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Allelic Dio3 control of brain development and behavior

Award Number: R01MH139529
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/24/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Allelic Dio3 control of brain development and behavior - Abstract Neurodevelopmental and neurological and mood disorders manifest a high prevalence in modern society and a marked sex bias, but their etiology remain poorly understood, hampering our efforts for their prevention, diagnosis and treatment. Although genome-wide association studies in the last two decades have greatly advanced our knowledge of the genetic basis for these conditions, identified candidate genes and their genetic variations only explain a small percentage of clinical cases. This divergence is dramatically illustrated by autism and schizophrenia, whose heritability is close to 80%, but for which genetic factors account for less than 20% of clinical cases. To identify new contributors to the etiology of these and related neurodevelopmental conditions, we propose that alterations in thyroid hormone states during development, which may occur due to environmentally-driven epigenetic phenomena, maternal thyroid disease or exposure to endocrine disruptors, contribute to the generation of neurodevelopmental disease and fit two well-established but undefined components in their etiology: environmental influence via epigenetic alterations and sex bias. We hypothesize that changes in the allelic expression and gene dosage of the imprinted gene Dio3, which controls thyroid hormone action in the developing central nervous system, leads to neurological deficits, affecting gene expression programs in the developing brain, brain sexual differentiation, brain morphology and behavior of relevance to neurodevelopmental and psychiatric conditions. We will use transgenic mouse models with alteration in Dio3 and developmental thyroid hormone exposure to test these hypotheses in the following Specific Aims: (i) To determine the neurological impact of aberrant Dio3 allelic expression; (ii) To evaluate the role of full DIO3 deficiency and altered Dio3 allelic expression in brain sexual differentiation and associated disease-relevant behaviors with a sexual bias. By using a dynamic mouse model of epigenetic dysregulation of Dio3, we anticipate our project will demonstrate that modifications in brain thyroid hormone states during development exert a substantial effect on the gene expression programs of the central nervous system, ultimately leading to disease-relevant neurological deficits impacting corticogenesis, brain morphology and hydrocephalus, and behaviors related to depression, anxiety, sociability, hyperactivity, sexual activity and reward. We ultimately expect that epigenetic markers and dysregulation of the Dio3 gene, and the changes in thyroid hormone status associated with them, can be used as evidence of exposures to thyroid hormone earlier in life and be utilized as predictors of susceptibility to neurodevelopmental conditions.


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: 2026 ( Subtotal = $466,738 )
2026	2026	MAINEHEALTH	110 FREE ST	PORTLAND	ME	04101	CUMBERLAND	USA	Mental Health Research Grants	000	1	6/30/2026	NEW	$466,738
														Subtotal = $466,738

Grand Total All Awards = $466,738

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Allelic Dio3 control of brain development and behavior

Award Number: R01MH139529

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/24/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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