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The monoamine neurotransmitter serotonin (5-HT) is an essential component of vertebrate cognitive function and the autonomous nervous system, regulating body temperature, sleep, appetite, and mood. Abnormal 5-HT signaling is implicated in a variety of disorders such as depression, anxiety, alcoholism, and obsessive-compulsive disorder. Synaptic serotonergic activity is primarily regulated by the recycling of 5-HT from the synaptic cleft by the presynaptic 5-HT transporter (SERT), a target for many psychostimulants and anti-depressants such as MDMA (Ecstasy) and Fluoxetine (Prozac). In the model system Caenorhabditis elegans (C. elegans), 5-HT is an active participant in a variety of motor, autonomic, and behavioral functions including egg-laying, pharyngeal pumping, locomotion, male mating, aging, and enhanced slowing. The goal of this work is to use the C. elegans model system to manipulate the SERT homolog (MOD-5) and examine regulatory genes controlling MOD-5 trafficking, localization, and activity. We characterized the behavioral phenotypes of endogenous 5-HT activity in C. elegans and in 5-HT transporter deletion mutants, especially those pertaining to locomotor function. We also describe a novel, food dependent immobilization phenotype and use genetic and pharmacological approaches to establish the role of 5-HT and MOD-5 within this phenotype. These techniques provide the necessary tools for use of this phenotype as the basis for a forward genetic screen which will provide unbiased assessments of transporter regulatory molecules. This work provides the foundation for elucidation of proteins that regulate determinants of serotonin transporter function and support normal serotonin transporter activity.

Angelman Syndrome (AS) is a devastating neurodevelopmental disorder characterized by developmental delay, speech impairment, movement disorder, sleep disorders and refractory epilepsy. AS is caused by loss of the Ube3a protein encoded for by the imprinted Ube3a gene. Ube3a is expressed nearly exclusively from the maternal chromosome in mature neurons. Mouse models have helped determine the molecular defects in AS, however findings have been inconsistent across laboratories. Work in our laboratory suggested that environmental factors may play a role in the phenotypes observed in AS model mice. As a result, we evaluated the possibility of non-genomic causes of variation in phenotypes observed in AS model mice. Here we demonstrate that maternal status and diet play a large role in the magnitude of a hypomyelination phenotype observed in these mice.

Thesis (Ph.D.)--Tufts University, 2001. / Adviser: Robin B. Kanarek. Submitted to the Dept. of Psychology. Includes bibliographical references (leaves 99-122). Access restricted to members of the Tufts University community. Also available via the World Wide Web;

Thesis (Ph.D.) - University of Queensland, / Includes bibliography.

The drug sensitivity of neurones of the Nucleus ventralis lateralis (VL) of the thalamus, and their synaptic activation by electrical stimulation of brachium conjunctivum (BC), precruciate cortex and entopenduncular nucleus, (EN) has been studied in anesthetized and in decerebrate cats. Cells evoked with short latency by BC stimulation were particularly sensitive to excitation by iontophoretically applied acetylcholine (ACh) and L-glutamate (LG) when compared with cells of more dorsal thalamic nuclei. The VL neurones did not exhibit such an enhanced sensitivity to DL-homocysteic acid and N-methyl aspartic acid. The α-methyl derivative of glutamic acid (α-MG) was found in many cases to depress or block the excitation of thalamic neurones by LG, but had no effect on ACh excitation. α-MG sometimes depressed the effects of other excitatory amino acids, but to a lesser degree than those produced by LG. Short latency single action potential and late burst responses evoked in VL by BC or cortical stimulation have been reported by other workers and were confirmed in this study. However, it was found that both cortical and BC stimulus evoked early burst responses which were observed only in anesthetized animals. EN stimulation evoked burst response in VL neurones with latencies of 4-22 msec. Both the early burst and the EN evoked responses could be converted to shorter latency single spikes by iontophoretically applied amino acids and ACh. ACh facilitated synaptic activation by cortical and BC stimuli but could either excite or depress the responses to EN stimulation. Iontophoretically applied atropine and dihydro-β-erythroidine blocked ACh excitation of VL cells but did not alter their synaptic activation, although atropine could reverse the ACh depression of EN evoked responses. Intravenous atropine in doses of 0.5-1.0 mgm/kgm also blocked these ACh effects, but in addition markedly reduced the BC evoked field response in VL without affecting the response to cortical stimulation. It was concluded that the pathways from EN and motor cortex to VL are unlikely to be cholinergically mediated, but that ACh may be the synaptic transmitter for at least part of the cerebello-thalamic pathway. Pentobarbital and α-chloralose were potent blockers of ACh excitation in VL neurones.. It was shown that neurones of EN give rise to collateral axon branches which project to VL and N. centrum-medianum. Stimulation of sensori-motor cortex evoked cell and field responses in the lateral, but not the medial parts of the centrum medianum-Parafascicular complex. / Medicine, Faculty of / Cellular and Physiological Sciences, Department of / Graduate

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