Intact neurovascular coupling is essential for normal brain function and health. Almost every specialized brain cell type has been implicated in neuronal-activity derived changes in brain blood volume and flow, including vasoactive neurons, astrocytes and pericytes. Recently, evidence from Dr. Elizabeth Hillman's laboratory suggests a role for endothelium derived vasodilation in the brain, expanding our understanding of the mechanisms of functional hyperemia in the brain. Endothelial dependent vasodilation and impaired functional hyperemia due to disease induced endothelial dysfunction has been widely studied in the peripheral vasculature. Endothelial dysfunction in cardio-metabolic disease states such as hypertension, diabetes, obesity and smoking is thought to be a key initiator and mediator of future cardiovascular events such as cardiovascular attacks and strokes. However, the effect of endothelial dysfunction on brain activity remains to be studied. Based on peripheral vasculature studies, we hypothesize that impaired endothelial vasoactivity in an appropriate metabolic disease will initially reduce stimulus-evoked hyperemia and alter resting state neurovascular activity without affecting neural activity. Over time, this reduced functional vasoactivity in the brain will cause neuronal death and damage. Several other pathways for metabolic disease induced brain damage have posited in the past - including cerebral hypo-perfusion, impaired autoregulation and blood brain barrier breakdown. We believe that neuronal damage resulting from impaired endothelium-dependent dynamic blood flow changes in the brain represents a novel pathway of interest in the link between cardiovascular disease and neurodegeneration. This pathway either initiates or acts in concert with previously proposed mechanisms in causing brain damage in systemic vascular disease states. To validate our hypotheses, we will use advanced wide-field multi-spectral imaging techniques to study changes in neuronal activity and brain blood flow in awake, mobile, head-fixed transgenic Thy1-GCaMP3 mice. These mice express the calcium fluorophore GCaMP3 in layer 2/3 and 5 neurons, allowing us to image wide- field neuronal activity. We will evaluate long-term changes in functional hyperemia in animals with streptozotocin- induced type 1 diabetes. We anticipate that neurovascular dysfunction will precede neuronal activity changes in these mice and will correlate with changes in vasodilators and vasoconstrictors in brain endothelium at the molecular level In the future, targeted rescue of endothelial vasoactivity will reduce neuronal damage and death. To our knowledge, this work is the first to study diabetes from induction to neuronal disease longitudinally in each animal under normal physiological conditions in vivo using powerful optical imaging techniques. While not only representing the future of brain imaging studies, this study will add important knowledge to preventing and treating neurodegeneration resulting from highly prevalent cardiovascular diseases.
The prevalence of Alzheimer's in the United States is high, now at 5 million in elderly individuals and the incidence and prevalence of cardiovascular risk factors like diabetes is rapidly increasing in both young and adult populations. We believe that endothelial dysfunction resulting from these diseases damages dynamic blood flow in the brain, causing neuronal death. In this proposal we aim to study the progression of diabetic effects on brain blood flow and neuronal health in mice to understand the underlying mechanisms and possibly discover new therapeutic targets.
| Shaik, Mohammed A; Hillman, Elizabeth M C (2018) Skip the salt: your brain might thank you. Nat Neurosci 21:154-155 |
| Kozberg, M; Hillman, E (2016) Neurovascular coupling and energy metabolism in the developing brain. Prog Brain Res 225:213-42 |
| Ma, Ying; Shaik, Mohammed A; Kim, Sharon H et al. (2016) Wide-field optical mapping of neural activity and brain haemodynamics: considerations and novel approaches. Philos Trans R Soc Lond B Biol Sci 371: |
| Ma, Ying; Shaik, Mohammed A; Kozberg, Mariel G et al. (2016) Resting-state hemodynamics are spatiotemporally coupled to synchronized and symmetric neural activity in excitatory neurons. Proc Natl Acad Sci U S A 113:E8463-E8471 |
| Kozberg, Mariel G; Ma, Ying; Shaik, Mohammed A et al. (2016) Rapid Postnatal Expansion of Neural Networks Occurs in an Environment of Altered Neurovascular and Neurometabolic Coupling. J Neurosci 36:6704-17 |
