Interleukin-11Rα2 in the hypothalamic arcuate nucleus affects depression-related behaviors and the AKT-BDNF pathway

Depression is a widespread emotional disorder with complex pathogenesis. An essential function of the hypothalamus is to regulate emotional disorders. However, further investigation is required to identify the pathogenic genes and molecular mechanisms that contribute to the onset of depression within the hypothalamus. Through RNA-sequencing analysis, this study identified the upregulated expression of interleukin-11 receptor alpha 2 (IL-11Rα2) in the hypothalamus of mice with chronic unpredictable stress (CUS)-induced depression. This substantial increase in IL-11Rα2, not IL-11Rα1 expression levels in the hypothalamus under the influence of CUS was found to be associated with depression-related behaviors. We further showed that IL-11Rα2 is expressed in the arcuate nucleus (ARC) proopiomelanocortin (POMC) neurons of the hypothalamus. Male and female mice exhibited behaviors association with depression, when IL-11Rα2 or its ligand IL-11 was overexpressed in the ARC POMC neurons through the action of an adeno-associated virus. In addition, reductions in the expression levels of proteins involved in the protein kinase B signaling pathways and brain-derived neurotrophic factor were observed upon overexpression of IL-11Rα2 in the hypothalamic ARC. This study emphasizes the importance of IL-11Rα2 in the hypothalamus ARC in the development of depression, and presents it as a potential novel target for depression treatment.