Modulation of depression-related behaviors by adiponectin AdipoR1 receptors in 5-HT neurons

Abstract

The adipocyte-derived hormone adiponectin has a broad spectrum of functions beyond metabolic control. We previously reported that adiponectin acts in the brain to regulate depression-related behaviors. However, its underlying neural substrates have not been identified. Here we show that adiponectin receptor 1 (AdipoR1) is expressed in the dorsal raphe nucleus (DRN) and colocalized with tryptophan hydroxylase 2 (TPH2), a marker of serotonin (5-HT) neurons. Selective deletion of AdipoR1 in 5-HT neurons induced anhedonia in male mice, as indicated by reduced female urine sniffing time and saccharin preference, and behavioral despair in female mice and enhanced stress-induced decrease in sucrose preference in both sexes. The expression levels of TPH2 were downregulated with a concurrent reduction of 5-HT-immunoreactivity in the DRN and its two major projection regions, the hippocampus and medial prefrontal cortex (mPFC), in male but not female mice lacking AdipoR1 in 5-HT neurons. In addition, serotonin transporter (SERT) expression was upregulated in both DRN projection fields of male mice but only in the mPFC of female mice. These changes presumably lead to decreased 5-HT synthesis and/or increased 5-HT reuptake, thereby reducing 5-HT transmission. The augmented behavioral responses to the selective serotonin reuptake inhibitor fluoxetine but not desipramine, a selective norepinephrine reuptake inhibitor, observed in conditional knockout male mice supports deficient 5-HT transmission underlying depression-related phenotypes. Our results indicate that adiponectin acts on 5-HT neurons through AdipoR1 receptors to regulate depression-related behaviors in a sex-dependent manner.

The BDNF-FoxO1 Axis in the medial prefrontal cortex modulates depressive-like behaviors induced by chronic unpredictable stress in postpartum female mice

“…In particular the postpartum period is considered the time of greatest risk for women to develop MDD [41]. In order to address response of susceptibility in postpartum female mice, we applied a short term SCUS (3 days CUS), which is the usually used strategy to evaluate the susceptibility to stress [42,43]. Our findings demonstrated that female mice after parturition showed similar depression-like phenotypes to virgin females, which means the parturition stress alone cannot induce depression, while postpartum female mice showed enhanced susceptibility to SCUS induced depression-related behavior compared to virgin females, which reminds that 3 days stress may be the threshold of time window for stress induced depressive behaviors in PPD model.…”

“…The other group (control) was handled daily. In some experiments, an abbreviated (3 days) subthreshold chronic unpredictable stress was used to assess stress susceptibility in normal control and postpartum female mice [43].…”

“…Testing was conducted according to previously published protocols [43]. Mice were habituated to drinking water from two stoppers fitted with ball-point sipper 50ml tubes for at least 1 week before testing.…”

“…The forced swimming test was conducted as described previously [43,57]. Briefly, mice were tested in a clear Plexiglas cylinder (25 cm high; 10 cm in diameter) containing 15-cm deep, 24°C warm water.…”

“…The locomotor activity was tested as described previously [33,43,57] and measured in the SuperFlex Fusion open field cages (40 × 40 × 30 cm, Omnitech Electronics Inc., Columbus, OH). The mice were acclimated to the testing room for 2-3 h and were then allowed to freely explore for 30 min under the illuminated conditions.…”