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Long-lasting consequences of early ethanol on network activity during sleep

Award Number: R01AA023181
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: 08/05/2014
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Long-lasting consequences of early ethanol on network activity during sleep - ABSTRACT/SUMMARY Fetal alcohol spectrum disorder (FASD) is one of the primary causes of intellectual disability in western nations, with neurobehavioral hallmarks such as deficits in learning, memory and mood. We propose that developmental ethanol (EtOH) exposure may induce long-lasting disruption of neural activity patterns during sleep which are known to be important for memory consolidation and synaptic homeostasis. If so, this would create a situation wherein the normal ability of the nervous system to repair and readjust itself during sleep would be impaired, resulting in a daily insult to nervous system function long after the EtOH exposure ended. In support of this hypothesis, during the past funding cycle we have demonstrated that developmental EtOH 1) disrupts and fragments adult non-REM sleep, 2) the extent of sleep disruption in adults predicts cognitive impairment, 3) the sleep impairment is associated with severe loss of parvalbumin (PV) and somatostatin (SST) expressing GABAergic interneurons which are known to contribute to sleep-wake architecture, 4) disruption of PV cell function through neuropentraxin knock-out replicates some aspects of developmental ethanol but not sleep, and 5) preventing cell loss induced by developmental EtOH with LiCl prevents sleep, anatomical, and cognitive impairments. In this renewal, we plan to further explore the mechanisms of developmental EtOH effects on sleep and waking with cell specific analyses. Aim 1 will test the hypothesis that selective optogenetic activation of spared GABAergic neurons will restore the deficits in sleep and cognition induced by developmental EtOH in transgenic mice (e.g., SST-Cre; Aim 1.1). In the same animals, we will correlate sleep-wake function/dysfunction/repair with anatomical structure of several identified GABAergic circuits (e.g., SST, reelin, vasoactive intestinal peptide (VIP)) in sleep-related regions including basal forebrain nuclei, hippocampus and neocortex. Data will include synaptic interactions of identified cell types using confocal and electron microscopy as well as Golgi analyses (Aim 1.2). Performing the anatomical analyses on animals that we have assayed for sleep/wake and cognitive function will allow us to directly relate structure (e.g., synaptic density) with neurobehavioral function/dysfunction/repair (e.g., slow-wave activity, excitatory/inhibitory [E/I] balance). Aim 2.1 examines to what extent PV/SST cells are killed by developmental EtOH, or alternatively have down-regulated phenotypic expression by tracking the fate of fluorescently labeled PV/SST neuron progenitors in Nkx2.1-Cre;Ai9 mice exposed to EtOH. This will provide information needed to guide attempts to restore GABAergic function after EtOH exposure. Aim 2.2 will transplant PV/SST interneuron progenitors into EtOH treated mice, to examine if re-populating GABAergic neurons in identified brain regions will restore sleep and/or cortical activity (e.g., slow- wave activity, E/I balance), as well as sleep-related cognitive function and circuit structure. If successful, results from this proposal could open a new window into both understanding and repair of early ethanol-induced neural and cognitive impairment.


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 = $408,844 )
2024	2024	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD BLDG 35	ORANGEBURG	NY	10962	ROCKLAND	USA	Alcohol Research Programs	000	10	7/30/2024	NON-COMPETING CONTINUATION	$408,844
														Subtotal = $408,844

Issue Date FY: 2023 ( Subtotal = $408,844 )
2023	2023	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD BLDG 35	ORANGEBURG	NY	10962	ROCKLAND	USA	Alcohol Research Programs	000	9	7/31/2023	NON-COMPETING CONTINUATION	$408,844
														Subtotal = $408,844

Issue Date FY: 2022 ( Subtotal = $408,407 )
2022	2022	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Alcohol Research Programs	002	8	7/25/2022	NON-COMPETING CONTINUATION	$408,844
2022	2018	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Alcohol Research Programs	001	5	6/29/2022	NON-COMPETING CONTINUATION	-$437
2022	2017	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Alcohol Research Programs	000	4	6/29/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $408,407

Issue Date FY: 2021 ( Subtotal = $408,844 )
2021	2021	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Alcohol Research Programs	002	7	7/23/2021	NON-COMPETING CONTINUATION	$408,844
2021	2020	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Alcohol Research Programs	001	6	2/2/2021	COMPETING CONTINUATION	$50,297
2021	2018	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Alcohol Research Programs	000	5	2/2/2021	NON-COMPETING CONTINUATION	-$50,297
														Subtotal = $408,844

Issue Date FY: 2020 ( Subtotal = $408,844 )
2020	2020	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Alcohol Research Programs	000	6	8/3/2020	COMPETING CONTINUATION	$408,844
														Subtotal = $408,844

Issue Date FY: 2018 ( Subtotal = $322,400 )
2018	2018	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Alcohol Research Programs	000	5	7/9/2018	NON-COMPETING CONTINUATION	$322,400
														Subtotal = $322,400

Issue Date FY: 2017 ( Subtotal = $322,400 )
2017	2017	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Alcohol Research Programs	000	4	7/17/2017	NON-COMPETING CONTINUATION	$322,400
														Subtotal = $322,400

Issue Date FY: 2016 ( Subtotal = $322,400 )
2016	2016	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC	150 BROADWAY SUITE 301	MENANDS	NY	12204	ALBANY	USA	Alcohol Research Programs	000	3	7/14/2016	NON-COMPETING CONTINUATION	$322,400
														Subtotal = $322,400

Issue Date FY: 2015 ( Subtotal = $312,728 )
2015	2015	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC	150 BROADWAY SUITE 301	MENANDS	NY	12204	ALBANY	USA	Alcohol Research Programs	000	2	8/1/2015	NON-COMPETING CONTINUATION	$312,728
														Subtotal = $312,728

Issue Date FY: 2014 ( Subtotal = $322,400 )
2014	2014	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC	150 BROADWAY SUITE 301	MENANDS	NY	12204	ALBANY	USA	Alcohol Research Programs	000	1	8/7/2014	NEW	$322,400
														Subtotal = $322,400

Grand Total All Awards = $3,646,111

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Long-lasting consequences of early ethanol on network activity during sleep

Award Number: R01AA023181

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: 08/05/2014

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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