Childhood epilepsy is associated with a significant risk for cognitive impairment. Understanding the mechanisms of these cognitive impairments may lead to novel therapies that minimize the adverse outcomes. We have previously shown that in rats, early-life seizures (ELS) result in substantial cognitive impairment. Preliminary data from our laboratory suggest that ELS are followed by abnormalities in neural coding and EEG oscillatory activity, both of which are believed to play a critical role in cognitive function. This project further investigates the mechanisms leading to cognitive impairments by determining the extent and relevance of brain oscillation dysfunction. We hypothesize that: i) ELS cause deficits in brain oscillatory activity;and ii) These deficits are responsible, at least in part for cognitive impairment. To reach our goal of determining the impact of ELS on oscillatory activity and its relationship to cognitive function in the developing and adult brain we will first characterize how ELS affect the developmental trajectory of oscillatory activity in hippocampus through use of multi-contact laminar electrodes in the hippocampus in non-anesthetized rat pups starting at postnatal day (P) 5. We will then analyze the relationships between oscillations and behavior in rats with and without ELS, both at the single unit and network levels. Place cell development and theta and gamma modulation of place cell firing (phase modulation, phase precession) will be studied in freely moving rats at P20 and P60 in a delayed spatial alternation task, and place cell properties will be compared between correct and incorrect trials in the same animals and between controls and ELS rats. To evaluate the effects of ELS on network properties, we will study spectral coherence on hippocampal (CA1-CA3) and hippocampal-prefrontal network function while rats are involved in a memory task. Having established the role of hippocampal oscillations in ELS-induced cognitive dysfunction in Specific Aim 1, we will then explore ways to improve cognition following ELS in Specific Aim 2. Specifically, we will evaluate the effect of artificially-induced theta and gamma oscillation on hippocampal function following ELS and whether behavioral training animals can modify hippocampal oscillations and subsequent learning. Taken together, these studies are likely to provide insights into the mechanisms and consequences behind network abnormalities of ELS and provide a strong framework for intervention.

Public Health Relevance

During the first few years of life children with seizures are at high risk for developing cognitive disorders. In preliminary studies we have evidence that abnormalities in hippocampal rhythms may contribute to cognitive deficits following early-life seizures. In this proposal we will determine if abnormalities of hippocampal oscillations following early-life seizures are responsible for the intellectual deficits seen in children with epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS073083-05
Application #
8606664
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Fureman, Brandy E
Project Start
2011-02-01
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2014
Total Cost
$268,119
Indirect Cost
$71,244
Name
University of Vermont & St Agric College
Department
Neurology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Holmes, Gregory L (2014) To know or not to know: does EEG monitoring in the paediatric intensive care unit add anything besides cost? Brain 137:1276-7
Hernan, Amanda E; Alexander, Abigail; Jenks, Kyle R et al. (2014) Focal epileptiform activity in the prefrontal cortex is associated with long-term attention and sociability deficits. Neurobiol Dis 63:25-34
Sitdikova, Guzel; Zakharov, Andrei; Janackova, Sona et al. (2014) Isoflurane suppresses early cortical activity. Ann Clin Transl Neurol 1:15-26
Burroughs, Scott A; Morse, Richard P; Mott, Steven H et al. (2014) Brain connectivity in West syndrome. Seizure 23:576-9
Titiz, A S; Mahoney, J M; Testorf, M E et al. (2014) Cognitive impairment in temporal lobe epilepsy: role of online and offline processing of single cell information. Hippocampus 24:1129-45
Hernan, Amanda E; Alexander, Abigail; Lenck-Santini, Pierre-Pascal et al. (2014) Attention deficit associated with early life interictal spikes in a rat model is improved with ACTH. PLoS One 9:e89812
Hernan, A E; Holmes, G L; Isaev, D et al. (2013) Altered short-term plasticity in the prefrontal cortex after early life seizures. Neurobiol Dis 50:120-6
Holmes, Gregory L (2013) EEG abnormalities as a biomarker for cognitive comorbidities in pharmacoresistant epilepsy. Epilepsia 54 Suppl 2:60-2
Isaeva, Elena; Isaev, Dmytro; Holmes, Gregory L (2013) Alteration of synaptic plasticity by neonatal seizures in rat somatosensory cortex. Epilepsy Res 106:280-3
Bender, Alex C; Natola, Heather; Ndong, Christian et al. (2013) Focal Scn1a knockdown induces cognitive impairment without seizures. Neurobiol Dis 54:297-307

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