# Epigenetic Influence on Thyroid Hormone Action in the Brain and on Behavior

> **NIH NIH R01** · MAINEHEALTH · 2020 · $389,000

## Abstract

The etiology of many neurodevelopmental disorders including autism, schizophrenia and
attention-deficit hyperactive disorder remains poorly understood. It is accepted that environmental
factors may be involved and that the heritability of those conditions is relatively high. Numerous
epidemiological and genome-wide association studies in affected populations have identified
environmental factors and candidate genes increasing the susceptibility to those conditions. However,
those genetic and environmental factors can only account for a small percentage of the clinical cases.
This suggests that additional environmental influences remain unidentified, and that the majority of
the heritable component of those conditions is of non-genetic origin.
 We hypothesize that brain overexposure to thyroid hormone during development is an important
factor contributing to both the environmental and non-genetic heritable components in the etiology of
neurodevelopmental disorders. To test this hypothesis, we will use mouse models with genetic and
epigenetic deficiency in DIO3, the main brain determinant controlling thyroid hormone action. In
Specific Aim #1, we will determine what are the consequences of allele-specific inactivation of Dio3
globally or specifically in neurons for the brain programs of gene expression, adult brain structure and
behavior.
 In Specific Aim #2, we will profile the fetal and neonatal brain expression and the adult brain
structure and behavior of genetically normal mouse descendants of ancestral mice that were exposed
to an excess of thyroid hormone during development. We will compare the results of developmental
gene expression in different parts of the brain with their adult behavior and with the altered
epigenome of exposed ancestors to define which brain developmental programs, brain regions, brain
functions, and related neurodevelopmental disorders that are affected by abnormal epigenetic
inheritance originated in ancestral overexposure to thyroid hormones.
 Based on the abnormal regulation of circadian rhythms that is typically associated with
neurodevelopmental disorders and is also observed in mice lacking the Dio3 gene, we will identify the
molecular and developmental basis by which developmental exposure to thyroid hormone excess
leads to the abnormal programming of the circadian clock (Specific Aim #3).
 We anticipate that our work will greatly advance our understanding of the etiology of complex
neurodevelopmental conditions and demonstrate the breakthrough concept that a developmental
excess of thyroid hormone influences the susceptibility to those conditions directly in the present
generation and indirectly in descendants via epigenetic mechanisms of inheritance.

## Key facts

- **NIH application ID:** 9815925
- **Project number:** 5R01MH096050-09
- **Recipient organization:** MAINEHEALTH
- **Principal Investigator:** Arturo Hernandez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $389,000
- **Award type:** 5
- **Project period:** 2012-06-26 → 2022-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9815925

## Citation

> US National Institutes of Health, RePORTER application 9815925, Epigenetic Influence on Thyroid Hormone Action in the Brain and on Behavior (5R01MH096050-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9815925. Licensed CC0.

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