Although the etiology of many psychiatric disorders remains largely unknown, it is accepted that the underlying causes of these pathologies involve multiple genetic and environmental factors. The marked gender bias in the prevalence of most of these conditions suggests that mechanisms of brain sexual differentiation and/or sex steroid action in the brain might be contributing to their pathophysiology. Thyroid hormones (TH) are known to exert profound effects in the developing brain as well as to antagonize in this tissue the action of estrogen (E) in the regulation of gene expression and behavior. Robust homeostatic mechanisms are in place to ensure that TH concentrations are appropriate for a particular brain region at a specific developmental stage. One of these mechanisms is the type 3 deiodinase (D3), an enzyme that degrades TH. D3 is highly expressed in the developing and adult brain and is encoded by an imprinted gene. Preliminary results in D3-deficient mice generated in our laboratory indicate that D3 is necessary for adequate TH status and TH-dependent gene expression in most brain regions, including the hypothalamus. The lack of an active D3 also results in alterations in brain structure, abnormal social behavior and decreased levels of certain neuropeptides related to behavioral functions. The goal of the present Exploratory and developmental Research Grant (R21) application is to determine the role of the type 3 deiodinase (D3) in the sexual differentiation of the brain and/or in sex steroid action in this tissue. Using D3-deficient mice, I propose i) To define the regulatory functions of D3 and TH in various paradigms of E action in the developing and adult brain;and ii) To determine the effect of D3 deficiency on the E-dependent regulation and sexual dimorphism of selected neuropeptides related to behavior. These initial studies may identify D3 as a novel factor involved in the sexual differentiation of the brain and may point to altered TH metabolism and action in the brain as an important process influencing brain development and function and determining adult behavior. These studies may open a new area of research into the mechanisms contributing to the neurobiology of neurological disorders. As these findings may apply to humans, this and future studies may provide novel targets for therapeutic interventions aimed at preventing and treating developmental and psychiatric disorders.

Public Health Relevance

The studies proposed will use normal mice and mice deficient in the type 3 deiodinase to determine whether this enzyme has a role in regulating sex steroid action in the developing and/or adult brain and therefore affects brain sexual differentiation and the generation of sexually dimorphic features in the central nervous system. The confirmation of this hypothesis will provide a novel mechanism that may shed some light into the etiology and pathophysiology of certain neurological conditions in humans that exhibit a gender bias and that are characterized by abnormal behavior, such as autism, schizophrenia, bipolar disorder, depression and others.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH083220-02
Application #
7877705
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Panchision, David M
Project Start
2009-06-20
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2012-04-30
Support Year
2
Fiscal Year
2010
Total Cost
$197,500
Indirect Cost
Name
Dartmouth College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Hernandez, Arturo (2018) Thyroid Hormone Deiodination and Action in the Gonads. Curr Opin Endocr Metab Res 2:18-23
Stohn, J P; Martinez, M E; Zafer, M et al. (2018) Increased aggression and lack of maternal behavior in Dio3-deficient mice are associated with abnormalities in oxytocin and vasopressin systems. Genes Brain Behav 17:23-35
Wu, Zhaofei; Martinez, M Elena; St Germain, Donald L et al. (2017) Type 3 Deiodinase Role on Central Thyroid Hormone Action Affects the Leptin-Melanocortin System and Circadian Activity. Endocrinology 158:419-430
Stohn, J Patrizia; Martinez, M Elena; Matoin, Kassey et al. (2016) MCT8 Deficiency in Male Mice Mitigates the Phenotypic Abnormalities Associated With the Absence of a Functional Type 3 Deiodinase. Endocrinology 157:3266-77
Martinez, M Elena; Karaczyn, Aldona; Stohn, J Patrizia et al. (2016) The Type 3 Deiodinase Is a Critical Determinant of Appropriate Thyroid Hormone Action in the Developing Testis. Endocrinology 157:1276-88
Martinez, Maria Elena; Cox, David F; Youth, Brian P et al. (2016) Genomic imprinting of DIO3, a candidate gene for the syndrome associated with human uniparental disomy of chromosome 14. Eur J Hum Genet 24:1617-1621
Martinez, M Elena; Charalambous, Marika; Saferali, Aabida et al. (2014) Genomic imprinting variations in the mouse type 3 deiodinase gene between tissues and brain regions. Mol Endocrinol 28:1875-86
Peeters, Robin P; Hernandez, Arturo; Ng, Lily et al. (2013) Cerebellar abnormalities in mice lacking type 3 deiodinase and partial reversal of phenotype by deletion of thyroid hormone receptor ?1. Endocrinology 154:550-61
Oxenkrug, Gregory (2013) Serotonin-kynurenine hypothesis of depression: historical overview and recent developments. Curr Drug Targets 14:514-21
Charalambous, Marika; Hernandez, Arturo (2013) Genomic imprinting of the type 3 thyroid hormone deiodinase gene: regulation and developmental implications. Biochim Biophys Acta 1830:3946-55

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