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

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 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 frontal cortex regulates innate exploratory behaviors and causally promotes exploratory decision-making. Thus, thyroid hormone acts directly on cerebral cortex in males to coordinate exploratory behaviors with whole-body metabolic state. To identify transcriptional programs that may mediate thyroid-dependent changes in exploratory behaviors, we conducted single-nucleus RNA sequencing (snRNAseq) of dorsal frontal cortex, centered on the secondary motor cortex, of control male mice or those exposed to systemic thyroid hormone (T3) treatment for 2.5 days. To address whether the T3-regulated transcriptional programs are a cell-autonomous response to T3 in cortical neurons, we also performed snRNAseq on a cohort of mice expressing either a mutant thyroid receptor derived from an individual with generalized thyroid resistance (DN-THR) or overexpression of the wild-type thyroid receptor (WT-THR). Datasets were analyzed to identify thyroid hormone-induced, cell-type specific transcriptional programs in the male mouse frontal cortex.