Neural plasticity is the process by which anatomical (structural) and physiological (functional) changes in the nervous system of an organism lead to alterations in behavior. This dissertation examines the structural and functional changes that occur during neural morphallaxis, a rare form of neural plasticity, in the annelid worm, Lumbriculus variegatus. Neural morphallaxis involves the reorganization of the animal's nervous system during segmental regeneration following injury. Here, I have examined neural morphallaxis of the giant fiber pathway, which mediates rapid escape reflex behaviors in Lumbriculus. Electrophysiological recording techniques, immunohistochemistry, and transmission electron microscopy were used to demonstrate that prior to injury and neural morphallactic regeneration, activation of the escape reflex neural circuitry is nonfunctional in specific regions of the worm's nervous system. Following body fragmentation, neural circuits underlying specific escape responses rapidly become functional. The speed of functional changes in sensory-to-giant interneuron physiology, less than 24 hours, did not coincide with significant anatomical changes to sensory afferent synapses, suggesting a role for the unsilencing of existing sensory synapses. Furthermore, I have discovered and described a sensory interneuron system that mediates sensory inputs via electrical synapses onto the giant interneuron pathway. This finding led to my hypothesis that the site of sensory plasticity during neural morphallaxis is not at the giant axon, but rather at the glutamatergic synapses between sensory neurons and their sensory interneuron targets. Results from this dissertation demonstrate that sensory inputs onto the giant interneuron pathway are functionally silent prior to neural morphallaxis and the awakening of ineffective synapses occurred rapidly, within hours, following injury. Neural morphallactic plasticity was determined to occur at glutamatergic synapses onto bilaterally paired sensory interneurons that were coupled to the giant interneuronal pathway. The early phase of morphallaxis is then followed by gradual structural and functional changes to enhance aspects of the escape response network. This research provides a foundation for future studies of the mechanisms underlying neural morphallactic regeneration in Lumbriculus variegatus and provides comparative insight into the evolution and plasticity of neural circuit underlying discrete animal behavior.

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<p>Obsessive-compulsive disorder (OCD) is a devastating illness that afflicts around 2% of the world's population with recurrent distressing thoughts (obsessions) and repetitive ritualistic behaviors (compulsions). While dysfunction at excitatory glutaminergic excitatory synapses leading to hyperactivity of the orbitofrontal cortex and head of the caudate - brain regions involved in reinforcement learning - are implicated in the pathology of OCD, clinical studies involving patients are unable to dissect the molecular mechanisms underlying this cortico-striatal circuitry defect. Since OCD is highly heritable, recent studies using mutant mouse models have shed light on the cellular pathology mediating OCD symptoms. These studies point toward a crucial role for deltaFosB, a persistent transcription factor that accumulates with chronic neuronal activity and is involved in various diseases of the striatum. Furthermore, elevated deltaFosB levels results in the transcriptional upregulation of Grin2b, which codes GluN2B, an N-methyl-D-aspartate glutamate receptor (NMDAR) subunit required for the formation and maintenance of silent synapses. Taken together, the current evidence indicates that deltaFosB-mediated expression of aberrant silent synapses in caudate medium spiny neurons (MSNs), in particular D1 dopamine-receptor expressing MSNs (D1 MSNs), mediates the defective cortico-striatal synaptic transmission that underlies compulsive behavior in OCD.</p> / Dissertation

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