Abstract

Evaluating cerebral energy metabolism at microscopic resolution is important for comprehensively understanding healthy brain function and its pathological alterations. Here, we resolve specific alterations in cerebral metabolism in vivo in Sprague Dawley rats utilizing minimally-invasive 2-photon fluorescence lifetime imaging (2P-FLIM) measurements of reduced nicotinamide adenine dinucleotide (NADH) fluorescence. Time-resolved fluorescence lifetime measurements enable distinction of different components contributing to NADH autofluorescence. Ostensibly, these components indicate different enzyme-bound formulations of NADH. We observed distinct variations in the relative proportions of these components before and after pharmacological-induced impairments to several reactions involved in glycolytic and oxidative metabolism. Classification models were developed with the experimental data and used to predict the metabolic impairments induced during separate experiments involving bicuculline-induced seizures. The models consistently predicted that prolonged focal seizure activity results in impaired activity in the electron transport chain, likely the consequence of inadequate oxygen supply. 2P-FLIM observations of cerebral NADH will help advance our understanding of cerebral energetics at a microscopic scale. Such knowledge will aid in our evaluation of healthy and diseased cerebral physiology and guide diagnostic and therapeutic strategies that target cerebral energetics.

© 2017 Optical Society of America

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2016 (1)

J. Lee, “Mitochondrial drug targets in neurodegenerative diseases,” Bioorg. Med. Chem. Lett. 26(3), 714–720 (2016).
[Crossref] [PubMed]

2015 (6)

A. I. Ivanov, C. Bernard, and D. A. Turner, “Metabolic responses differentiate between interictal, ictal and persistent epileptiform activity in intact, immature hippocampus in vitro,” Neurobiol. Dis. 75, 1–14 (2015).
[Crossref] [PubMed]

M. A. Yaseen, V. J. Srinivasan, I. Gorczynska, J. G. Fujimoto, D. A. Boas, and S. Sakadžić, “Multimodal optical imaging system for in vivo investigation of cerebral oxygen delivery and energy metabolism,” Biomed. Opt. Express 6(12), 4994–5007 (2015).
[Crossref] [PubMed]

A. J. Walsh and M. C. Skala, “Optical metabolic imaging quantifies heterogeneous cell populations,” Biomed. Opt. Express 6(2), 559–573 (2015).
[Crossref] [PubMed]

U. Winkler and J. Hirrlinger, “Crosstalk of signaling and metabolism mediated by the NAD+/NADH redox state in brain cells,” Neurochem. Res. 40(12), 2394–2401 (2015).
[Crossref] [PubMed]

D. Liu, T. Evans, and F. Zhang, “Applications and advances of metabolite biosensors for metabolic engineering,” Metab. Eng. 31, 35–43 (2015).
[Crossref] [PubMed]

G. Yellen and R. Mongeon, “Quantitative two-photon imaging of fluorescent biosensors,” Curr. Opin. Chem. Biol. 27, 24–30 (2015).
[Crossref] [PubMed]

2014 (2)

E. Roussakis, J. A. Spencer, C. P. Lin, and S. A. Vinogradov, “Two-photon antenna-core oxygen probe with enhanced performance,” Anal. Chem. 86(12), 5937–5945 (2014).
[Crossref] [PubMed]

T. S. Blacker, Z. F. Mann, J. E. Gale, M. Ziegler, A. J. Bain, G. Szabadkai, and M. R. Duchen, “Separating NADH and NADPH fluorescence in live cells and tissues using FLIM,” Nat. Commun. 5, 3936 (2014).
[Crossref] [PubMed]

2013 (2)

M. L. Marziaz, K. Frazier, P. B. Guidry, R. A. Ruiz, I. Petrikovics, and D. C. Haines, “Comparison of brain mitochondrial cytochrome c oxidase activity with cyanide LD(50) yields insight into the efficacy of prophylactics,” J. Appl. Toxicol. 33(1), 50–55 (2013).
[Crossref] [PubMed]

M. A. Yaseen, S. Sakadžić, W. Wu, W. Becker, K. A. Kasischke, and D. A. Boas, “In vivo imaging of cerebral energy metabolism with two-photon fluorescence lifetime microscopy of NADH,” Biomed. Opt. Express 4(2), 307–321 (2013).
[Crossref] [PubMed]

2012 (1)

B. K. Wright, L. M. Andrews, M. R. Jones, C. Stringari, M. A. Digman, and E. Gratton, “Phasor-FLIM analysis of NADH distribution and localization in the nucleus of live progenitor myoblast cells,” Microsc. Res. Tech. 75(12), 1717–1722 (2012).
[Crossref] [PubMed]

2011 (6)

M. Zhao, J. Nguyen, H. Ma, N. Nishimura, C. B. Schaffer, and T. H. Schwartz, “Preictal and ictal neurovascular and metabolic coupling surrounding a seizure focus,” J. Neurosci. 31(37), 13292–13300 (2011).
[Crossref] [PubMed]

Y. P. Hung, J. G. Albeck, M. Tantama, and G. Yellen, “Imaging cytosolic NADH-NAD+ redox state with a genetically encoded fluorescent biosensor,” Cell Metab. 14(4), 545–554 (2011).
[Crossref] [PubMed]

