Investigation of the relationship and mechanisms between anosmia and cognitive dysfunction in rats

The mechanism and direction of the relationship between anosmia and neurodegenerative diseases is not yet fully understood. In this thesis study, olfactory epithelial damage and neuronal damage-mediated anosmia/hyposmia models were created by administering two pharmacological agents, ZnSO4 and methimazole, in rats and the possible relationship between cognitive function and loss of sense of smell evaluated by various behavioral tests was examined. In this study, in vivo and in vitro experiments were performed on a 6-week-old, Wistar albino male rat (n=18; 217±18 g). It was aimed to create an acute anosmia model with mucosal damage and HVCN1 channel blockade with intranasal ZnSO4 administration and a chronic anosmia model by destroying olfactory neurons with apoptosis with methimazole (75-300 mg/kg, i.p.) injection. The validation of whether experimental models created in rats caused the development of anosmia was evaluated by Buried Food Test (BFT). Subsequently, various behavioral tests were performed to evaluate possible neurocognitive changes and electrophysiological experiments were performed to evaluate the possible change in LTP. While there was no significant difference between the groups in terms of finding buried food in the basal BFT session (Control: 7.7±1.78 min, Methimazole: 9.3±1.89 min, Zinc sulfate: 6.1±1.99 min), the validity of the anosmia model was confirmed in the BFT sessions 1 month and 2 months after the anosmia models were created (1st month- Control: 8.5±2.39 min, both anosmia groups 15±0 min; p<0.005 etc. Control; 2nd month- Control: 8.0±0.92 min, Methimazole: 15±0 min; Zinc sulfate: 14,75±0,49; p<0.001 vs Control). Loss of sense of smell led to a significant reduction in body weight compared to the Control group (Control 86.2±9.4% (181g) vs Methimazole 70.3±5.86% (146.5 g) and Zinc Sulfate 61.6±3.18% (127.6 g)). In the Morris Water Maze (MWM) test, which evaluates hippocampal learning-memory performance, it was observed that all groups showed significant learning performance and the time to find the escape platform was significantly reduced, but no statistically significant difference was found between the groups. In the Novel Object Recognition (NOR) test, in which prefrontal learning-memory performance was evaluated, a significant difference was found between the Control and Methimazole groups (Control= %83,8; Methimazole=%37,8; p<0,05). Passive avoidance (PA) test findings, which assess fear-driven learning-memory performance associated with the limbic system, also showed impaired learning in the anosmic groups (Control: 50.3±97 sec vs Methimazole: 11.5±9.7 sec , Zinc sulfate: 2.1±0.4 sec.).; p<0,05 Control vs Methimazole and p<0,01 Control vs Zinc sulfate). When the number of defecations was evaluated with the Elevated Plus Maze (EPM) and Open Field tests in which anxiety was evaluated, no significant difference was found between the groups. The findings of the Forced Swim Test (FST), which evaluates depression-like behavior, also showed that there was no significant difference between the groups. LTP records evaluated in electrophysiological experiments on dentate gyrus showed that there was learning/potentiation in all animals and anosmia did not impair the learning functions associated with dentate gyrus. In the light of our findings, it was concluded that anosmia does not have a negative effect on hippocampal learning and memory, but has a negative effect on the prefrontal cortex and amygdala. Further electrophysiological studies on these regions and cellular studies to elucidate the mechanism are recommended.