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.
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.
|Patterson, Katelin P; Barry, Jeremy M; Curran, Megan M et al. (2017) Enduring Memory Impairments Provoked by Developmental Febrile Seizures Are Mediated by Functional and Structural Effects of Neuronal Restrictive Silencing Factor. J Neurosci 37:3799-3812|
|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|
|Massey, Andrew T; Lerner, David K; Holmes, Gregory L et al. (2016) ACTH Prevents Deficits in Fear Extinction Associated with Early Life Seizures. Front Neurol 7:65|
|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|
|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; Sakkaki, Sophie; Barriere, Sylvain J et al. (2016) Temporal Coordination of Hippocampal Neurons Reflects Cognitive Outcome Post-febrile Status Epilepticus. EBioMedicine 7:175-90|
|Holmes, Gregory L (2016) Effect of Seizures on the Developing Brain and Cognition. Semin Pediatr Neurol 23:120-6|
|Blumberg, Benjamin J; Flynn, Sean P; Barriere, Sylvain J et al. (2016) Efficacy of nonselective optogenetic control of the medial septum over hippocampal oscillations: the influence of speed and implications for cognitive enhancement. Physiol Rep 4:|
|Holmes, Gregory L (2015) Cognitive impairment in epilepsy: the role of network abnormalities. Epileptic Disord 17:101-16|
Showing the most recent 10 out of 40 publications