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. We established a rat model with focal limbic seizures exhibiting high frequency discharges in the hippocampus, but slow 1-3 Hz activity in the neocortex, decreased cortical blood flow and metabolism, as well as decreased behavioral responsiveness resembling the human disorder. In this model we found that important subcortical arousal systems including brainstem and basal forebrain cholinergic neurons are depressed. These finding suggest that sleep-like cortical slow waves may occur in focal limbic seizures because of decreased subcortical arousal. In addition we found that putative descending GABAergic systems including the lateral septum and anterior hypothalamus are strongly activated by focal limbic seizures. Based on these findings, our central hypothesis is that focal limbic seizures activate inhibitory systems which depress subcortical arousal leading to sleep-like cortical slow waves and impaired consciousness. We plan to investigate this hypothesis at the level of neurons, networks, and behavior in a rodent model. Recent work has also raised the exciting prospect of restoring subcortical arousal to improve cortical function during seizures. Therefore, our aims are to first investigate the inputs to subcortical arousal systems using whole-cell electrophysiology to determine incoming synaptic activity; and using optogenetics to selectively activate or inhibit input pathways. Second, we will determine which subcortical arousal systems are critical for depressed cortical function by electrically or optogenetically restoring outputs from these systems during focal limbic seizures, and measure effects on the cortex through electrophysiology recordings and high-field functional magnetic resonance imaging (fMRI). Third, we will examine the effects of focal limbic seizures on attention and decision-making tasks and investigate the ability of restored subcortical arousal to improve behavioral responsiveness during seizures. The integration of information across these levels will increase our understanding of abnormal long-range network changes in epilepsy, potentially leading to new therapeutic options in the treatment of this disorder.