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Thyroid hormone remodels cortex to coordinate body-wide metabolism and exploration

Affiliations
  • 1Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Society of Fellows, Harvard University, Cambridge, MA 02138, USA.
  • 2Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
  • 3Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
  • 4Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
  • 5Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 6Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
  • 7Department of Neurobiology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
  • 8Center for Computational Biomedicine, Harvard Medical School, Boston, MA 02215, USA.
  • 9Department of Chemical Physiology & Biochemistry, Oregon Health & Science University, Portland, OR 97239, USA.
  • 10Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 11Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: bernardo_sabatini@hms.harvard.edu.

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August 23, 2024

Abstract

Animals adapt to environmental conditions by modifying the function of their internal organs, including the brain. To be adaptive, alterations in behavior must be coordinated with the functional state of organs throughout the body. Here, we find that thyroid hormone-a regulator of metabolism in many peripheral organs-directly activates cell-type-specific transcriptional programs in the frontal cortex of adult male mice. These programs are enriched for axon-guidance genes in glutamatergic projection neurons, synaptic regulatory genes in both astrocytes and neurons, and pro-myelination factors in oligodendrocytes, suggesting widespread plasticity of cortical circuits. Indeed, whole-cell electrophysiology revealed that thyroid hormone alters excitatory and inhibitory synaptic transmission, an effect that requires thyroid hormone-induced gene regulatory programs in presynaptic neurons. Furthermore, thyroid hormone action in the frontal cortex regulates innate exploratory behaviors and causally promotes exploratory decision-making. Thus, thyroid hormone acts directly on the cerebral cortex in males to coordinate exploratory behaviors with whole-body metabolic state.

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