing in vivo Kcnn2 manipulation, in vivo imaging and behavior analysis (Torii lab.), electrophysiology and epigenetic analyses (Hashimoto-Torii lab.). By combining a unique reporter system that we developed with these cutting-edge techniques, we will uncover hitherto unknown epigenetic mechanisms leading to neurobehavioral problems in FASD, and develop potentially novel interventions.


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 = $0 )
2024	2023	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Alcohol Research Programs	000	5	5/3/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $401,625 )
2023	2023	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Alcohol Research Programs	000	5	12/29/2022	NON-COMPETING CONTINUATION	$361,463
2023	2023	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Alcohol Research Programs	001	5	3/14/2023	NON-COMPETING CONTINUATION	$40,162
														Subtotal = $401,625

Issue Date FY: 2022 ( Subtotal = $803,248 )
2022	2022	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Alcohol Research Programs	002	4	6/25/2022	SUPPLEMENT FOR EXPANSION	$401,623
2022	2022	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Alcohol Research Programs	001	4	6/16/2022	NON-COMPETING CONTINUATION	$40,163
2022	2022	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Alcohol Research Programs	000	4	12/24/2021	NON-COMPETING CONTINUATION	$361,462
														Subtotal = $803,248

Issue Date FY: 2021 ( Subtotal = $401,625 )
2021	2021	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Alcohol Research Programs	001	3	2/23/2021	NON-COMPETING CONTINUATION	$40,163
2021	2021	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Alcohol Research Programs	000	3	12/15/2020	NON-COMPETING CONTINUATION	$361,462
														Subtotal = $401,625

Issue Date FY: 2020 ( Subtotal = $401,625 )
2020	2020	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Alcohol Research Programs	000	2	12/27/2019	NON-COMPETING CONTINUATION	$361,462
2020	2020	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Alcohol Research Programs	001	2	4/2/2020	NON-COMPETING CONTINUATION	$40,163
														Subtotal = $401,625

Issue Date FY: 2019 ( Subtotal = $401,625 )
2019	2019	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Alcohol Research Programs	000	1	1/23/2019	NEW	$401,625
														Subtotal = $401,625

Grand Total All Awards = $2,409,748

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Mechanisms and treatments of learning deficits in Fetal Alcohol Spectrum Disorders

Award Number: R01AA026272

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: 01/25/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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