http://hdl.handle.net/1721.1/7593 2013-06-19T04:01:15Z http://hdl.handle.net/1721.1/79187 Intracranial electroencephalography signatures of the induction of general anesthesia with Propofol Weiner, Veronica Sara General anesthesia is a drug-induced, reversible behavioral state characterized by hypnosis (loss of consciousness), amnesia (loss of memory), analgesia (loss of pain perception), akinesia (loss of movement), and hemodynamic stability (stability and control of the cardiovascular, respiratory, and autonomic nervous systems). Each year, more than 25 million patients receive general anesthesia in the United States. Anesthesia-related morbidity is a significant medical problem, including nausea, vomiting, respiratory distress, post-operative cognitive dysfunction, and post-operative recall. To eliminate anesthesia-related morbidity, the brain systems involved in producing general anesthesia must be identified and characterized, and methods must be devised to monitor those brain systems and guide drug administration. A priority for anesthesia research is to identify the brain networks responsible for the characteristic electroencephalography (EEG) signals of anesthesia in relation to sensory, cognitive, memory, and pain systems. In this thesis, we recorded simultaneous intracranial and surface EEG, and single unit data in patients with intractable epilepsy who had been previously implanted with clinical and/or research electrodes. The aims of this research were to characterize the neural signals of anesthesia in a regionally and temporally precise way that is relevant to clinical anesthesia, and to identify dynamic neuronal networks that underlie these signals. We demonstrated region-specific, frequency-band-specific changes in neural recordings at loss of consciousness. We related these findings to theories of how anesthetic drugs may impart their behavioral effects. Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2013.; Cataloged from PDF version of thesis. Vita.; Includes bibliographical references. 2013-01-01T00:00:00Z http://hdl.handle.net/1721.1/79186 Dynamics of dopamine signaling and network activity in the striatum during learning and motivated pursuit of goals Howe, Mark W. (Mark William) Learning to direct behaviors towards goals is a central function of all vertebrate nervous systems. Initial learning often involves an exploratory phase, in which actions are flexible and highly variable. With repeated successful experience, behaviors may be guided by cues in the environment that reliably predict the desired outcome, and eventually behaviors can be executed as crystallized action sequences, or "habits", which are relatively inflexible. Parallel circuits through the basal ganglia and their inputs from midbrain dopamine neurons are believed to make critical contributions to these phases of learning and behavioral execution. To explore the neural mechanisms underlying goal-directed learning and behavior, I have employed electrophysiological and electrochemical techniques to measure neural activity and dopamine release in networks of the striatum, the principle input nucleus of the basal ganglia as rats learned to pursue rewards in mazes. The electrophysiological recordings revealed training dependent dynamics in striatum local field potentials and coordinated neural firing that may differentially support both network rigidity and flexibility during pursuit of goals. Electrochemical measurements of real-time dopamine signaling during maze running revealed prolonged signaling changes that may contribute to motivating or guiding behavior. Pathological over or under-expression of these network states may contribute to symptoms experienced in a range of basal ganglia disorders, from Parkinson's disease to drug addiction. Thesis (Ph. D. in Neuroscience)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2013.; Cataloged from PDF version of thesis. "February 2013."; Includes bibliographical references (p. 118-126). 2013-01-01T00:00:00Z http://hdl.handle.net/1721.1/79184 Selectivity and development of the visual word form area King, Li-Wei An area of left occipitotemporal cortex commonly referred to as the visual word form area (VWFA), has consistently been shown to activate during the processing of written language. However, the exact nature of the region's selectivity is still under debate. In this thesis, I explore the selectivity of the visual word form area at three different levels. First, I examine whether the VWFA differentiates between letter strings of different lexicality and pronounceability and argue that the VWFA's selectivity is greatly influenced by attention. Second, I explore the developmental course of mirror discrimination in the VWFA, and show that children do not display adult-like mirror discrimination of letters even into early adolescence. Finally, I look at the developmental course of VWFA selectivity for words compared to nonlinguistic visual stimuli. While children have adult-like activation patterns when words are compared to a low-level visual control, they show less specialization compared to adults when objects are used as a control. Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, February 2013.; Cataloged from PDF version of thesis. "February 2013."; Includes bibliographical references (p. 95-113). 2013-01-01T00:00:00Z http://hdl.handle.net/1721.1/79141 Regulation of synaptic function and plasticity by cyclin-dependent kinase 5 Su, Susan C. (Susan Chih-Chieh) The neuronal serine/threonine kinase cyclin-dependent kinase 5 (Cdk5) is activated by its regulatory subunit, p35, to post-translationally modify substrates through phosphorylation. In this thesis, I provide several lines of evidence that Cdk5 plays a critical role in synaptic function and plasticity. First, we characterized the function of Cdk5 in learning and memory by region-specific Cdk5 ablation. From multiple Cdk5 conditional knockout mouse models, we determined that Cdk5 is essential for memory formation and synaptic plasticity. Loss of Cdk5 in the hippocampus disrupts the cAMP pathway due to increased phosphodiesterase proteins. This dysregulation of cAMP signaling can be attenuated by a phosphodiesterase inhibitor to restore levels of protein phosphorylation, synaptic plasticity, and memory. Moreover, forebrain-specific deletion of Cdk5 affected multiple aspects of behavior that can partially be rescued by lithium treatment. We next identified the N-type calcium channels as a presynaptic substrate of Cdk5. We described how Cdk5-mediated phosphorylation of the N-type calcium channel increased calcium influx and channel open probability. This in turn enhanced the association of the N-type calcium channel with the active zone protein RIM1, which impacted vesicle docking and neurotransmission. Finally, we identified the postsynaptic density protein Shank3 as a Cdk5 substrate and observed that Cdk5-mediated phosphorylation of Shank3 plays a critical role in maintaining dendritic spine morphology and synaptic plasticity. Our collective results demonstrate a central role for Cdk5 in regulating both presynaptic and postsynaptic functions and provide better insight into how specific targets of Cdk5 can impact a general mechanism underlying synaptic transmission, synaptic plasticity, and cognitive function. Thesis (Ph. D. in Neuroscience)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, February 2013.; This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.; Cataloged from student-submitted PDF version of thesis. "February 2013." Page 192 blank.; Includes bibliographical references. 2013-01-01T00:00:00Z