Y. Zhao, J. Jin, Q. Hu, H.-M. Zhou, J. Yi, Z. Yu, L. Xu, X. Wang, Y. Yang, and J. Loscalzo, “Genetically encoded fluorescent sensors for intracellular NADH detection,” Cell Metab. 14(4), 555–566 (2011).
[Crossref] [PubMed]

E. Baraghis, A. Devor, Q. Fang, V. J. Srinivasan, W. Wu, F. Lesage, C. Ayata, K. A. Kasischke, D. A. Boas, and S. Sakadzić, “Two-photon microscopy of cortical NADH fluorescence intensity changes: correcting contamination from the hemodynamic response,” J. Biomed. Opt. 16(10), 106003 (2011).
[Crossref] [PubMed]

C. Stringari, A. Cinquin, O. Cinquin, M. A. Digman, P. J. Donovan, and E. Gratton, “Phasor approach to fluorescence lifetime microscopy distinguishes different metabolic states of germ cells in a live tissue,” Proc. Natl. Acad. Sci. U.S.A. 108(33), 13582–13587 (2011).
[Crossref] [PubMed]

C. A. Thorling, X. Liu, F. J. Burczynski, L. M. Fletcher, G. C. Gobe, and M. S. Roberts, “Multiphoton microscopy can visualize zonal damage and decreased cellular metabolic activity in hepatic ischemia-reperfusion injury in rats,” J. Biomed. Opt. 16(11), 116011 (2011).
[Crossref] [PubMed]

2010 (2)

A. A. Heikal, “Intracellular coenzymes as natural biomarkers for metabolic activities and mitochondrial anomalies,” Biomarkers Med. 4(2), 241–263 (2010).
[Crossref] [PubMed]

M. V. Ivannikov, M. Sugimori, and R. R. Llinás, “Calcium clearance and its energy requirements in cerebellar neurons,” Cell Calcium 47(6), 507–513 (2010).
[Crossref] [PubMed]

2009 (5)

R. Cao, B. T. Higashikubo, J. Cardin, U. Knoblich, R. Ramos, M. T. Nelson, C. I. Moore, and J. C. Brumberg, “Pinacidil induces vascular dilation and hyperemia in vivo and does not impact biophysical properties of neurons and astrocytes in vitro,” Cleve. Clin. J. Med. 76(Suppl 2), S80–S85 (2009).
[Crossref] [PubMed]

M. M. Schmidt and R. Dringen, “Differential effects of iodoacetamide and iodoacetate on glycolysis and glutathione metabolism of cultured astrocytes,” Front. Neuroenergetics 1, 1 (2009).
[Crossref] [PubMed]

V. V. Ghukasyan and F.-J. Kao, “Monitoring cellular metabolism with fluorescence lifetime of reduced nicotinamide adenine dinucleotide,” J. Phys. Chem. C 113(27), 11532–11540 (2009).
[Crossref]

Q. Yu and A. A. Heikal, “Two-photon autofluorescence dynamics imaging reveals sensitivity of intracellular NADH concentration and conformation to cell physiology at the single-cell level,” J. Photochem. Photobiol. B 95(1), 46–57 (2009).
[Crossref] [PubMed]

D. Chorvat and A. Chorvatova, “Multi-wavelength fluorescence lifetime spectroscopy: a new approach to the study of endogenous fluorescence in living cells and tissues,” Laser Phys. Lett. 6(3), 175–193 (2009).
[Crossref]

2008 (4)

O. S. Finikova, A. Y. Lebedev, A. Aprelev, T. Troxler, F. Gao, C. Garnacho, S. Muro, R. M. Hochstrasser, and S. A. Vinogradov, “Oxygen microscopy by two-photon-excited phosphorescence,” ChemPhysChem Eur. J. Chem. Phys. Phys. Chem. 9, 1673–1679 (2008).

M. A. Digman, V. R. Caiolfa, M. Zamai, and E. Gratton, “The phasor approach to fluorescence lifetime imaging analysis,” Biophys. J. 94(2), L14–L16 (2008).
[Crossref] [PubMed]

T. H. Chia, A. Williamson, D. D. Spencer, and M. J. Levene, “Multiphoton fluorescence lifetime imaging of intrinsic fluorescence in human and rat brain tissue reveals spatially distinct NADH binding,” Opt. Express 16(6), 4237–4249 (2008).
[Crossref] [PubMed]

D. Li, W. Zheng, and J. Y. Qu, “Time-resolved spectroscopic imaging reveals the fundamentals of cellular NADH fluorescence,” Opt. Lett. 33(20), 2365–2367 (2008).
[Crossref] [PubMed]

2007 (2)

M. C. Skala, K. M. Riching, A. Gendron-Fitzpatrick, J. Eickhoff, K. W. Eliceiri, J. G. White, and N. Ramanujam, “In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia,” Proc. Natl. Acad. Sci. U.S.A. 104(49), 19494–19499 (2007).
[Crossref] [PubMed]

