The Influence of BDNF on Anhedonic Behavior in an In Vivo Model of Chronic Unpredictable Mild Stress

Depression is a significant global medico-societal concern. The serotonin system plays a pivotal role in modulating responses to acute stress and is implicated in the development of depressive and anxiety disorders. Recent research has increasingly focused on the potentially beneficial impacts of activating previously less-studied 5-HT4R and 5-HT7R subtypes on cognitive functions in the context of anxiety and depression. Additionally, intercellular adhesion molecules have been associated with the structural remodeling of neurons related to stress and mood disorders, potentially establishing functional connections with serotonin receptors. Furthermore, it is established that the exogenous administration of the neurotrophic factor BDNF can ameliorate the functioning of serotonergic neurons in the brains of rodents. This study aimed to investigate the influence of exogenously administered BDNF on the expression of 5-HT4R, 5-HT7R, and CD44 during a depressive-like state induced by chronic unpredictable mild stress (CUMS) in C57Bl/6 mice. The findings demonstrated that intranasal BDNF administration at a dose of 0.4 μg/kg for seven days sustained normal sucrose preference levels in animals following 21 days of CUMS exposure. While BDNF treatment did not impact the CUMS-induced reduction in mRNA expression of 5-HT4R and 5-HT7R across examined brain regions (cortex, hippocampus, and cerebellum), it did prevent the decrease in CD44 and TrkB receptor expression levels in the hippocampus. Additionally, it maintained BDNF expression levels in the cortex, although not in other brain regions. These results suggest that the application of BDNF in CUMS models has an antidepressant effect without directly affecting serotonin receptors, but probably by modulating 5-HT7R-CD44 interactions.