Transcutaneous auricular vagal nerve stimulation inhibits hypothalamic P2Y1R expression and attenuates weight gain without decreasing food intake in Zucker diabetic fatty rats

Zucker diabetic fatty (ZDF) rats that harbor a mutation in the leptin receptor innately develop type 2 diabetes (T2D) with obesity. Transcutaneous auricular vagal nerve stimulation (taVNS) has an antidiabetic effect in ZDF rats. However, the underlying mechanisms of the weight-gain attenuating effect in ZDF rats by taVNS is still unclear. This study aimed to assess whether the weight-gain attenuating effect of taVNS in ZDF rats is associated with changes in the central nervous system (CNS) expression of P2Y1 receptors (P2Y1R). Adult male ZDF rats were subjected to taVNS and transcutaneous non-vagal nerve stimulation (tnVNS). Their food intake and body weight were recorded daily and weekly, respectively. P2Y1R expression in the hypothalamus, amygdala, and hippocampus was evaluated by western blotting. Hypothalamic P2Y1R expressing cells were detected using immunohistochemistry. Naïve ZDF rats were much heavier ( p < 0.05) than their lean littermates (ZL rats), with elevated hypothalamic P2Y1R expression ( p < 0.05). Further, taVNS but not tnVNS attenuated weight gain ( p < 0.05) without decreasing food intake ( p > 0.05) and suppressed hypothalamic P2Y1R expression in ZDF rats ( p < 0.05). Moreover, P2Y1R showed major expression in astrocytes of ZDF rats’ hypothalamus. ZDF rats innately develop obesity associated with elevated hypothalamic P2Y1R expression. taVNS attenuates weight gain in ZDF rats without changes in food intake, suggesting increased energy expenditure. Whether the reduced hypothalamic P2Y1R expression in response to taVNS is mechanistically linked to the increased energy expenditure remains to be determined.

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

10.21203/rs.3.rs-22344/v1 ◽

2020 ◽

Author(s):

Yutian Yu ◽

Xun He ◽

Yu Wang ◽

Jinling Zhang ◽

Chunzhi Tang ◽

...

Keyword(s):

Prefrontal Cortex ◽

Nerve Stimulation ◽

Cingulate Cortex ◽

Brain Regions ◽

Rodent Model ◽

Vagal Nerve ◽

Vagal Nerve Stimulation ◽

Depressive Effect ◽

Zucker Diabetic Fatty Rats ◽

Zdf Rats

Abstract 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.

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