Impairment of neurovascular coupling in the hippocampus due to decreased nitric oxide bioavailability supports early cognitive dysfunction in type 2 diabetic rats

Numerous epidemiological and preclinical studies have established a strong correlation between type 2 diabetes (T2DM) and cognitive impairment and T2DM is now established as an undisputable risk factor in different forms of dementia. However, the mechanisms underlying cognitive impairment in T2DM are still not fully understood. The temporal and spatial coupling between neuronal activity and cerebral blood flow (CBF) -neurovascular coupling (NVC) -is essential for normal brain function. Neuronal-derived nitric oxide ((NO)-N-center dot) produced through the nNOS-NMDAr pathway, is recognized as a key messenger in NVC, especially in the hippocampus. Of note, impaired hippocampal perfusion in T2DM patients has been closely linked to learning and memory dysfunction. In this study, we aimed to investigate the functionality of NVC, in terms of neuronal -(NO)-N-center dot signaling and spatial memory performance, in young Goto-Kakizaki (GK) rats, a non-obese model of T2DM. For that, we performed direct and simultaneous measurements of (NO)-N-center dot concentration dynamics and microvascular CBF changes in the hippocampus upon glutamatergic activation. We found that limited (NO)-N-center dot bioavailability, connected to shorter and faster (NO)-N-center dot transients in response to glutamatergic neuronal activation, is associated with decreased hemody-namic responses and a decline in spatial memory performance. This evidence supports a close mechanistic as-sociation between neuronal-triggered (NO)-N-center dot concentration dynamics in the hippocampus, local microvascular responses, and cognitive performance in young diabetic animals, establishing the functionality of NVC as a critical early factor to consider in the cascade of events leading to cognitive decline in T2DM. These results suggest that strategies capable to overcome the limited (NO)-N-center dot bioavailability in early stages of T2DM and maintaining a functional NVC pathway may configure pertinent therapeutic approaches to mitigate the risk for cognitive impairment in T2DM.

Automated summary

Numerous studies have shown a strong correlation between type 2 diabetes (T2DM) and cognitive impairment. This study investigates the role of neurovascular coupling (NVC) in T2DM and its impact on cognitive performance. The results suggest that limited availability of nitric oxide (NO) in the hippocampus is associated with decreased hemodynamic responses and spatial memory decline in young diabetic animals.