<p>  </p> <p>Pediatric hydrocephalus is a complex neurological condition associated with a pathological accumulation of cerebrospinal fluid (CSF), typically within the brain ventricular system. Pediatric hydrocephalus can be primary (due to genetic abnormalities or idiopathic causes), or secondary to injuries such as hemorrhage, trauma, or infection. The current permanent treatment paradigms for pediatric hydrocephalus are exclusively surgical and include the diversion of CSF via shunt or ventriculostomy. These surgical interventions are wrought with failures, burdening both the United States healthcare system and patients with repeat neurosurgical procedures. Thus, the development of nonsurgical interventions to treat hydrocephalus represents a clinically unmet need. To study hydrocephalus, we use a genetic rat model of primary neonatal hydrocephalus, the <em>Tmem67</em>P394L mutant. In several proof-of-concept studies, we identify antagonism of the transient receptor potential vanilloid 4 (TRPV4) channel and associated upstream regulatory kinase, serum-and-glucocorticoid-induced kinase 1 (SGK1) as therapeutics for the treatment of hydrocephalus. Using <em>in vitro</em> models of the choroid plexus epithelium, the tissue which produces CSF, we show compelling proof-of-mechanism for TRPV4 antagonism and SGK1 inhibition at preventing CSF production. Therefore, the studies in this dissertation provide substantive evidence on the role of TRPV4 in the choroid plexus in health and disease. </p>

Drosophila melanogaster is an attractive model organism for the study of numerous fundamental processes including nervous system development and function. This is due to the power of Drosophila genetics combined with the high degree of similarity between this organism and vertebrate systems, not only at the molecular level but also at the cellular and behavioural levels. The first part of my thesis focused on trophic interactions occurring in Drosophila larval central nervous system. Specifically, it describes the interaction of serotonin (5HT)-producing neurons with other three groups of neurons: the larval photoreceptors expressing Rhodopsin 5 (Rh5), the photoreceptor subset expressing Rhodopsin 6 (Rh6), and the larval circadian pacemakers (LNv). I found that both Rh5-and Rh6-expressing fibers contact a 5-HT arborization in the larval optic neuropil, where the 5-HT processes also overlaps with the dendrites of the LNv. The results of my experiments also indicate that the Rh6-expressing terminus is the neural process providing the signal required for the outgrowth of the serotonergic arborization. Furthermore, proper branching of this arborization requires normal Rae function. These findings further support the importance of extrinsic and intrinsic signalling for the assembly ofthe nervous system. The remainder of my studies attempted to investigate candidate neurons modulating Drosophila larval photobehaviour. Using the larval response to light as a behavioural paradigm and neuronal silencing experiments, my results demonstrate that 5HT neurons located in the brain regulate the larval photoresponse during development. In addition, my findings suggest that this modulation occurs at a central level and that is mediated by 5-HT1A(Dro) receptors. These observations provide new insights into the functions of serotonergic neurons in Drosophila as well as how neuromodulators shape neuronal circuit function and ultimately behaviour. / Thesis / Doctor of Philosophy (PhD)

Trace elements are involved in many biological processes and serve important functions to maintain the normal development of the central nervous system (CNS). In the CNS, iron (Fe), copper (Cu), and zinc (Zn) are some of the most important elements that play critical roles as catalysts, cofactors, and structural components for many cellular enzymes and proteins. The deficiency or excess of these metals may lead to various neurological disorders. Demyelination is a condition of loss of myelin and leads to neurological diseases like Multiple Sclerosis. Myelin consists of transition metals and hence it would be interesting to study concentrations of these elements in normal and demyelinated models. X-Ray Fluorescence (XRF) is a popular non-destructive technique applied in trace element studies. The principle involves exciting a sample and detecting characteristic X-rays, which provide information on elemental concentrations in the sample. In the present studies the feasibility of XRF for trace element studies was explored. A total of 120 samples of brain and spinal cord tissues were collected from Long Evans (control) and Long Evans Shaker (dysmyelinated)–an incomplete formation of myelin sheaths–rats at ages of 3 weeks and 16 weeks. The samples were excited using x-rays from an Energy Dispersive X-Ray Diffraction (EDXRF) set-up. The spectral data was collected using an Silicon Drift Detector (SDD) and the resultant data were analysed to see if statistically significant changes in concentrations were present in the samples. The results were discussed and suggestions for future work were made. / Thesis / Master of Science (MSc)

No description available.

No description available.

No description available.

No description available.

No description available.

No description available.

No description available.