title: Impaired cognitive ability and anxiety-like behavior following acute seizures in the Theiler's virus model of temporal lobe epilepsy.
abstract: Viral infection of the CNS can result in encephalitis and acute seizures, increasing the risk for later-life epilepsy. We have previously characterized a novel animal model of temporal lobe epilepsy that recapitulates key sequela in the development of epilepsy following viral infection. C57BL/6J mice inoculated with the Daniel's strain of Theiler's Murine Encephalomyelitis Virus (TMEV; 3×10(5) PFU, i.c.) display acute limbic seizures that secondarily generalize. A majority of acutely seized animals develop spontaneous seizures weeks to months later. As part of our investigation, we sought to assess behavioral comorbidity following TMEV inoculation. Anxiety, depression, cognitive impairment, and certain psychoses are diagnosed in persons with epilepsy at rates far more frequent than in the general population. We used a battery of behavioral tests to assess anxiety, depression, cognitive impairment, and general health in acutely seized animals inoculated with TMEV and compared behavioral outcomes against age-matched controls receiving a sham injection. We determined that TMEV-seized animals are less likely to move through the exposed center of an open field and are less likely to enter into the lighted half of a light/dark box; both behaviors may be indicative of anxiety-like behavior. TMEV-seized animals also display early and persistent reductions in novel object exploration during novel object place tasks and do not improve in their ability to find a hidden escape platform in Morris water maze testing, indicative of impairment in episodic and spatial memory, respectively. Cresyl violet staining at 35 and 250 days after injection reveals bilateral reductions in hippocampal area, with extensive sclerosis of CA1 evident bilaterally along the rostral-caudal axis. Early and persistent behavioral changes in the TMEV model provide surrogate markers for assessing disease progression as well as endpoints in screening for the efficacy of novel compounds to manage both seizure burden and comorbid conditions.
authors.affiliation: Interdepartmental Program in Neuroscience, University of Utah, 1401 MREB, 20 North 1900 East, Salt Lake City, UT 84132.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Umpierre
authors.affiliation: Interdepartmental Program in Neuroscience, University of Utah, 1401 MREB, 20 North 1900 East, Salt Lake City, UT 84132.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Remigio
authors.affiliation: Department of Pharmacology and Toxicology, University of Utah.
authors.forename: E Jill
authors.initials: EJ
authors.lastname: Dahle
authors.affiliation: Department of Pharmacology and Toxicology, University of Utah.
authors.forename: Kate
authors.initials: K
authors.lastname: Bradford
authors.affiliation: Anticonvulsant Drug Development Program, University of Utah, 417 Wakara Way, Suite 3211, Salt Lake City, UT 84108, USA.
authors.forename: Anitha B
authors.initials: AB
authors.lastname: Alex
authors.affiliation: Department of Pharmacology and Toxicology, University of Utah; Anticonvulsant Drug Development Program, University of Utah, 417 Wakara Way, Suite 3211, Salt Lake City, UT 84108, USA.
authors.forename: Misty D
authors.initials: MD
authors.lastname: Smith
authors.affiliation: Interdepartmental Program in Neuroscience, University of Utah, 1401 MREB, 20 North 1900 East, Salt Lake City, UT 84132; Department of Pharmacology and Toxicology, University of Utah; Anticonvulsant Drug Development Program, University of Utah, 417 Wakara Way, Suite 3211, Salt Lake City, UT 84108, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: West
authors.affiliation: Interdepartmental Program in Neuroscience, University of Utah, 1401 MREB, 20 North 1900 East, Salt Lake City, UT 84132; Department of Pharmacology and Toxicology, University of Utah; Anticonvulsant Drug Development Program, University of Utah, 417 Wakara Way, Suite 3211, Salt Lake City, UT 84108, USA.
authors.forename: H Steve
authors.initials: HS
authors.lastname: White
authors.affiliation: Interdepartmental Program in Neuroscience, University of Utah, 1401 MREB, 20 North 1900 East, Salt Lake City, UT 84132; Department of Pharmacology and Toxicology, University of Utah; Anticonvulsant Drug Development Program, University of Utah, 417 Wakara Way, Suite 3211, Salt Lake City, UT 84108, USA. Electronic address: karen.wilcox@hsc.utah.edu.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Wilcox
mesh_terms: D000208:Acute Disease; D000818:Animals; D001008:Anxiety Disorders / Q000209:etiology* / Q000473:pathology; D001522:Behavior, Animal; D056547:CA1 Region, Hippocampal / Q000473:pathology; D003072:Cognition Disorders / Q000209:etiology*; D015897:Comorbidity; D004195:Disease Models, Animal; D018450:Disease Progression; D004833:Epilepsy, Temporal Lobe / Q000150:complications* / Q000473:pathology / Q000523:psychology*; D006624:Hippocampus / Q000473:pathology*; D008297:Male; D008569:Memory Disorders / Q000209:etiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009483:Neuropsychological Tests; D012598:Sclerosis / Q000473:pathology; D012640:Seizures / Q000209:etiology* / Q000473:pathology; D017945:Theilovirus; D013997:Time Factors
keywords: Acute seizures; Cognitive impairment; Novel object place recognition; Temporal lobe epilepsy; Viral encephalitis