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CB1-mediated signaling in developmental ethanol effects

Award Number: R01AA029686
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: 09/18/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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CB1-mediated signaling in developmental ethanol effects - Project Summary During pregnancy, alcohol abuse produces persistent changes in the fetal brain, causing behavioral impairments throughout life. These conditions are defined as fetal alcohol spectrum disorder (FASD). Most concerningly, regular binge drinking during pregnancy causes cognitive and socio-behavioral deficits in offspring. However, the molecular mechanisms underlying persistent alcohol-induced neurobehavioral impairments are not fully understood. Our previous studies demonstrated that alcohol exposure results in CB1 signaling defects in neonatal mice (P7) that cause neurodegeneration and behavioral deficits in adults. Other data also implicate CB1 in the teratogenic effects of alcohol. However, whether synaptic and behavioral deficits are due to alcohol-induced changes in CB1 and its signaling events within the adult hippocampus (HP) and prefrontal cortical (PFC) regions remains largely unknown. CB1s are mainly expressed in glutamatergic and GABAergic neurons. They can elicit cell-type-specific signaling depending on where they are activated and contribute to neuronal and behavior outcomes. CB1 activity also regulates gene expression via epigenetics; however, the mechanisms are unknown. Our recent pilot findings suggested that human third-trimester-equivalent alcohol exposure in neonatal mice caused persistent cognitive and social behavior deficits. These behavioral changes were accompanied by increased CB1 expression, histone methylation, and reduced expression of genes essential for synaptic structure and function in specific neuronal types. These findings suggest that alcohol alters the transcriptional control of gene expression and synaptic function in a given cell type in the PFC and HP. This proposal will test the hypothesis that a mechanism underlying synaptic dysfunction in the PFC and HP contributing to behavioral deficits is enhanced CB1 activity and histone methylation by postnatal alcohol leading to aberrant synaptic gene expression. This proposal will test these hypotheses in PFC and HP using cell-type-specific (Cre or CreERT2) RiboTag (TRAP) technology to study CB1 and histone methylation events altered by postnatal alcohol exposure (PAE). We will pay special attention to evidence of aberrant regulation of histone methylation responsive genes related to spine and synaptic vesicle function. Additionally, we will investigate the role of histone methylation on synaptic structure and function by conditional deletion (cKO) of the CB1 gene or a gene encoding a histone-methylation-related enzyme (FloxP lines) in the specific neuronal type (CreERT2) in the adult PFC and HP. Finally, we will mechanistically test the effects of modulating histone methylation levels using cKO of CB1 or histone methylation enzyme function in specific neuronal types to rescue adult cognitive and social behaviors. These studies will use sex-dependent models to perform a combined epigenetic, synaptic, and behavioral analysis of the response to PAE. Our goals in this proposal are to identify the mechanisms underlying the long-lasting changes in CB1 and histone-methylation-related transcriptional and synaptic changes in the PFC and HP and determine their contributions to the persistent cognitive and socio- behavioral deficits resulting from PAE. The findings will elucidate pathways and provide possible novel targets for therapeutic intervention in PAE-related neurological disease.


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 = $447,588 )
2025	2025	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD BLDG 35	ORANGEBURG	NY	10962	ROCKLAND	USA	Alcohol Research Programs	000	3	7/30/2025	NON-COMPETING CONTINUATION	$447,588
														Subtotal = $447,588

Issue Date FY: 2024 ( Subtotal = $453,587 )
2024	2024	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD BLDG 35	ORANGEBURG	NY	10962	ROCKLAND	USA	Alcohol Research Programs	000	2	6/28/2024	NON-COMPETING CONTINUATION	$453,587
														Subtotal = $453,587

Issue Date FY: 2023 ( Subtotal = $454,653 )
2023	2023	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD BLDG 35	ORANGEBURG	NY	10962	ROCKLAND	USA	Alcohol Research Programs	000	1	9/18/2023	NEW	$454,653
														Subtotal = $454,653

Grand Total All Awards = $1,355,828

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CB1-mediated signaling in developmental ethanol effects

Award Number: R01AA029686

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: 09/18/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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