The objectives presented below will be tackled in a multidisciplinary fashion, encompassing in vivo electrochemistry, neurosurgery, imaging techniques, basic molecular biosciences, genetic and rodent behavior approaches. Additionally, we aim at translating the mechanistic and technological developments into potential application to human therapeutics.
1. The study of how the brain maintains its integrity by controlling its own blood supply in terms of the potential role of neuronal-derived nitric oxide as a diffusional mediator of neurovascular coupling. To assess whether impaired neurovascular coupling at the effector vasculature sites impinges on Alzheimer´s disease and aging.
Energy supply to the brain may impose a limit to neural activity. Thus, the neurovascular coupling process is critical for proper brain function and integrity.
Recording electrochemically in real time from microarrays inserted in the brain in vivo will permit to study the diffusible cooperative signal volume communication established by nitric oxide between neurons and the vasculature.
To ascertain the significance for health and disease issues the concept will be critically analyzed in rodent models of Alzheimer disease and aging.
2. The analysis of the mechanism of action of neuronal-derived nitric oxide in mastering brain energetics under stimulation (glutamatergic) conditions.
Experimental evidence, spanning from in vivo approaches to cellular and molecular studies, have highlighted unsolved issues in brain metabolism and led to the formulation of conflicting hypothesis and concepts.
The hypothesis is that, upon neuronal activation, nitric oxide is a master regulator of brain energetic metabolism rendering local cells dependent on glycolysis in spite of the abundance of O2. A consistent and integrated interpretation is mechanistically supported by partial and reversible inhibition of mitochondrial respiration by neuronal-derived nitric oxide.
3. To develop sensing technology for research and for application in therapeutics strategies.
Direct chemical measurements in the brain of live and behaving animals is expected to lead to a better understanding the role of neurochemicals in brain function. The hypothesis entails developing chemical sensing technologies with very high spatial resolution at micrometer to nanometer scale at level of synapse in a second-by-second to millisecond time scale, chemically selective and multiplexed allowing recording multiple neurochemicals simultaneously.
In addition to proof its worth as broadly applicable research tools these technologies may also develop for application in therapeutic strategies.
4. The nitrate:nitrite: nitric oxide axis in the modulation of gut microbiome and ensued implications for the gut-brain axis.
Diet shapes gut microbiota and carries bioactive compounds such as nitrate that upon intragastric reduction to nitric oxide maintains gut homeostasis, impacting on neural functions. It is anticipated that the modulation of gastrointestinal functions during dysbiosis by dietary nitrate through nitric oxide production recovers altered gut and nervous functions in germ-free animals. Ascertaining the significance of the nitrate-nitrite-vagus interplay for health and disease issues, as a novel homeostatic mechanism controlled by dietary behavior, is conducive to the development of therapeutic interventions.
5. The health-promoting effects of plant-derived polyphenols and ascorbic acid.
Endowed with redox properties that enable them to participate in the modulation of cellular redox pathways the polyphenols will be studied in the framework of the previous goals and models. Specifically, the analysis of the mechanisms of actions as potential neuromodulators, anti-inflammatory and vascular protectors, preserving functional integrity of vasculature through activation of signaling pathways and universal transcription factors as well as nitric oxide synthase independent catalyzers of nitric oxide production from nitrite.