Brain states and circuit mechanisms underlying sleep and general anesthesia

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2014.Cataloged from PDF version of thesis.Includes bibliographical references.During sleep and general anesthesia, the brain enters a state of decreased arousal and consciousness is transiently suspended. How this transition occurs is a fundamental and unsolved question in neuroscience. The neural dynamics that disrupt consciousness have not been identified, and the circuit mechanisms that generate these dynamics remain unknown. Furthermore, understanding the neural basis of sleep and anesthesia is key to improving clinical monitoring of patients undergoing general anesthesia and to advancing treatments of sleep disorders and neurological conditions such as coma. In this thesis, I combine intracranial electrophysiology in human subjects with optogenetic manipulation of thalamocortical circuits in mice to identify the neural dynamics underlying sleep and anesthesia. I first show that loss of consciousness during propofol general anesthesia is associated with the abrupt onset of slow oscillations that disrupt cortical networks. I then demonstrate that activation of the thalamic reticular nucleus generates slow wave activity and decreases arousal state, identifying a causal mechanism that generates physiological and behavioral signs of sleep. Finally, I study patients undergoing deep general anesthesia at levels corresponding to medically induced coma, and show that this state is marked by local cortical dynamics consistent with impaired cerebral metabolism. Taken together, these results identify a set of neural dynamics associated with unconscious states, and demonstrate specific mechanisms for how they disrupt brain function. These findings provide new insight into the neuroscience of arousal states, and suggest clinical approaches that could improve patient care.by Laura D. Lewis.Ph. D