R. Moreno-Sánchez, S. Rodríguez-Enríquez, A. Marín-Hernández, and E. Saavedra, “Energy metabolism in tumor cells,” FEBS J. 274(6), 1393–1418 (2007).
[Crossref] [PubMed]

2006 (4)

Y. Wu, W. Zheng, and J. Y. Qu, “Sensing cell metabolism by time-resolved autofluorescence,” Opt. Lett. 31(21), 3122–3124 (2006).
[Crossref] [PubMed]

M. T. Lin and M. F. Beal, “Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases,” Nature 443(7113), 787–795 (2006).
[Crossref] [PubMed]

O. Kann and R. Kovács, “Mitochondria and neuronal activity,” Am. J. Physiol. Cell Physiol. 292(2), C641–C657 (2006).
[Crossref] [PubMed]

X. D. Zhang, E. Deslandes, M. Villedieu, L. Poulain, M. Duval, P. Gauduchon, L. Schwartz, and P. Icard, “Effect of 2-deoxy-D-glucose on Various Malignant Cell Lines in vitro,” Anticancer Res. 26(5A), 3561–3566 (2006).
[PubMed]

2005 (2)

H. D. Vishwasrao, A. A. Heikal, K. A. Kasischke, and W. W. Webb, “Conformational dependence of intracellular NADH on metabolic state revealed by associated fluorescence anisotropy,” J. Biol. Chem. 280(26), 25119–25126 (2005).
[Crossref] [PubMed]

K. Blinova, S. Carroll, S. Bose, A. V. Smirnov, J. J. Harvey, J. R. Knutson, and R. S. Balaban, “Distribution of mitochondrial NADH fluorescence lifetimes: steady-state kinetics of matrix NADH interactions,” Biochemistry 44(7), 2585–2594 (2005).
[Crossref] [PubMed]

2004 (6)

H. Hirase, J. Creso, and G. Buzsáki, “Capillary level imaging of local cerebral blood flow in bicuculline-induced epileptic foci,” Neuroscience 128(1), 209–216 (2004).
[Crossref] [PubMed]

R. Niesner, B. Beker, P. Schlüsche, and K.-H. Gericke, “Noniterative biexponential fluorescence lifetime imaging in the investigation of cellular metabolism by means of NAD(P)H autofluorescence,” ChemPhysChem Eur. J. Chem. Phys. Phys. Chem. 5, 1141–1149 (2004).

M. R. Duchen, “Mitochondria in health and disease: perspectives on a new mitochondrial biology,” Mol. Aspects Med. 25(4), 365–451 (2004).
[Crossref] [PubMed]

A. Nimmerjahn, F. Kirchhoff, J. N. D. Kerr, and F. Helmchen, “Sulforhodamine 101 as a specific marker of astroglia in the neocortex in vivo,” Nat. Methods 1(1), 31–37 (2004).
[Crossref] [PubMed]

V. N. Uversky, “Neurotoxicant-induced animal models of Parkinson’s disease: understanding the role of rotenone, maneb and paraquat in neurodegeneration,” Cell Tissue Res. 318(1), 225–241 (2004).
[Crossref] [PubMed]

K. A. Kasischke, H. D. Vishwasrao, P. J. Fisher, W. R. Zipfel, and W. W. Webb, “Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis,” Science 305(5680), 99–103 (2004).
[Crossref] [PubMed]

2003 (2)

N. Li, K. Ragheb, G. Lawler, J. Sturgis, B. Rajwa, J. A. Melendez, and J. P. Robinson, “Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production,” J. Biol. Chem. 278(10), 8516–8525 (2003).
[Crossref] [PubMed]

H. T. Ma, C. H. Wu, and J. Y. Wu, “Initiation of spontaneous epileptiform events in the rat neocortex in vivo,” J. Neurophysiol. 91(2), 934–945 (2003).
[Crossref] [PubMed]

2002 (1)

S. Huang, A. A. Heikal, and W. W. Webb, “Two-photon fluorescence spectroscopy and microscopy of NAD(P)H and flavoprotein,” Biophys. J. 82(5), 2811–2825 (2002).
[Crossref] [PubMed]

2001 (2)

D. Attwell and S. B. Laughlin, “An energy budget for signaling in the grey matter of the brain,” J. Cereb. Blood Flow Metab. 21(10), 1133–1145 (2001).
[Crossref] [PubMed]

T. H. Schwartz and T. Bonhoeffer, “In vivo optical mapping of epileptic foci and surround inhibition in ferret cerebral cortex,” Nat. Med. 7(9), 1063–1067 (2001).
[Crossref] [PubMed]

1999 (1)

S. Schuchmann, K. Buchheim, H. Meierkord, and U. Heinemann, “A relative energy failure is associated with low-Mg2+ but not with 4-aminopyridine induced seizure-like events in entorhinal cortex,” J. Neurophysiol. 81(1), 399–403 (1999).
[PubMed]

1995 (2)

M. Wakita, G. Nishimura, and M. Tamura, “Some characteristics of the fluorescence lifetime of reduced pyridine nucleotides in isolated mitochondria, isolated hepatocytes, and perfused rat liver in situ,” J. Biochem. 118(6), 1151–1160 (1995).
[Crossref] [PubMed]

