A novel approach for imaging brain-behavior relationships in mice reveals unexpected metabolic patterns during seizures in the absence of tissue plasminogen activator

Martine M. Mirrione; Wynne K. Schiffer; Joanna S. Fowler; Dave L. Alexoff; Stephen L. Dewey; Stella E. Tsirka

doi:10.1016/j.neuroimage.2007.06.032

A novel approach for imaging brain-behavior relationships in mice reveals unexpected metabolic patterns during seizures in the absence of tissue plasminogen activator

Martine M. Mirrione, Wynne K. Schiffer, Joanna S. Fowler, Dave L. Alexoff, Stephen L. Dewey, Stella E. Tsirka

Research output: Contribution to journal › Article › peer-review

104 Scopus citations

Abstract

Medically refractory seizures cause inflammation and neurodegeneration. Seizure initiation thresholds have been linked in mice to the serine protease tissue plasminogen activator (tPA); mice lacking tPA exhibit resistance to seizure induction, and the ensuing inflammation and neurodegeneration are similarly suppressed. Seizure foci in humans can be examined using PET employing 2-deoxy-2[¹⁸F]fluoro-d-glucose (¹⁸FDG) as a tracer to visualize metabolic dysfunction. However, there currently exist no such methods in mice to correlate measures of brain activation with behavior. Using a novel method for small animal PET data analysis, we examine patterns of ¹⁸FDG uptake in wild-type and tPA^-/- mice and find that they correlate with the severity of drug-induced seizure initiation. Furthermore, we report unexpected activations that may underlie the tPA modulation of seizure susceptibility. The methods described here should be applicable to other mouse models of human neurological disease.

Original language	English (US)
Pages (from-to)	34-42
Number of pages	9
Journal	NeuroImage
Volume	38
Issue number	1
DOIs	https://doi.org/10.1016/j.neuroimage.2007.06.032
State	Published - Oct 15 2007
Externally published	Yes

Bibliographical note

Funding Information:
The authors would like to thank the members of the BNL cyclotron facility, Michael Schueller, David J. Schyler, Colleen Shea, and Youwen Xu, for the 18 FDG preparation. We would also like to thank Shiva Kothari for assisting in verifying baseline glucose levels between genotypes. This work was supported by the National Science Foundation Integrative Graduate Education and Research Traineeship — Minerals, Metals, Metalloids and Toxicity Program at Stony Brook University (M.M.M), National Institutes of Health (R01NS42168) and American Heart Association-Established Investigator Award (S.E.T) and USDOE/OBER DE-AC02-98CH10886 and NIDA DA15041 and DA15082 (S.L.D).

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title = "A novel approach for imaging brain-behavior relationships in mice reveals unexpected metabolic patterns during seizures in the absence of tissue plasminogen activator",

abstract = "Medically refractory seizures cause inflammation and neurodegeneration. Seizure initiation thresholds have been linked in mice to the serine protease tissue plasminogen activator (tPA); mice lacking tPA exhibit resistance to seizure induction, and the ensuing inflammation and neurodegeneration are similarly suppressed. Seizure foci in humans can be examined using PET employing 2-deoxy-2[18F]fluoro-d-glucose (18FDG) as a tracer to visualize metabolic dysfunction. However, there currently exist no such methods in mice to correlate measures of brain activation with behavior. Using a novel method for small animal PET data analysis, we examine patterns of 18FDG uptake in wild-type and tPA-/- mice and find that they correlate with the severity of drug-induced seizure initiation. Furthermore, we report unexpected activations that may underlie the tPA modulation of seizure susceptibility. The methods described here should be applicable to other mouse models of human neurological disease.",

author = "Mirrione, {Martine M.} and Schiffer, {Wynne K.} and Fowler, {Joanna S.} and Alexoff, {Dave L.} and Dewey, {Stephen L.} and Tsirka, {Stella E.}",

note = "Funding Information: The authors would like to thank the members of the BNL cyclotron facility, Michael Schueller, David J. Schyler, Colleen Shea, and Youwen Xu, for the 18 FDG preparation. We would also like to thank Shiva Kothari for assisting in verifying baseline glucose levels between genotypes. This work was supported by the National Science Foundation Integrative Graduate Education and Research Traineeship — Minerals, Metals, Metalloids and Toxicity Program at Stony Brook University (M.M.M), National Institutes of Health (R01NS42168) and American Heart Association-Established Investigator Award (S.E.T) and USDOE/OBER DE-AC02-98CH10886 and NIDA DA15041 and DA15082 (S.L.D). ",

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AU - Dewey, Stephen L.

AU - Tsirka, Stella E.

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N2 - Medically refractory seizures cause inflammation and neurodegeneration. Seizure initiation thresholds have been linked in mice to the serine protease tissue plasminogen activator (tPA); mice lacking tPA exhibit resistance to seizure induction, and the ensuing inflammation and neurodegeneration are similarly suppressed. Seizure foci in humans can be examined using PET employing 2-deoxy-2[18F]fluoro-d-glucose (18FDG) as a tracer to visualize metabolic dysfunction. However, there currently exist no such methods in mice to correlate measures of brain activation with behavior. Using a novel method for small animal PET data analysis, we examine patterns of 18FDG uptake in wild-type and tPA-/- mice and find that they correlate with the severity of drug-induced seizure initiation. Furthermore, we report unexpected activations that may underlie the tPA modulation of seizure susceptibility. The methods described here should be applicable to other mouse models of human neurological disease.

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A novel approach for imaging brain-behavior relationships in mice reveals unexpected metabolic patterns during seizures in the absence of tissue plasminogen activator

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