Cellular Links between Neuronal Activity and Energy Homeostasis

Shetty, Pavan K.; Galeffi, Francesca; Turner, Dennis A.

doi:10.3389/fphar.2012.00043

Cited by 66 publications

(60 citation statements)

References 189 publications

(241 reference statements)

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“…When a region of the brain is activated, the metabolic rate of the tissue, along with glucose and O 2 utilization, go up (Shetty and others 2012). The increase in blood flow is thought to match the increased metabolic need of the tissue.…”

Section: The Function Of Functional Hyperemiamentioning

confidence: 99%

Mechanisms Mediating Functional Hyperemia in the Brain

2017

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Neuronal activity within the brain evokes local increases in blood flow, a response termed functional hyperemia. This response ensures that active neurons receive sufficient oxygen and nutrients to maintain tissue function and health. In this review, we discuss the functions of functional hyperemia, the types of vessels that generate the response, and the signaling mechanisms that mediate neurovascular coupling, the communication between neurons and blood vessels. Neurovascular coupling signaling is mediated primarily by the vasoactive metabolites of arachidonic acid (AA), by nitric oxide, and by K+. While much is known about these pathways, many contentious issues remain. We highlight two controversies, the role of glial cell Ca2+ signaling in mediating neurovascular coupling and the importance of capillaries in generating functional hyperemia. We propose signaling pathways that resolve these controversies. In this scheme, capillary dilations are generated by Ca2+ increases in astrocyte endfeet, leading to production of AA metabolites. In contrast, arteriole dilations are generated by Ca2+ increases in neurons, resulting in production of nitric oxide and AA metabolites. Arachidonic acid from neurons also diffuses into astrocyte endfeet where it is converted into additional vasoactive metabolites. While this scheme resolves several discrepancies in the field, many unresolved challenges remain and are discussed in the final section of the review.

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Section: The Function Of Functional Hyperemiamentioning

confidence: 99%

Mechanisms Mediating Functional Hyperemia in the Brain

2017

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“…Neurons readily import lactate, which is then converted to pyruvate and oxidized in the mitochondria. Defects in mitochondrial function are associated with several progressive neurodegenerative diseases [141]. There may also be a link between specific defects in mitochondrial pyruvate metabolism, because reduced PDH activity has been detected in neurons from mouse and human brains in the context of several neurological diseases [142–144].…”

Section: Physiology and Pathophysiology Of Mitochondrial Pyruvate Tramentioning

confidence: 99%

Mitochondrial pyruvate transport: a historical perspective and future research directions

McCommis

Finck

2015

Biochemical Journal

199

160

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Pyruvate is the end-product of glycolysis, a major substrate for oxidative metabolism, and a branching point for glucose, lactate, fatty acid and amino acid synthesis. The mitochondrial enzymes that metabolize pyruvate are physically separated from cytosolic pyruvate pools and rely on a membrane transport system to shuttle pyruvate across the impermeable inner mitochondrial membrane (IMM). Despite long-standing acceptance that transport of pyruvate into the mitochondrial matrix by a carrier-mediated process is required for the bulk of its metabolism, it has taken almost 40 years to determine the molecular identity of an IMM pyruvate carrier. Our current understanding is that two proteins, mitochondrial pyruvate carriers MPC1 and MPC2, form a hetero-oligomeric complex in the IMM to facilitate pyruvate transport. This step is required for mitochondrial pyruvate oxidation and carboxylation – critical reactions in intermediary metabolism that are dysregulated in several common diseases. The identification of these transporter constituents opens the door to the identification of novel compounds that modulate MPC activity, with potential utility for treating diabetes, cardiovascular disease, cancer, neurodegenerative diseases, and other common causes of morbidity and mortality. The purpose of the present review is to detail the historical, current and future research investigations concerning mitochondrial pyruvate transport, and discuss the possible consequences of altered pyruvate transport in various metabolic tissues.

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“…Whereas both cytosolic and mitochondrial pathways generate the critical metabolic co-factor NADH (nicotinamide adenine nucleotide), metabolic FADH 2 pathways and O 2 consumption primarily occur within mitochondria (Foster et al 2005, McKenna et al 2006, Shetty et al 2012). Fluorescence of either NADH (at 460 nm) (Aubin 1979, Kasischke et al 2011) or FAD+ (at 515 nm) (Zhao et al 2011) can be used to monitor energy metabolism (Foster et al 2005, Galeffi et al 2007, Galeffi et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Metabolic responses differentiate between interictal, ictal and persistent epileptiform activity in intact, immature hippocampus in vitro

Ivanov

Bernard

Turner

2015

Neurobiology of Disease

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Interictal spikes, ictal responses, and status epilepticus are characteristic of abnormal neuronal activity in epilepsy. Since these events may involve different energy requirements, we evaluated metabolic function (assessed by simultaneous NADH and FAD imaging and tissue O2 recordings) in the immature, intact mouse hippocampus (P5-P7, in vitro) during spontaneous interictal spikes and ictal-like events (ILEs), induced by increased neuronal network excitability with either low Mg2+ media or decreased inhibition with bicuculline. In low Mg2+ medium NADH fluorescence showed a small decrease both during the interictal build-up leading to an ictal event and before ILE occurrences, but a large positive response during and after ILEs (up to 10% net change). Tissue O2 recordings (pO2) showed an oxygen dip (indicating oxygen consumption) coincident with each ILE at P5 and P7, closely matching an NADH fluorescence increase, indicating a large surge in oxidative metabolism. The ILE O2 dip was significantly larger at P7 as compared to P5 suggesting a higher metabolic response at P7. After several ILEs at P7, continuous, low voltage activity (late recurrent discharges: LRDs) occurred. During LRDs, whilst the epileptiform activity was relatively small (low voltage synchronous activity) oxygen levels remained low and NADH fluorescence elevated, indicating persistent oxygen utilization and maintained high metabolic demand. In bicuculline, NADH fluorescence levels decreased prior to the onset of epileptiform activity, followed by a slow positive phase, which persisted during interictal responses. Metabolic responses can thus differentiate between interictal, ictal-like and persistent epileptiform activity resembling status epilepticus, and confirm that spreading depression did not occur. These results demonstrate clear translational value to the understanding of metabolic requirements during epileptic conditions.

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Cellular Links between Neuronal Activity and Energy Homeostasis

Cited by 66 publications

References 189 publications

Mechanisms Mediating Functional Hyperemia in the Brain

Mechanisms Mediating Functional Hyperemia in the Brain

Mitochondrial pyruvate transport: a historical perspective and future research directions

Metabolic responses differentiate between interictal, ictal and persistent epileptiform activity in intact, immature hippocampus in vitro

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