L. K. Klaidman, A. C. Leung, and J. D. Adams., “High-performance liquid chromatography analysis of oxidized and reduced pyridine dinucleotides in specific brain regions,” Anal. Biochem. 228(2), 312–317 (1995).
[Crossref] [PubMed]

1993 (1)

J. C. Pettersen and S. D. Cohen, “The effects of cyanide on brain mitochondrial cytochrome oxidase and respiratory activities,” J. Appl. Toxicol. 13(1), 9–14 (1993).
[Crossref] [PubMed]

1992 (1)

J. R. Lakowicz, H. Szmacinski, K. Nowaczyk, and M. L. Johnson, “Fluorescence lifetime imaging of free and protein-bound NADH,” Proc. Natl. Acad. Sci. U.S.A. 89(4), 1271–1275 (1992).
[Crossref] [PubMed]

1990 (1)

E. Lenartowicz, “A complex effect of arsenite on the formation of alpha-ketoglutarate in rat liver mitochondria,” Arch. Biochem. Biophys. 283(2), 388–396 (1990).
[Crossref] [PubMed]

1983 (1)

E. Dóra, “Glycolysis and epilepsy-induced changes in cerebrocortical NAD/NADH redox state,” J. Neurochem. 41(6), 1774–1777 (1983).
[Crossref] [PubMed]

1981 (1)

N. R. Kreisman, J. C. Lamanna, M. Rosenthal, and T. J. Sick, “Oxidative metabolic responses with recurrent seizures in rat cerebral cortex: role of systemic factors,” Brain Res. 218(1-2), 175–188 (1981).
[Crossref] [PubMed]

1980 (1)

R. T. Tenny, F. W. Sharbrough, R. E. Anderson, and T. M. Sundt., “Correlation of intracellular redox states and pH with blood flow in primary and secondary seizure foci,” Ann. Neurol. 8(6), 564–573 (1980).
[Crossref] [PubMed]

1979 (1)

B. Chance, B. Schoener, R. Oshino, F. Itshak, and Y. Nakase, “Oxidation-reduction ratio studies of mitochondria in freeze-trapped samples: NADH and flavoprotein fluorescence signals,” J. Biol. Chem. 254(11), 4764–4771 (1979).
[PubMed]

1976 (1)

A. Gafni and L. Brand, “Fluorescence decay studies of reduced nicotinamide adenine dinucleotide in solution and bound to liver alcohol dehydrogenase,” Biochemistry 15(15), 3165–3171 (1976).
[Crossref] [PubMed]

1975 (1)

T. E. Duffy, D. C. Howse, and F. Plum, “Cerebral energy metabolism during experimental status epilepticus,” J. Neurochem. 24(5), 925–934 (1975).
[Crossref] [PubMed]

1970 (1)

H. Koenig and A. Patel, “Biochemical basis for fluorouracil neurotoxicity: the role of Krebs cycle inhibition by fluoroacetate,” Arch. Neurol. 23(2), 155–160 (1970).
[Crossref] [PubMed]

1966 (1)

R. Guarneri and V. Bonavita, “Nicotinamide Adenine Dinucleotides in the Developing Rat Brain,” Brain Res. 2(2), 145–150 (1966).
[Crossref] [PubMed]

1965 (1)

B. Chance, D. Jamieson, and H. Coles, “Energy-linked pyridine nucleotide reduction - inhibitory effects of hyperbaric oxygen in vitro and in vivo,” Nature 206, 257 (1965).

1962 (2)

B. Chance, P. Cohen, F. Jobsis, and B. Schoener, “Intracellular oxidation-reduction states in vivo,” Science 137(3529), 499–508 (1962).
[Crossref] [PubMed]

Y. Avi-Dor, J. M. Olson, M. D. Doherty, and N. O. Kaplan, “Fluorescence of pyridine nucleotides in mitochondria,” J. Biol. Chem. 237, 2377–2383 (1962).

1959 (1)

B. Chance and B. Thorell, “Localization and Kinetics of reduced pyridine nucleotide in living cells by microfluorometry,” J. Biol. Chem. 234, 3044–3050 (1959).
[PubMed]

1958 (2)

B. Chance and H. Baltscheffsky, “Respiratory enzymes in oxidative phosphorylation, VII, Binding of intramitochondrial reduced pyridine nucleotide,” J. Biol. Chem. 233(3), 736–739 (1958).
[PubMed]

B. Chance and M. Baltscheffsky, “Spectroscopic effects of adenosine diphosphate upon the respiratory pigments of rat-heart-muscle sarcosomes,” Biochem. J. 68(2), 283–295 (1958).
[Crossref] [PubMed]

1956 (1)

P. Boyer, H. Theorell, L. Pokras, L. G. Sillén, and B. Thorell, “The change in reduced diphosphopyridine nucleotide (dpnh) fluorescence upon combination with liver alcohol dehydrogenase (adh),” Acta Chem. Scand. 10, 447–450 (1956).
[Crossref]

1953 (1)

L. J. Berry and R. B. Mitchell, “The relation of the tricarboxylic acid cycle to bacterial infection. II. The effect of fluoroacetate, arsenite, citrate, and succinate on Salmonella typhimurium infections in mice,” J. Infect. Dis. 93(1), 83–92 (1953).
[Crossref] [PubMed]

Adams, J. D.

