The aim of this project is to study why rapid eye movement (REM) sleep is an anticonvulsant state and to test whether stimulation of REM-promoting brain regions prevents seizures. Experiments will focus on the pedunculopontine nucleus (PPT), a midbrain cholinergic region that densely innervates the thalamus. Electrophysiological and optical recordings will be done in the thalamus, neocortex, and hippocampus in healthy and epileptic rats. The central motivating hypothesis is that REM is a neuroprotective state due to the wide-spread cortical asynchrony observed in this state which arises, in part, due to cholinergic signaling in the thalamus.
Specific Aim 1. 1 will test how electrical stimulation of the PPT affects acetylcholine binding in the thalamus and the firing patterns of cortical and thalamic neurons in healthy rats. These experiments will establish a database of how the brain reacts to different kinds of stimulations so that if a therapeutic protocol is discovered, its neurophysiological mechanism of action can be better understood.
Specific Aim 1. 2 will test whether these same stimulation protocols change the seizure threshold in the kindling model of epilepsy. I hypothesize that those stimulations that induce strong thalamic acetylcholine binding will also be those that induce cortical asynchrony and most effectively suppress seizure spread in the evoked kindling model.
Specific Aim 2 will then test whether electrical stimulation of the PPT is effective in suppressing seizures in a chronic epilepsy model induced by intra-hippocampal kainic acid injection. Seizures will be predicted online, and stimulation of the PPT will be given when seizures are likely. These experiments will further our understanding of the link between seizures and sleep and will guide future clinical studies to assess whether REM promoting brain regions should be targeted in patients suffering from epilepsy.
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