Anxiety-like behavior in female mice is modulated by STAT3 signaling in midbrain dopamine neurons

The central signaling actions of cytokines are mediated by signal transducer and activator of transcription (STAT3). STAT3 activation plays a pivotal role in the behavioral responses to the adiposity hormone leptin, including in midbrain dopamine (DA) neurons where it mediates the influence of leptin to diminish physical activity and running reward in male mice. Leptin also has anxiolytic effects which have been tied to the mesolimbic DA system. To assess the contribution of STAT3 signaling in mesolimbic DA neurons on feeding, mesolimbic DA tone and anxiodepressive behaviors in female mice, we generated DA-specific STAT3 knockout mice by crossing mice expressing Cre under the control of the dopamine transporter with STAT3-LoxP mice. Feeding, locomotion, wheel running, conditioned place preference for palatable food and amphetamine locomotor sensitization were unaffected by DA-specific STAT3 deletion. Conversely, knockout mice exhibited heightened anxiety-like behavior (open field test and elevated plus maze) along with increased basal and stress-induced plasma corticosterone, whereas indices of behavioral despair (forced swim and tail-suspension tasks) were unchanged. In accordance with biochemical evidence of increased D1 receptor signaling (phospho-DARPP32_Thr34) in the central nucleus of the amygdala (CeA) of knockout mice, local microinjections of a D1 receptor antagonist reversed the anxiogenic phenotype of knockout mice. In addition to alluding to sex differences in the signaling mechanisms mediating anxiety-like behavior, our findings suggest that activation of STAT3 in midbrain dopamine neurons projecting to the CeA dampens anxiety in a D1R-dependent manner in female mice.