Key result
T2D in young rats is linked to reduced nitric oxide, impaired hemodynamics, and spatial memory decline.
Why the study?
Type 2 diabetes is a risk factor for dementia, but the underlying mechanisms of cognitive impairment remain not fully understood.
Impaired hippocampal NVC may contribute to early cognitive decline in T2DM; leaves open whether NO-targeted interventions alter human outcomes.
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) 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 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 concentration dynamics and microvascular CBF changes in the hippocampus upon glutamatergic activation. We found that limited •NO bioavailability, connected to shorter and faster •NO transients in response to glutamatergic neuronal activation, is associated with decreased hemodynamic responses and a decline in spatial memory performance. This evidence supports a close mechanistic association between neuronal-triggered •NO 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 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.
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Gonçalves et al. (2022) studied Type 2 diabetes. Type 2 diabetes (Goto-Kakizaki rat model) was evaluated on Nitric oxide concentration dynamics, microvascular cerebral blood flow changes, and spatial memory performance. Type 2 diabetes in young rats was associated with limited nitric oxide bioavailability, decreased hemodynamic responses, and a decline in spatial memory performance.
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