Browsing by Subject "Neurovascular coupling"

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    Mechanisms of Blood Flow Regulation in the Retina: Glial Calcium Signaling Regulates Capillary, but Not Arteriole Diameter
    (2016-12) Biesecker, Kyle
    Blood flow is tightly regulated in the central nervous system to ensure neurons receive sufficient oxygen and glucose. When neuronal activity increases, nearby blood vessels dilate to increase local blood flow, a phenomenon termed functional hyperemia. Two key controversies have arisen concerning the mechanisms that underlie functional hyperemia. Firstly, the role of glial Ca2+ signaling in triggering vessel dilations is unclear. Some evidence suggests that glial Ca2+ signals precede vessel dilations, but blocking glial Ca2+ signaling does not alter functional hyperemia. Secondly, data has been presented arguing both for and against the ability of capillaries to actively dilate during functional hyperemia. Herein, I demonstrate that glial Ca2+ signaling does play a key role in regulating capillary diameter, but is not necessary for regulating arteriole diameter. Additionally, capillaries can actively dilate during functional hyperemia responses. These findings suggest that glial Ca2+ signaling contributes to blood flow regulation in the central nervous system by triggering capillary dilations during functional hyperemia.
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    Modulation of neurovascular coupling in the retina:effects of oxygen and diabetic retinopathy.
    (2011-07) Mishra, Anusha
    Neurovascular coupling is a process by which neuronal activity leads to localized increases in blood flow in the central nervous system. When neurovascular coupling results in hyperperfusion of the neural tissue, the response is termed functional hyperemia and serves to satisfy the increased energy demand of active neurons. In brain slices, high [O2] alters neurovascular coupling, decreasing activity-dependent vasodilations and increasing vasoconstrictions. However, in vivo, hyperoxia has no effect on neurovascular coupling. In order to resolve these conflicting reports of O2 modulation, I examined neurovascular coupling in both ex vivo and in vivo rat retina preparations. In the ex vivo retina, 100% O2 reduced the amplitude of light-evoked arteriole vasodilations by 3.9-fold and increased the amplitude of vasoconstrictions by 2.6-fold when compared to responses in atmospheric [O2] (21%), consistent with slice data. Oxygen exerted its effect by decreasing vasodilatory prostaglandin signaling and increasing vasoconstrictory 20-hydroxyeicosatetraenoic acid signaling. However, in vivo, hyperoxia (breathing 100% O2) had no effect on light-evoked arteriole vasodilations or on blood flow. We found that the differing effects of O2 arise because retinal pO2 increases to a much greater extent in the ex vivo preparation (to 548 mmHg) than in vivo (to 53 mmHg; Yu et al. Am J Physiol 267:H2498-H2507). When retinal pO2 was raised to 53 mmHg in the ex vivo retina, no change in neurovascular coupling was observed. These results demonstrate that although O2 can modulate neurovascular signaling pathways when pO2 is raised high enough, such levels are not attained in vivo, even when an animal breaths 100% O2. Functional hyperemia can also be modulated by pathological conditions. It is diminished in the retinas of diabetic patients, possibly contributing to the development of diabetic retinopathy. I investigated the mechanism responsible for this loss in a streptozotocin-induced rat model of type 1 diabetes. Here I show that light-evoked arteriole dilation was reduced by 58% in these diabetic rats at 7 month survival time. The diabetic retinas showed neither a decrease in the thickness of the retinal layers nor an increase in neuronal loss, although signs of early glial reactivity were observed. Functional hyperemia is believed to be mediated, at least in part, by glial cells and we found that glial-evoked vasodilation was reduced by 60% in diabetic animals. An upregulation of inducible nitric oxide synthase (iNOS) was detected by immunohistochemistry, and inhibition of iNOS restored both light- and glial-evoked dilations to control levels. These findings suggest that high NO levels resulting from iNOS upregulation alters glial control of vessel diameter and may underlie the loss of functional hyperemia observed in diabetic retinopathy. I further tested whether inhibiting iNOS reverses the loss of flicker-induced vasodilation in diabetic rat retinas in vivo. Flicker-evoked arteriolar dilations were diminished by 61% in diabetic animals, compared to non-diabetic controls. Treating diabetic animals with aminoguanidine (an iNOS inhibitor), either acutely via IV injection or long-term in drinking water, restored flicker-induced arteriole dilations in diabetic rats to control levels. The amplitude of the electroretinogram b-wave was similar in control and diabetic animals, suggesting that the deficit in functional hyperemia was not due to a reduction in neuronal activity. These findings demonstrate that inhibiting iNOS with AG is effective in preventing the loss of, and restoring, normal flicker-induced vasodilation in the diabetic rat retina. Treatment with iNOS inhibitors early in the course of diabetes has the potential to slow the progression of retinopathy by maintaining normal neurovascular coupling.
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    Study of spontaneous bold fluctuation in animal and human brains
    (2010-09) Liu, Xiao
    Spontaneous blood-oxygen-level-dependent (BOLD) signals acquired at the resting state have recently been found to fluctuate coherently within many anatomically-connected and functionally-specific brain networks, and it may reflect an orderly organization of ongoing brain activity. Understanding this phenomenon may help us not only to understand some fundamental mechanisms of brain functions but also to find its applications in clinical field. However, the mechanisms underlying this phenomenon remains elusive, and even its neural origin is still controversial. This dissertation aimed to understand spontaneous BOLD fluctuation from its neurophysiological basis, its modulation under different brain states, and its role in brain functions. With five projects performed both on animals and humans, we have found that i) spontaneous BOLD fluctuation under deep burst-suppression anesthesia originates from underlying spontaneous neural activity, ii) spontaneous BOLD fluctuation is sensitive to changes in anesthesia depth, reflecting reorganization of ongoing brain activity at different consciousness level, iii) the resting-state visual network is spatially reorganized into activated and non-activated coherent network under continuous stimulation, and iv) the correlation strength within individuals' resting-state network can affect their evoked response to identical stimulations. These findings clearly support the functional significance of spontaneous BOLD fluctuation widely observed in animals and humans brain and provide new insights into its underlying mechanisms.