Association between increased inflammatory cytokine expression in the lateral habenular nucleus and depressive-like behavior induced by unpredictable chronic stress in rats

Depression induced by unpredictable chronic stress (UCS) has been widely studied using animal models. However, its underlying pathological mechanisms remain unclear. Increased inflammatory cytokines (ICs) in the central nervous system (CNS) are closely related to depressive disorder. UCS was used as an animal model in this study to investigate how UCS-induced changes in cytokine signaling lead to depression. We found that UCS could increase ICs in the CNS, especially in the habenular nucleus (Hb). UCS resulted in decreased expression of Menin in Hb and increased the activation of the NF-κB signaling pathway. Local administration of tumor necrosis factor-α in the lateral Hb (LHb) could induce depressive-like behavior in rats. The anti-inflammatory drug aspirin and the NF-κB inhibitor pyrrolidine dithiocarbamate could alleviate depressive-like behavior. This phenomenon was not observed for local administration in the dorsal raphe nucleus and paraventricular nucleus. These results indicate that LHb is the main central target for ICs to regulate depressive-like behaviors. We also found that LHb lesions could improve the inflammatory response in the hippocampus, reduce the activation of the NF-κB signaling pathway and the expression of ICs, and increase the expression of brain-derived neurotrophic factor and its receptor tropomyosin receptor kinase B, collectively improving the neuroinflammation caused by UCS. Moreover, LHb lesions improve not only hippocampal neurogenesis damage caused by UCS by activating the PI3K/mTOR signaling pathway but also hippocampal function by reducing the expression of apoptosis-related proteins, including phosphorylated p53, Bax, Bcl2, and cleaved-caspase3. In conclusion, our study sheds light on the pathogenesis of ICs-induced depression. Anti-inflammation in the CNS could be a new strategy in the treatment of depression.