Fluoxetine Reveals Nuances to Memory Task Interpretation in an Streptozotocin-Induced Diabetic Mouse Model

Diabetes mellitus (DM) is a disease characterized by poor blood-glucose regulation. DM patients are 2x more likely to develop cognitive decline, depression, and anxiety. While research reliably reports cognitive dysfunction, preclinical studies have noted heightened freezing behavior in the fear conditioning test (FCT),which is traditionally indicative of improved memory. It is suggested that this is mediated by a depressive-like phenotype, whereby animals are expressing heightened reactivity to the negative stimuli, not improved memory. ​ Based off prior research, this study tested depression-mediated sensitivity to aversive stimuli using an antidepressant, fluoxetine (FLX), to modulate the relationship between FCT results and depressive-like behaviors.​ Hippocampal qPCR analyses assessed gene expression related to neuroinflammation and synaptic plasticity. Results showed that hyperglycemia increased depressive-like behaviors in the FST (p = .044) and MB tests (p = .002), with FLX treatment further reducing scores in MB (p = .004).As expected in the FCT, hyperglycemia exaggerated freezing behavior (p = .030), indicating an increased salience to aversive stimuli, as this effect was corrected by FLX (p =.046), modulating freezing behaviors to the controls. No significant effects were observed in OF. Lastly, qPCR analyses did not reveal significant changes in gene expression. ​Results support that hyperglycemia leads to a depressive-like phenotype that heightens fear responses, with FLX modulating the latter. The absence of gene changes suggests alternative mechanisms contributing to these effects. Future research should explore alternative pathways to improve therapeutic interventions.