Date of Award

January 2021

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Hal Blumenfeld

Abstract

Consciousness as a concept has historically been exclusively examined in the study of philosophy, but in the past few decades, consciousness has become increasingly relevant in neuroscience and neurology practice. This thesis describes two projects in rodent models related to the study of neural mechanisms associated with consciousness. In the first project, we investigated the relationship of the lateral septum (LS) and basal forebrain (BF), a key arousal center, during focal limbic seizures that result in cortical slow-wave activity associated with loss of consciousness in a rat model. The network inhibition hypothesis posits that focal limbic seizures impair consciousness by activating subcortical inhibitory centers, including LS, which in turn inhibits key arousal centers including cholinergic neurons of the BF. This project aimed to establish the anatomical and functional relationship between LS and BF. We injected anterograde and retrograde neuronal tracers in LS and BF respectively and found direct connections between LS neurons and BF cholinergic neurons, in addition to indirect connections between LS and BF via the thalamic paratennial nucleus (PT). We measured PT activity during electrically induced focal hippocampal seizures and found that PT activity decreased during a focal seizure in association with slow-wave activity in the cortex, similar to that seen during sleep, implicating PT’s functional role as an intermediary in the LS to BF circuit pathway. PT’s modulatory role on arousal may be exploited as a therapeutic target, such as with thalamic stimulation, for consciousness-impairing focal seizures. In the second project, we established a novel auditory conscious perception behavioural task for the head-fixed mouse on a stationary wheel. Recent data from human studies suggested several electrographic correlates of conscious perception, including late event-related potentials and forward-sweeping broadband gamma activation. It is unknown if these markers are present in animal models. Furthermore, there is no well-established paradigm for studying conscious perception in rodents. We designed two auditory tasks based on the go/no-go (GNG) and lick-left/lick-right (LLLR) paradigms. Four animals were trained on the GNG task but did not show further progress after four weeks of training. Ten animals were trained on a modified version of the LLLR task using a motorized waterspout. Two animals reached an accuracy of >90% after 6 weeks of training, with the remaining eight trending towards improvement. Future work will focus on obtaining electrophysiological data during task performance to derive neural correlates of conscious perception in mice, which would offer insights into the mechanism of perception-altering disease states such as migraine or seizure “auras” and schizophrenia.

Comments

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

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