Introduction: Type 2 diabetes (T2D) is an established risk factor for the development of neurodegenerative diseases as Alzheimer’s (AD) and Parkinson’s Disease (PD)(1). The carotid bodies (CBs), peripheral chemoreceptors classically defined as O2 sensors, have been recently described to have a role in energy and glucose homeostasis and its dysfunction associated with the development of dysmetabolic states (2). In agreement with the tole of CB in dysmetanolic states, the abolishment of CBs activity, via the resection or neuromodulation of its sensitive nerve, the carotid sinus nerve (CSN), prevented and reverted dysmetabolic features of prediabetic and T2D animal models (3). Herein, we evaluated if the modulation of CB through the CSN resection may prevent the impact of metabolic dysregulation on cognition and synaptic plasticity. 

Methods: Male wistar rats (8-10 weeks of age) fed a high fat-high sucrose (HFHSu) (60% lipid rich diet plus 35% sucrose in drinking water), or a standard (CTL) diet for fifteen weeks. After this period animals were randomly assigned to CSN resection or sham surgery. Metabolic profile and behavior were evaluated at 14 (before surgery) and 20 weeks of diet (5 weeks post-surgery). After final behavioral assessment, electrophysiological recordings in hippocampal brain slices were performed to evaluate synaptic function and plasticity, by recording fEPSPs in hippocampus CA1 area, evoked by Schaffer-colateral stimulation. We also assessed whether the induction or the maintenance of long-term potentiation (LTP) is altered between experimental conditions. Experiments followed the 2010/63/EU Directive and were approved by the NMS Ethics Committee and the Portuguese Authority for Animal Health. Significance between the means was calculated by one-way ANOVA with multiple comparison tests. Differences were considered significant at p<0.05.

Results: HFHSu animals exhibited insulin resistance and glucose intolerance, and CSN resection reversed these phenotypes (p<0.05). Behaviorally, HFHSu-animals: 1) spent 62% less time interacting with the novel/own object in the novel object recognition (NOR) test (p<0.05); 2) sniff 91% less time novel/own scent and take 80% more time to identify the novel block in block test (p<0.05) and 3) exhibit 43% less alternative behavior in the y-maze test in comparison with CTLs. (p<0.05). All these effects were prevented by CSN resection (p<0.05), except for the Y-maze test. Electrophysiological recordings showed no alterations in baseline synaptic transmission nor in PPF (pair pulse facilitation) but showed that in HFHSu sham rats, LTP expression is increased (p<0.05). This effect was not observed in CTL animals and was completely reversed in HFHSu-CSN denervated rats (p<0.05). 

Conclusions: Altogether, we showed that HFHSu diet promoted peripheral dysmetabolism leading to cognitive functions impairment, and that CSN resection was able to restore cognitive performance and synaptic plasticity function. These results show that the modulation of CB activity could be used as a therapeutic approach to prevent neurodegenerative diseases associated with T2D.