L. K. Klaidman, A. C. Leung, and J. D. Adams., “High-performance liquid chromatography analysis of oxidized and reduced pyridine dinucleotides in specific brain regions,” Anal. Biochem. 228(2), 312–317 (1995).
[Crossref] [PubMed]

Albeck, J. G.

Y. P. Hung, J. G. Albeck, M. Tantama, and G. Yellen, “Imaging cytosolic NADH-NAD+ redox state with a genetically encoded fluorescent biosensor,” Cell Metab. 14(4), 545–554 (2011).
[Crossref] [PubMed]

Anderson, R. E.

R. T. Tenny, F. W. Sharbrough, R. E. Anderson, and T. M. Sundt., “Correlation of intracellular redox states and pH with blood flow in primary and secondary seizure foci,” Ann. Neurol. 8(6), 564–573 (1980).
[Crossref] [PubMed]

Andrews, L. M.

B. K. Wright, L. M. Andrews, M. R. Jones, C. Stringari, M. A. Digman, and E. Gratton, “Phasor-FLIM analysis of NADH distribution and localization in the nucleus of live progenitor myoblast cells,” Microsc. Res. Tech. 75(12), 1717–1722 (2012).
[Crossref] [PubMed]

Aprelev, A.

O. S. Finikova, A. Y. Lebedev, A. Aprelev, T. Troxler, F. Gao, C. Garnacho, S. Muro, R. M. Hochstrasser, and S. A. Vinogradov, “Oxygen microscopy by two-photon-excited phosphorescence,” ChemPhysChem Eur. J. Chem. Phys. Phys. Chem. 9, 1673–1679 (2008).

Attwell, D.

D. Attwell and S. B. Laughlin, “An energy budget for signaling in the grey matter of the brain,” J. Cereb. Blood Flow Metab. 21(10), 1133–1145 (2001).
[Crossref] [PubMed]

Avi-Dor, Y.

Y. Avi-Dor, J. M. Olson, M. D. Doherty, and N. O. Kaplan, “Fluorescence of pyridine nucleotides in mitochondria,” J. Biol. Chem. 237, 2377–2383 (1962).

Ayata, C.

E. Baraghis, A. Devor, Q. Fang, V. J. Srinivasan, W. Wu, F. Lesage, C. Ayata, K. A. Kasischke, D. A. Boas, and S. Sakadzić, “Two-photon microscopy of cortical NADH fluorescence intensity changes: correcting contamination from the hemodynamic response,” J. Biomed. Opt. 16(10), 106003 (2011).
[Crossref] [PubMed]

Bain, A. J.

T. S. Blacker, Z. F. Mann, J. E. Gale, M. Ziegler, A. J. Bain, G. Szabadkai, and M. R. Duchen, “Separating NADH and NADPH fluorescence in live cells and tissues using FLIM,” Nat. Commun. 5, 3936 (2014).
[Crossref] [PubMed]

Balaban, R. S.

K. Blinova, S. Carroll, S. Bose, A. V. Smirnov, J. J. Harvey, J. R. Knutson, and R. S. Balaban, “Distribution of mitochondrial NADH fluorescence lifetimes: steady-state kinetics of matrix NADH interactions,” Biochemistry 44(7), 2585–2594 (2005).
[Crossref] [PubMed]

Baltscheffsky, H.

B. Chance and H. Baltscheffsky, “Respiratory enzymes in oxidative phosphorylation, VII, Binding of intramitochondrial reduced pyridine nucleotide,” J. Biol. Chem. 233(3), 736–739 (1958).
[PubMed]

Baltscheffsky, M.

B. Chance and M. Baltscheffsky, “Spectroscopic effects of adenosine diphosphate upon the respiratory pigments of rat-heart-muscle sarcosomes,” Biochem. J. 68(2), 283–295 (1958).
[Crossref] [PubMed]

Baraghis, E.

E. Baraghis, A. Devor, Q. Fang, V. J. Srinivasan, W. Wu, F. Lesage, C. Ayata, K. A. Kasischke, D. A. Boas, and S. Sakadzić, “Two-photon microscopy of cortical NADH fluorescence intensity changes: correcting contamination from the hemodynamic response,” J. Biomed. Opt. 16(10), 106003 (2011).
[Crossref] [PubMed]

Beal, M. F.

M. T. Lin and M. F. Beal, “Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases,” Nature 443(7113), 787–795 (2006).
[Crossref] [PubMed]

Becker, W.

Beker, B.

R. Niesner, B. Beker, P. Schlüsche, and K.-H. Gericke, “Noniterative biexponential fluorescence lifetime imaging in the investigation of cellular metabolism by means of NAD(P)H autofluorescence,” ChemPhysChem Eur. J. Chem. Phys. Phys. Chem. 5, 1141–1149 (2004).

Bernard, C.

