Date of Award

January 2023

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Hal Blumenfeld

Abstract

Patients with temporal lobe seizures can suffer debilitating loss of consciousness during ictal episodes. Rat models have previously implicated the inhibition of brainstem and basal forebrain cholinergic neurons has been related to cortical impairment during these periods of impaired consciousness. However, there are still other subcortical pathways that remain largely unexplored. Recording multiunit activity in the locus coeruleus (LC) in an awake mouse model will help elucidate its potential role in this pathophysiology. We hypothesized that there would be decreased activity in the LC during periods of ictal unconsciousness. Recordings were performed using head-fixed mice running on a wheel with chronically implanted bipolar electrodes in the right orbitofrontal cortex (OFC) and bilateral hippocampi (HC). Focal limbic seizures were induced via the application of current pulses into the HC and multiunit recordings were simultaneously taken from the LC. We observed a statistically significant decrease in firing of LC neurons during ictal impairment, there was also a concurrent, significant increase in power in the 1-4Hz band in the OFC. This is the first evidence of a pathway involving the LC contributing to depressed arousal in focal limbic seizures. Further elucidation of these, and other pathways, will contribute better mechanistic understanding of ictal unconsciousness and may lead to novel, improved treatments for people with epilepsy.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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