Thyrotropin-releasing hormone (TRH) is a neuropeptide with a variety of hormonal and neurotransmitter/neuromodulator functions. In particular, TRH has pronounced acute antidepressant effects in both humans and animals, and has been implicated in the mediation of the effects of other antidepressive therapies. Two G-protein coupled receptors, TRH-R1 and TRH-R2, have been identified. Here we report the generation and phenotypic characterization of mice deficient in TRH-R1. The TRH-R1 knockout (KO) mice have central hypothyroidism and mild hyperglycemia, but exhibit normal growth and development and normal body weight and food intake. Behaviorally, the TRH-R1 KO mice display increased anxiety and depression levels while behaving normally in a number of other aspects examined. These results provide the first direct evidence that the endogenous TRH system is involved in mood regulation and this function is carried out through TRH-R1 mediated neural pathways.