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Background: It has long been known that thyroid disease can lead to changes in energy metabolism, thermoregulation, and anxiety behavior. While these actions have been partially attributed to thyroid hormone (TH) receptor α1 (TRα1) action in the brain, the precise neuroanatomical substrates have remain elusive. Methods: We used PET-CT scans to identify brain regions affected by TH. We then inhibited TRα1 signaling specifically in the most affected region, the zona incerta (ZI), a still mysterious region previously implicated in thermogenesis and anxiety. To this end, we used an adeno-associated virus (AAV) expressing a dominant-negative TRα1R384C in wild-type mice and phenotyped the animals. Finally, we used tyrosine hydroxylase-Cre mice to test specifically the contribution of ZI dopaminergic neurons. Results: Our data showed that AAV-mediated inhibition of TRα1 signaling in the ZI lead to increased energy expenditure at thermoneutrality, while body temperature regulation remained unaffected. Moreover, circulating glucocorticoid levels were increased, and a mild habituation problem was observed in the open field test. No effects were observed when TRα1 signaling was selectively inhibited in dopaminergic neurons. Conclusions: Our findings suggest that altered TH signaling in the ZI is not involved in body temperature regulation but can affect basal metabolism and modulates stress responses. [ABSTRACT FROM AUTHOR]