A. I. Ivanov, C. Bernard, and D. A. Turner, “Metabolic responses differentiate between interictal, ictal and persistent epileptiform activity in intact, immature hippocampus in vitro,” Neurobiol. Dis. 75, 1–14 (2015).
[Crossref] [PubMed]

Berry, L. J.

L. J. Berry and R. B. Mitchell, “The relation of the tricarboxylic acid cycle to bacterial infection. II. The effect of fluoroacetate, arsenite, citrate, and succinate on Salmonella typhimurium infections in mice,” J. Infect. Dis. 93(1), 83–92 (1953).
[Crossref] [PubMed]

Blacker, T. S.

T. S. Blacker, Z. F. Mann, J. E. Gale, M. Ziegler, A. J. Bain, G. Szabadkai, and M. R. Duchen, “Separating NADH and NADPH fluorescence in live cells and tissues using FLIM,” Nat. Commun. 5, 3936 (2014).
[Crossref] [PubMed]

Blinova, K.

K. Blinova, S. Carroll, S. Bose, A. V. Smirnov, J. J. Harvey, J. R. Knutson, and R. S. Balaban, “Distribution of mitochondrial NADH fluorescence lifetimes: steady-state kinetics of matrix NADH interactions,” Biochemistry 44(7), 2585–2594 (2005).
[Crossref] [PubMed]

Boas, D. A.

Bonavita, V.

R. Guarneri and V. Bonavita, “Nicotinamide Adenine Dinucleotides in the Developing Rat Brain,” Brain Res. 2(2), 145–150 (1966).
[Crossref] [PubMed]

Bonhoeffer, T.

T. H. Schwartz and T. Bonhoeffer, “In vivo optical mapping of epileptic foci and surround inhibition in ferret cerebral cortex,” Nat. Med. 7(9), 1063–1067 (2001).
[Crossref] [PubMed]

Bose, S.

K. Blinova, S. Carroll, S. Bose, A. V. Smirnov, J. J. Harvey, J. R. Knutson, and R. S. Balaban, “Distribution of mitochondrial NADH fluorescence lifetimes: steady-state kinetics of matrix NADH interactions,” Biochemistry 44(7), 2585–2594 (2005).
[Crossref] [PubMed]

Boyer, P.

P. Boyer, H. Theorell, L. Pokras, L. G. Sillén, and B. Thorell, “The change in reduced diphosphopyridine nucleotide (dpnh) fluorescence upon combination with liver alcohol dehydrogenase (adh),” Acta Chem. Scand. 10, 447–450 (1956).
[Crossref]

Brand, L.

A. Gafni and L. Brand, “Fluorescence decay studies of reduced nicotinamide adenine dinucleotide in solution and bound to liver alcohol dehydrogenase,” Biochemistry 15(15), 3165–3171 (1976).
[Crossref] [PubMed]

Brumberg, J. C.

R. Cao, B. T. Higashikubo, J. Cardin, U. Knoblich, R. Ramos, M. T. Nelson, C. I. Moore, and J. C. Brumberg, “Pinacidil induces vascular dilation and hyperemia in vivo and does not impact biophysical properties of neurons and astrocytes in vitro,” Cleve. Clin. J. Med. 76(Suppl 2), S80–S85 (2009).
[Crossref] [PubMed]

Buchheim, K.

S. Schuchmann, K. Buchheim, H. Meierkord, and U. Heinemann, “A relative energy failure is associated with low-Mg2+ but not with 4-aminopyridine induced seizure-like events in entorhinal cortex,” J. Neurophysiol. 81(1), 399–403 (1999).
[PubMed]

Burczynski, F. J.

C. A. Thorling, X. Liu, F. J. Burczynski, L. M. Fletcher, G. C. Gobe, and M. S. Roberts, “Multiphoton microscopy can visualize zonal damage and decreased cellular metabolic activity in hepatic ischemia-reperfusion injury in rats,” J. Biomed. Opt. 16(11), 116011 (2011).
[Crossref] [PubMed]

Buzsáki, G.

H. Hirase, J. Creso, and G. Buzsáki, “Capillary level imaging of local cerebral blood flow in bicuculline-induced epileptic foci,” Neuroscience 128(1), 209–216 (2004).
[Crossref] [PubMed]

Caiolfa, V. R.

M. A. Digman, V. R. Caiolfa, M. Zamai, and E. Gratton, “The phasor approach to fluorescence lifetime imaging analysis,” Biophys. J. 94(2), L14–L16 (2008).
[Crossref] [PubMed]

Cao, R.

R. Cao, B. T. Higashikubo, J. Cardin, U. Knoblich, R. Ramos, M. T. Nelson, C. I. Moore, and J. C. Brumberg, “Pinacidil induces vascular dilation and hyperemia in vivo and does not impact biophysical properties of neurons and astrocytes in vitro,” Cleve. Clin. J. Med. 76(Suppl 2), S80–S85 (2009).
[Crossref] [PubMed]

Cardin, J.

R. Cao, B. T. Higashikubo, J. Cardin, U. Knoblich, R. Ramos, M. T. Nelson, C. I. Moore, and J. C. Brumberg, “Pinacidil induces vascular dilation and hyperemia in vivo and does not impact biophysical properties of neurons and astrocytes in vitro,” Cleve. Clin. J. Med. 76(Suppl 2), S80–S85 (2009).
[Crossref] [PubMed]

Carroll, S.

