MeA Tac2-Nk3R signaling mediates sex-specific stress susceptibility and weight gain deficits in mice

Major Depressive Disorder (MDD) affects women at nearly twice the rate of men, yet the specific mechanisms driving this sex disparity remain poorly understood. Fluctuations in body weight, including both loss and gain, are common features of MDD, suggesting a potential link between metabolic state and stress susceptibility. Current treatments often lack sex-specific efficacy, highlighting a critical need to identify novel pathways. This study explores how body weight mediates sex differences in depression susceptibility, focusing on the tachykinin 2 (Tac2) and its receptor Nk3R pathway within the medial amygdala (MeA).

Researchers subjected male and female mice to two weeks of social isolation during adolescence to induce stress. They assessed depressive- and anxiety-like behaviors using sucrose preference test (SPT), forced swimming test (FST), social interaction test (SI), elevated plus maze (EPM), novelty suppressed feeding test (NSF), and open field test (OFT). Interventions included 20% and 40% calorie restriction (CR), and a high-fat diet. The study also investigated the role of Tac2 in the medial amygdala (MeA) and its receptor, Nk3R, through pharmacological blockade and genetic knockout models to evaluate their impact on weight gain and behavioral outcomes.

Social isolation induced depressive-like behaviors in female but not male mice across multiple tests (SPT, FST, SI, EPM, NSF, OFT). Female mice also exhibited slower weight gain during isolation compared to controls and isolated males. Interestingly, 20% calorie restriction, which suppressed weight gain, led to depressive-like behaviors in both male and female mice, whereas 40% CR exerted an antidepressant effect. Conversely, a high-fat diet that compensated for slowed weight gain rescued depressive-like behaviors in socially isolated female mice. They found increased peptide tachykinin 2 (Tac2) within the medial amygdala (MeA) mediated slowed weight gain and depressive-like behaviors in isolated mice. Pharmacological blockade or genetic knockout of the Nk3 receptor (Nk3R), the receptor for Tac2, reversed both the weight gain deficits and depressive-like behaviors. This suggests a direct link between MeA Tac2-Nk3R signaling, body weight regulation, and stress susceptibility.

Pharmacological blockade or genetic knockout of the Nk3R reversed both the weight gain deficits and depressive-like behaviors, highlighting its critical role in mediating stress responses.