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This project has explored whether zebrafish can model human neurological disease, using retinal degeneration as the prototype. The retinal degenerations are a major cause of morbidity, being the commonest cause of blindness in the Western world. Age-related macular degeneration, the commonest retinal degeneration, affects 1 in 20 of the population, and is not treatable. The project began with an F2 mutagenesis screen for candidate blind fish, using an optokinetic assay. Blind fish were characterised using a variety of histological techniques and transplantation studies. Two strains of fish were then selected for more detailed genetic analysis, as they appeared to have a photoreceptor degeneration resembling human retinal degenerations. This involved further mapping of the genes responsible for the phenotype in these two mutants and candidate gene selection.

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No description available.

I have collated data on the number of ganglia and the fusion patterns of neuromeres from over 750 species. This data set, when mapped onto an insect phylogeny, allows the patterns of nerve cords from across the whole of the insects to be seen. For the first time trends through evolution can be identified in the insects. There are independent evolutionary trends towards neuromere fusion in several insect lineages. Most fusion of neuromeres occurs either with the metathoracic neuromere or with the terminal ganglion. There is also evidence for some neuromeres having separated from ganglia to which they had been fused. There are many convergent fusion patterns across the insects particularly in the holometabolous orders. To investigate possible mechanisms that drive the diversity of neuromere position and fusion patterns the position of the fifth abdominal neuromere of the locust <i>Schistocerca gregaria </i>and the cricket<i> Acheta domesicta</i> was modelled. Cost minimization and physical tension models, using data on the size and number of axons in the connectives and main peripheral nerves, were used to study whether the observed position of the neuromere in either species matched predicted positions. The results show that the predictions from some tension-based models match the observed neuromere position for both the locust and the cricket, whereas, the cost minimisation models do not match the observed position of the neuromere in either species. To investigate whether there are any correlations between the fusion patterns and positions of neuromeres, and ganglion size, anatomy and, body size and shape a comparative study of neuromere fusion pattern in ground beetles and neuromere position in hoverflies was used. Neuromere position varies as the sizes of adjacent ganglia vary. Body size but not body shape varies with degree of fusion and neuromere position. Eye size and antenna length vary with ganglion size, and eye size varies with the degree of fusion, when controlling for body size.

The pulmonate snail, <i>Helix aspersa</i>, has the ability to survive long bouts of anoxia by depressing its metabolism. Direct calorimetry was used to measure the metabolic heat production of the snails in this state. During 24-48 hrs of anoxia, heat production varied with the oxygen levels and fell as low as 2% of that during normoxia. The <i>Helix </i>central nervosa system also depressed its metabolism during anoxia. Electrophysiological recordings revealed decreases in both action potential firing (spike arrest) and membrane conductance (channel arrest). These processes allow the maintenance of ionic gradients during a period when ion pumping has presumably been down-regulated to conserve ATP. These abilities to respond to anoxia were found in both whole brains and isolated neurons. The mitochondrial inhibitor antimycin resulted in responses very similar to those seen in anoxia. This may be due to the fact that mitochondrial blockade with antimycin results in an increased production of reactive oxygen species, intracellular messengers which have been implicated in the anoxia responses of several cell types. The similar responses of anoxia and antimycin suggest that a high concentration of oxygen radicals triggers entry into metabolic depression. Support for this hypothesis came from neurons incubated in ascorbate (an antioxidant). With the amount of reactive oxygen species diminished, these neurons no longer responded to an anoxic challenge, evidence for the importance of reactive oxygen species in the anoxia response of snails. During anoxia, intracellular calcium levels are protected by an upregulated Ca²⁺ pump, resulting in the rapid clearance of any calcium transients and a decreased basal calcium level. These experiments have revealed the potential for the snail to become a model organism in the study of oxygen sensing and metabolic depression.

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The majority of organisms on Earth, from cyanobacteria upwards, contain an internal timing mechanism that allows them to make optimum use of the rhythmic abundance of many environmental resources (e.g. sunlight). In mammals, the master circadian (i.e. daily) clock is contained within the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. The clock is thought to consist, at the simplest level, of a number of autoregulatory negative feedback loops involving the products of the <I>cryptochrome </I>(<I>mCry1 </I>and <I>mCry2</I>) and <I>period </I>(<I>mPer1, mPer2 </I>and <I>mPer3</I>) genes. These loops are driven by the positive factors encoded by the <I>clock </I>and <I>Bmal 1 </I>genes. Chapter 3 of this dissertation presents immunocytochemical data showing that the expression of mPER1 and mPER2 protein is rhythmic in the SCN, both in mice entrained to a light-dark cycle or in continuous darkness. In contrast, the expression of mTIM is constitutive under all lighting conditions. These are thus functional differences in gene expression between mice and the fruitfly <I>Drosophila</I>, where <I>tim</I> is a central, rhythmic clock component. The clock can be reset (i.e. phase advanced or delayed) by light incident on the retina during the night. Experimental data, both <I>in vivo</I> and <I>in vitro</I>, suggest that <I>mCry</I> genes are central oscillator components insensitive to light, whereas <I>mPer1 </I>and <I>mPer2</I> are up-regulated by resetting light pulses. Resetting by light pulses which delay the clock occurs rapidly (within 1-2 cycles), whereas the full expression of advances of the clock can take several cycles to be completed.

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No description available.