Diabetes mellitus is a growing public health crisis, affecting 29% of the population in the United States. An important consequences of diabetes is cognitive decline and increased incidence of neurodegenerative disease. One factor in this decline may be vascular dysfunction. In the CNS, blood flow increases in response to increased neural activity, a process called functional hyperemia. In pathology, this process can become impaired, which may prevent the active neurons from receiving the nutrients and oxygen they need to meet their increased metabolic needs. Functional hyperemia is impaired in the retina in diabetes before any overt signs of damage. There is also evidence to suggest impairment in blood flow regulation in the brain, but it is unclear if those impairments are due to a loss of functional hyperemia. Research in patients with type 1 diabetes and animal models of diabetes has shown reduced increases in blood flow in response to a stimulus. However, no studies have simultaneously recorded blood flow and neuronal activity, which is necessary to describe how the relationship between neural activity and blood flow, functional hyperemia, is altered. A gap remains in our knowledge of how functional hyperemia changes in the brain in diabetes. We hypothesize that functional hyperemia in diabetes will be altered through an uncoupling of the neural activity and blood flow, so that equivalent increases in neural activity do not elicit the same increase in blood flow.
In aim 1, the proposed experiment will measure functional hyperemia in a mouse model of type 1 diabetes by simultaneously measuring blood flow (using laser Doppler flowmetry) and evoked neural activity (using Ca2+ signaling and electrocorticography) in the visual cortex in response to a drifting grating stimulus. In this way, it can be determined if there are alterations in functional hyperemia in the visual cortex as a consequence of diabetes. We further hypothesize that alterations in blood flow in diabetes are mediated by overexpression of nitric oxide (NO) due to increased expression of inducible nitric oxide synthase (iNOS). iNOS expression is increased in inflammation and pathology, and previous studies have found increased iNOS expression in the brain in animal models of diabetes. It has also been shown that giving diabetic animals inhibitors of iNOS restores functional hyperemia in the retina.
In aim 2, we will test this hypothesis by giving the selective iNOS inhibitors aminoguanidine and 1400W intravenously to diabetic mice and examining the effects of the inhibitors on evoked neural activity and blood flow to determine how iNOS inhibition affects functional hyperemia. We will also give 1400W chronically from the induction of diabetes in order to study the effects of long term iNOS inhibition on functional hyperemia. Identifying impairments in functional hyperemia in type 1 diabetes is an essential step in understanding the etiology of the impairments seen in diabetes and provides a promising target for therapeutic intervention.
An important consequence of diabetes mellitus is increased incidence of cognitive decline and neurodegenerative disorders. Changes in functional hyperemia, the process by which increases in neural activity recruit additional blood flow, may be a factor in diabetes related brain pathology as a loss of functional hyperemia prevents active neurons from receiving sufficient nutrients and oxygen. This proposal will look at potential alterations in functional hyperemia in diabetes, extending previous research showing blood flow changes in the brain with diabetes and providing new insights into the relationship between neural activity and blood flow.
| Nippert, Amy R; Mishra, Anusha; Newman, Eric A (2018) Keeping the Brain Well Fed: The Role of Capillaries and Arterioles in Orchestrating Functional Hyperemia. Neuron 99:248-250 |
