TY - JOUR
T1 - Modulation of depression-related behaviors by adiponectin AdipoR1 receptors in 5-HT neurons
AU - Meng, Fantao
AU - Garza, Jacob C.
AU - Liu, Jing
AU - Lei, Yun
AU - Kirov, Sergei A.
AU - Guo, Ming
AU - Lu, Xin Yun
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2021/8
Y1 - 2021/8
N2 - 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.
AB - 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.
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U2 - 10.1038/s41380-020-0649-0
DO - 10.1038/s41380-020-0649-0
M3 - Article
C2 - 31980728
AN - SCOPUS:85078322747
SN - 1359-4184
VL - 26
SP - 4205
EP - 4220
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 8
ER -