Transcutaneous auricular vagal nerve stimulation inhibits P2X7R expression in limbic brain regions and reverses depression-like behavior in Zucker diabetic fatty rats

Background Previous studies confirmed that Zucker diabetic fatty rats (ZDF, fa/fa) develop type 2 diabetes (T2D) with depression-like behavior innately, and transcutaneous auricular vagal nerve stimulation (taVNS) was found to have anti-diabetic and anti-depressive effect in ZDF rats. However, there is still a lack of molecular-biological evidence that ZDF rats are a good rodent model of depression, and how does taVNS take the anti-depressive effect to the ZDF rats. P2 × 7R, a purinergic receptor most-related to inflammation and depression, is found to be elevated in depressed brains and is gradually considered as a potential therapeutic target for depression. Methods We deployed taVNS and transcutaneous none vagal nerve stimulation (tnVNS) to ZDF rats. We applied forced swimming test (FST) to evaluate to the depression-like behavior of the rats. We used Western blot to test the P2 × 7R expression in the hypothalamus, amygdala, hippocampus, prefrontal cortex, and cingulate cortex of the rats. Furthermore, we used immunohistochemical staining to colocalize the P2 × 7R expressing cells in the ZDF rats’ brains. Results We found that compared with their lean littermates (ZL rats), naïve ZDF rats developed depression-like behavior innately with elevated P2 × 7R expression in their limbic brain regions (hypothalamus, amygdala, hippocampus, prefrontal cortex, and cingulate cortex); and taVNS but not tnVNS inhibited the P2 × 7R expression in their limbic brain regions and reversed the depression-like behavior. Moreover, P2 × 7R was found majorly expressing in astrocytes and microglia of ZDF rats. Conclusions ZDF rats are a good rodent model of depression, and taVNS plays an anti-depressive effect in ZDF rats by inhibiting glial P2 × 7R expression in their limbic brain regions.