Abstract
Neurovascular and neurometabolic coupling are critical and complex processes underlying brain function. Perturbations in the regulation of these processes are, likely, early dysfunctional alterations in pathological brain aging and age-related neurodegeneration. Evidences support the role of nitric oxide (•NO) as a key messenger both in neurovascular coupling, by signaling from neurons to blood vessels, and in neurometabolic coupling, by modulating O2 utilization by mitochondria. In the present study, we investigated the functionality of neurovascular and neurometabolic coupling in connection to •NO signaling and in association to cognitive performance during aging. For this, we performed in vivo simultaneous measurements of •NO, O2 and cerebral blood flow (CBF) in the hippocampus of F344 rats along chronological age in response to glutamatergic activation and in correlation with cognitive performance. Firstly, it is evidenced the temporal sequence of events upon glutamate stimulation of hippocampal dentate gyrus, encompassing the local and transitory increase of •NO followed by transitory local changes of CBF and pO2. Specifically, the transient increase of •NO is followed by an increase of CBF and biphasic changes of the local pO2. We observed that, although the glutamate-induced •NO dynamics were not significantly affected by aging, the correspondent hemodynamic was progressively diminished accompanying a decline in learning and memory. Noteworthy, in spite of a compromised blood supply, in aged rats we observed an increased ΔpO2 associated to the hemodynamic response, suggestive of a decrease in the global metabolic rate of O2. Furthermore, the impairment in the neurovascular coupling observed along aging in F344 rats was mimicked in young rats by promoting an unbalance in redox status toward oxidation via intracellular generation of superoxide radical. This observation strengthens the idea that oxidative stress may have a critical role in the neurovascular uncoupling underlying brain aging and dysfunction. Overall, data supports an impairment of neurovascular response in connection with cognition decline due to oxidative environment-dependent compromised •NO signaling from neurons to vessels during aging.
Highlights
The brain is an organ with high metabolic and energetic requirements, and despite representing only 2% of the total body weight, the adult brain receives over 15% of the cardiac output and consumes more than 20% of the body’s total glucose and oxygen sources (Rolfe and Brown, 1997)
We have performed simultaneous measurements of NO concentration dynamics, pO2 and cerebral blood flow (CBF) responses associated to glutamatergic activation in the dentate gyrus of the hippocampus at three different ages
Our findings revealed age-dependent changes in the dynamic profile of NO, CBF and pO2 associated with a decline in learning and memory function evaluated by a spatial reference memory version of the Morris water maze test
Summary
The brain is an organ with high metabolic and energetic requirements, and despite representing only 2% of the total body weight, the adult brain receives over 15% of the cardiac output and consumes more than 20% of the body’s total glucose and oxygen sources (Rolfe and Brown, 1997). Further considering the limited reserves and the high energetic demands, it sounds clear that brain function is critically dependent on adequate blood supply and proper delivery of bioenergetic substrates to support its information processing capabilities through neurotransmission (Zlokovic, 2011). The local intensity of neuronal activity continuously determines both the dynamic regulation of cerebral blood flow (CBF) – neurovascular coupling – and utilization of glucose and O2 by different cell types – neurometabolic coupling (Ledo et al, 2017). A matter of debate, it has been suggested that cerebral energy metabolism (including both the transport and utilization of oxygen and glucose) is altered during aging (Yin et al, 2016)
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