K. Blinova, S. Carroll, S. Bose, A. V. Smirnov, J. J. Harvey, J. R. Knutson, and R. S. Balaban, “Distribution of mitochondrial NADH fluorescence lifetimes: steady-state kinetics of matrix NADH interactions,” Biochemistry 44(7), 2585–2594 (2005).
[Crossref] [PubMed]

Chance, B.

B. Chance, B. Schoener, R. Oshino, F. Itshak, and Y. Nakase, “Oxidation-reduction ratio studies of mitochondria in freeze-trapped samples: NADH and flavoprotein fluorescence signals,” J. Biol. Chem. 254(11), 4764–4771 (1979).
[PubMed]

B. Chance, D. Jamieson, and H. Coles, “Energy-linked pyridine nucleotide reduction - inhibitory effects of hyperbaric oxygen in vitro and in vivo,” Nature 206, 257 (1965).

B. Chance, P. Cohen, F. Jobsis, and B. Schoener, “Intracellular oxidation-reduction states in vivo,” Science 137(3529), 499–508 (1962).
[Crossref] [PubMed]

B. Chance and B. Thorell, “Localization and Kinetics of reduced pyridine nucleotide in living cells by microfluorometry,” J. Biol. Chem. 234, 3044–3050 (1959).
[PubMed]

B. Chance and M. Baltscheffsky, “Spectroscopic effects of adenosine diphosphate upon the respiratory pigments of rat-heart-muscle sarcosomes,” Biochem. J. 68(2), 283–295 (1958).
[Crossref] [PubMed]

B. Chance and H. Baltscheffsky, “Respiratory enzymes in oxidative phosphorylation, VII, Binding of intramitochondrial reduced pyridine nucleotide,” J. Biol. Chem. 233(3), 736–739 (1958).
[PubMed]

Chia, T. H.

Chorvat, D.

D. Chorvat and A. Chorvatova, “Multi-wavelength fluorescence lifetime spectroscopy: a new approach to the study of endogenous fluorescence in living cells and tissues,” Laser Phys. Lett. 6(3), 175–193 (2009).
[Crossref]

Chorvatova, A.

D. Chorvat and A. Chorvatova, “Multi-wavelength fluorescence lifetime spectroscopy: a new approach to the study of endogenous fluorescence in living cells and tissues,” Laser Phys. Lett. 6(3), 175–193 (2009).
[Crossref]

Cinquin, A.

C. Stringari, A. Cinquin, O. Cinquin, M. A. Digman, P. J. Donovan, and E. Gratton, “Phasor approach to fluorescence lifetime microscopy distinguishes different metabolic states of germ cells in a live tissue,” Proc. Natl. Acad. Sci. U.S.A. 108(33), 13582–13587 (2011).
[Crossref] [PubMed]

Cinquin, O.

C. Stringari, A. Cinquin, O. Cinquin, M. A. Digman, P. J. Donovan, and E. Gratton, “Phasor approach to fluorescence lifetime microscopy distinguishes different metabolic states of germ cells in a live tissue,” Proc. Natl. Acad. Sci. U.S.A. 108(33), 13582–13587 (2011).
[Crossref] [PubMed]

Cohen, P.

B. Chance, P. Cohen, F. Jobsis, and B. Schoener, “Intracellular oxidation-reduction states in vivo,” Science 137(3529), 499–508 (1962).
[Crossref] [PubMed]

Cohen, S. D.

J. C. Pettersen and S. D. Cohen, “The effects of cyanide on brain mitochondrial cytochrome oxidase and respiratory activities,” J. Appl. Toxicol. 13(1), 9–14 (1993).
[Crossref] [PubMed]

Coles, H.

B. Chance, D. Jamieson, and H. Coles, “Energy-linked pyridine nucleotide reduction - inhibitory effects of hyperbaric oxygen in vitro and in vivo,” Nature 206, 257 (1965).

Creso, J.

H. Hirase, J. Creso, and G. Buzsáki, “Capillary level imaging of local cerebral blood flow in bicuculline-induced epileptic foci,” Neuroscience 128(1), 209–216 (2004).
[Crossref] [PubMed]

Deslandes, E.

X. D. Zhang, E. Deslandes, M. Villedieu, L. Poulain, M. Duval, P. Gauduchon, L. Schwartz, and P. Icard, “Effect of 2-deoxy-D-glucose on Various Malignant Cell Lines in vitro,” Anticancer Res. 26(5A), 3561–3566 (2006).
[PubMed]

Devor, A.

E. Baraghis, A. Devor, Q. Fang, V. J. Srinivasan, W. Wu, F. Lesage, C. Ayata, K. A. Kasischke, D. A. Boas, and S. Sakadzić, “Two-photon microscopy of cortical NADH fluorescence intensity changes: correcting contamination from the hemodynamic response,” J. Biomed. Opt. 16(10), 106003 (2011).
[Crossref] [PubMed]

Digman, M. A.

