Remote effects of focal hippocampal seizures on neocortical function

PROJECT SUMMARY / ABSTRACT
Seizures have both local and remote effects on nervous system function. Temporal lobe epilepsy is a common
and debilitating neurological disorder, characterized by focal seizures arising from limbic structures, including
the hippocampus. Interestingly, focal temporal lobe seizures often cause functional deficits such as impaired
consciousness, which is not expected from local hippocampal impairment alone. Human focal temporal lobe
seizures with impaired consciousness show slow waves on electro-encephalography (EEG) and decreased
cerebral blood flow in the neocortex, distant from the hippocampus. The mechanisms by which focal seizures
in the hippocampus cause depressed function in the neocortex are not known. Our previous work in a rat
model with focal limbic seizures reproduced the human findings and suggested that decreased subcortical
arousal produces impaired consciousness during seizures. Importantly, neurostimulation of subcortical arousal
systems was capable of restoring cortical function and behavioral responses during seizures, offering hope for
restored arousal in human epilepsy. Therefore, our central hypothesis is that focal limbic seizures decrease
subcortical arousal, causing cortical slow waves and impaired consciousness. However, the fundamental
mechanisms of these changes have not been determined. We recently developed a novel awake head-fixed
mouse model of focal limbic seizures, providing unique opportunities to investigate network, neurotransmitter
and neuronal mechanisms in relation to behavior. We found that both increased inhibition and decreased
excitation may contribute in parallel to depressed subcortical arousal in limbic seizures. In addition, depressed
arousal in multiple neurotransmitter systems may contribute to impaired cortical function. We now plan to
capitalize on strengths of the awake mouse model to employ techniques including high field fMRI, genetically
encoded fluorescent neurotransmitter sensors, optogenetics, single cell electrophysiology and behavioral
testing to fully investigate the mechanisms of impaired arousal in seizures. Therefore, our aims are to first
investigate the network mechanisms of impaired arousal in focal limbic seizures in the awake mouse model.
We will map cortical and subcortical networks by fMRI, followed by direct electrophysiological recordings,
stimulation and disconnection experiments to identify key network nodes. Second, we will analyze the
neurotransmitter changes in depressed cortical function. We will use genetically encoded fluorescent indicators
and optogenetics to determine the roles of increased inhibition and decreased excitation in depressed
subcortical arousal; and will investigate which arousal neurotransmitters contribute to impaired cortical function
and behavior. Third, we will relate the activity of single neurons to behavior in focal limbic seizures, using
juxtacellular recordings of identified subcortical arousal neurons and whole cell recordings of cortical neurons.
The integration of information across these levels in the awake model will have important translational value to
guide development of new treatments aimed at restoring consciousness during and following seizures.

Grant Number: 5R01NS066974-14
NIH Institute/Center: NIH
Principal Investigator: HAL BLUMENFELD