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 #
5R01NS073083-02
Application #
8217078
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
2012-02-01
Budget End
2013-01-31
Support Year
2
Fiscal Year
2012
Total Cost
$345,625
Indirect Cost
$126,875
Name
Dartmouth College
Department
Neurology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Mahoney, J Matthew; Titiz, Ali S; Hernan, Amanda E et al. (2016) Short-Range Temporal Interactions in Sleep; Hippocampal Spike Avalanches Support a Large Milieu of Sequential Activity Including Replay. PLoS One 11:e0147708
Holmes, Gregory L (2016) Effect of Seizures on the Developing Brain and Cognition. Semin Pediatr Neurol 23:120-6
Buckley, Ashura W; Holmes, Gregory L (2016) Epilepsy and Autism. Cold Spring Harb Perspect Med 6:a022749
Barry, Jeremy M; Holmes, Gregory L (2016) Why Are Children With Epileptic Encephalopathies Encephalopathic? J Child Neurol 31:1495-1504
Barry, Jeremy M; Tian, Chengju; Spinella, Anthony et al. (2016) Spatial cognition following early-life seizures in rats: Performance deficits are dependent on task demands. Epilepsy Behav 60:1-6
Barry, Jeremy M; Sakkaki, Sophie; Barriere, Sylvain J et al. (2016) Temporal Coordination of Hippocampal Neurons Reflects Cognitive Outcome Post-febrile Status Epilepticus. EBioMedicine 7:175-90
Flynn, Sean P; Barriere, Sylvain; Barrier, Sylvain et al. (2015) Status Epilepticus Induced Spontaneous Dentate Gyrus Spikes: In Vivo Current Source Density Analysis. PLoS One 10:e0132630
Savotchenko, Alina; Romanov, Arthur; Isaev, Dmytro et al. (2015) Neuraminidase inhibition primes short-term depression and suppresses long-term potentiation of synaptic transmission in the rat hippocampus. Neural Plast 2015:908190
Isaeva, Elena; Romanov, Arthur; Holmes, Gregory L et al. (2015) Status epilepticus results in region-specific alterations in seizure susceptibility along the hippocampal longitudinal axis. Epilepsy Res 110:166-70
Holmes, Gregory L; Tian, Chengju; Hernan, Amanda E et al. (2015) Alterations in sociability and functional brain connectivity caused by early-life seizures are prevented by bumetanide. Neurobiol Dis 77:204-19

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