B. K. Wright, L. M. Andrews, M. R. Jones, C. Stringari, M. A. Digman, and E. Gratton, “Phasor-FLIM analysis of NADH distribution and localization in the nucleus of live progenitor myoblast cells,” Microsc. Res. Tech. 75(12), 1717–1722 (2012).
[Crossref] [PubMed]

C. Stringari, A. Cinquin, O. Cinquin, M. A. Digman, P. J. Donovan, and E. Gratton, “Phasor approach to fluorescence lifetime microscopy distinguishes different metabolic states of germ cells in a live tissue,” Proc. Natl. Acad. Sci. U.S.A. 108(33), 13582–13587 (2011).
[Crossref] [PubMed]

M. A. Digman, V. R. Caiolfa, M. Zamai, and E. Gratton, “The phasor approach to fluorescence lifetime imaging analysis,” Biophys. J. 94(2), L14–L16 (2008).
[Crossref] [PubMed]

Doherty, M. D.

Y. Avi-Dor, J. M. Olson, M. D. Doherty, and N. O. Kaplan, “Fluorescence of pyridine nucleotides in mitochondria,” J. Biol. Chem. 237, 2377–2383 (1962).

Donovan, P. J.

C. Stringari, A. Cinquin, O. Cinquin, M. A. Digman, P. J. Donovan, and E. Gratton, “Phasor approach to fluorescence lifetime microscopy distinguishes different metabolic states of germ cells in a live tissue,” Proc. Natl. Acad. Sci. U.S.A. 108(33), 13582–13587 (2011).
[Crossref] [PubMed]

Dóra, E.

E. Dóra, “Glycolysis and epilepsy-induced changes in cerebrocortical NAD/NADH redox state,” J. Neurochem. 41(6), 1774–1777 (1983).
[Crossref] [PubMed]

Dringen, R.

M. M. Schmidt and R. Dringen, “Differential effects of iodoacetamide and iodoacetate on glycolysis and glutathione metabolism of cultured astrocytes,” Front. Neuroenergetics 1, 1 (2009).
[Crossref] [PubMed]

Duchen, M. R.

T. S. Blacker, Z. F. Mann, J. E. Gale, M. Ziegler, A. J. Bain, G. Szabadkai, and M. R. Duchen, “Separating NADH and NADPH fluorescence in live cells and tissues using FLIM,” Nat. Commun. 5, 3936 (2014).
[Crossref] [PubMed]

M. R. Duchen, “Mitochondria in health and disease: perspectives on a new mitochondrial biology,” Mol. Aspects Med. 25(4), 365–451 (2004).
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Figures (5)

Fig. 1
Fig. 1

(a) Perfusion system for local delivery of metabolic inhibitors to cortical surface under a sealed cranial window, with (for select experiments involving induced focal seizure activity) screw electrodes for EEG recordings (b) table of tested pharmacological reagents and their corresponding influence on metabolic activity or pathology.

Fig. 2
Fig. 2

Pharmacologically-induced manipulations to anaerobic glycolysis and aerobic oxidative metabolism. (a) Simplified illustration of glycolysis (step I) and oxidative metabolism (steps I-III), highlighting the pharmacological manipulations induced in this study (b-e) NADH intensity image collected in vivo from the rat cerebral cortex (b) under baseline conditions and (c) after topical application of Potassium cyanide. (d-e) corresponding SR101 fluorescence, highlighting astrocyte cell bodies and providing morphological guidance for imaging. Time-resolved profiles of NADH fluorescence were obtained at each pixel in the field of view before and after pharmacological manipulations. The increase in NADH intensity appears spatially uniform across the field of view. Scale bar: 50 µm.

Fig. 3
Fig. 3

(a) Representative time-resolved profiles of endogenous NADH fluorescence in the rat cortex after pharmacological manipulation, summed over the entire field of view and normalized (b) and computed average lifetime of NADH fluorescence in solution and in vivo under varied metabolic conditions. (c) Pharmacologically-induced changes to NADH intensity from baseline levels, computed by integrating the time-resolved fluorescence profiles in pixels corresponding to astrocytic cell bodies and neuropil * indicates significantly different from baseline in vivo measurement. Error bars indicate standard error across all pixels over all measurements.

Fig. 4
Fig. 4

Calculated metrics for the 4 resolvable components (c1 - c4) of in vivo NADH autofluorescence after metabolic inhibition at various reaction steps. * indicates significant difference from baseline.

Fig. 5
Fig. 5

Scatter plots of the computed NADH lifetime parameters utilized for classification algorithms. Classification models used intensity change (ΔI), mean lifetime (<τ>), and amplitude-weighted lifetimes (ατi, i: 1-4) as input parameters.

Tables (1)

Tables Icon

Table 1 Alterations in NADH FLIM metrics associated with impairments to different metabolic processes

Equations (5)

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I theoretical ( t )= I offset + i=1 N α i exp( t τ i )
I measured ( t )=IRF( t )( I 0 δ( t )+ I theoretical ( t ) )
F=Fluorescence= i=1 4 α i τ i
τ = i=1 4 α i τ i i=1 4 α i
f i =FractionalFluorescenc e i = α i τ i i=1 4 α i τ i

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