Adult neurogenesis is defined as the generation of new nerve cells in the adult central nervous system (CNS). Stimulating neurogenesis may potentially offer a therapeutic approach for neurodegenerative diseases such as Parkinson???s disease. However, it is not clear why neurogenesis does not normally replace neurons lost in these diseases. As a first step to address this problem it is necessary to identify mechanisms that regulate adult neurogenesis in the normal and diseased brain and further, determine if manipulating these mechanisms may offer therapeutic potential. In this thesis, we identify activin A, a member of the transforming growth factor ?? (TGF??) superfamily, as a significant regulator of neurogenesis. We demonstrate that mRNA encoding activin A is expressed after a KA injury, and that inhibition of this activin A profoundly impairs neurogenesis in the hippocampus. Further we demonstrate that activin A impairs gliosis and also has potent anti-inflammatory effects in the injured hippocampus. Finally, we provide evidence that the majority of activin A???s neurogenic effect results from its potent anti-inflammatory actions. Our study draws a clear link between neurogenesis and inflammation in the CNS and is the first to provide evidence that this process is regulated through activin signalling. Since inflammation is now believed to be an important component of many neurological diseases we suggest that therapeutic compounds that enhance activin A signalling may offer a therapeutic approach for treating these diseases by suppressing inflammation and stimulating neurogenesis.

Thesis (B.A.)--Haverford College, Dept. of Psychology, 2008. / Includes bibliographical references.

Thesis (Ph. D.)--University of Oregon, 2004. / Typescript. Includes vita and abstract. Includes bibliographical references (leaves 198-211). Also available for download via the World Wide Web; free to University of Oregon users.

The central nervous system of the cockroach is able to recover following nerve lesions, by specific re-innervation of targets. Some aspects of such regeneration were studied in vitro and in vivo to discover how this is achieved. Neural explants from the cockroach central nervous system were maintained in culture for UP to six months. The effect of various parameters, such as temperature and growth medium composition upon the rate and extent of fibre outgrowth was studied. There was no apparent selectivity in the formation of connections between co-cultured neural or muscular explants, suggesting that the cues necessary for specific re-innervation in vivo may be absent in vitro. Under normal conditions, outgrowth usually began by about five days in culture. The delay before onset of fibre outgrowth, however, was reduced by prior section of nerves in situ two to three weeks before explantation of ganglia into culture. Outgrowth from these nerves which had received a 'conditioning lesion' was observed as soon as 12-24 hours after explantation into culture. Similarly, functional recovery occurred sooner in vivo after equivalent operations: normal function returned to animals more quickly after a second lesion to the same nerve, than after one lesion only. The morphology of an identifiesd motoneurone was studied by intracellular cobalt injection, to assess the effect of maintenance in culture, or of different nerve lesions performed in vivo. Nerve lesions caused changes in the branching pattern of this identified neurone. The extent of change appeared to be determined largely by the overall extent of damage to the nervous system. Direct damage to the cell was not a pre-requisite for changes to occur. In many cases, supernumerary branches entered territory which was normally foreign to the motoneurone. In some areas this growth appeared to be random, while in others sprouts gave the appearance of following paths of degenerating nerve fibres. It is concluded that at least some adult insect neurones are capable of extensive regenerative growth, and of undergoing a high degree of structural modification, both in vivo and in vitro, indicating that some plasticity is a feature of the adult insect nervous system.

1. The giant neurone in the left pedal ganglion of Helisoma trivolvis is homologous with the giant dopamine containing neurone of Planorbis corneus. The neurones have a similar morphology, and both react with glyoxylic acid to produce fluorescence indicative of dopamine. The neurone is referred to as the giant dopaminergic neurone (GDN). 2. Conditions for the extension of neurites and the formation of chemical junctions in culture have been determined for the H. trivolvis GDN. 3. Some electrical properties of the GDN were altered when it was maintained in culture. The peak spike amplitude was increased, action potential half width was decreased and the firing pattern changed. 4. In culture, the GDN formed chemical connections only with neurones with which it was known to form chemical connections in-situ. The chemical connections were of the same sign as those observed in-situ. They formed rapidly within 18 hours, but were not stable and were lost within 48 hours to be replaced by electrical connections. 5. Chemical junctions formed in both directions between the GDN and the large serotonergic neurone (LSN). The direction in which junctions formed could be influenced by plating each neurone out at different times. 6. Local application of dopamine to the axon or axon hillock, but not the soma of the isolated GDN, evoked a fast strongly desensitising, depolarising response. 7. Intracellular perfusion of the GTP analogue GDP-?-S abolished the hyperpolarising effect of dopamine but left the fast depolarising effect intact. 8. Dopamine evoked small unitary outward currents, in outside-out patches prepared from the axon and axon hillock of the isolated GDN. 9. The results suggest that the fast depolarising response to dopamine of the GDN and its follower neurones is directly ligand gated. This is the first evidence of an ion channel that is directly gated by dopamine.

Dopamine is one of a number of neurotransmitter candidates found in the insect CNS, It has been localised in a number of neurones, and others have been shown to respond to the application of dopamine. This study investigates the response of the common inhibitory motoneurone D3 to dopamine, and its ionic basis. The response to dopamine is distinguished pharmacologically from responses to noradrenaline, octopamlne and acetylcholine, all neurotransmitter candidates within the insect CNS, and it is concluded that a receptor specific for dopamine is present on this cell. Finally, this putative dopamine receptor is characterised pharmacologically, and its position relative to the extant classification schemes for mammalian receptors, and its similarity or otherwise to other invertebrate dopamine receptors is discussed.

In order for a human being to process complex thought, cells within the brain must communicate with each other in a very precise manner. The mechanisms which underlie the development of these connections, however, are poorly understood and thus require a thorough investigation. In this dissertation, we attempt to identify components involved in stabilizing synaptic contacts and the mechanisms by which synaptic proteins are trafficked to newly forming contact sites. Interestingly, we also identify a gene involved in the formation of the myotome. To identify proteins involved in stabilizing synaptic contacts, we characterized the function of 4.1B in developing zebrafish embryos. 4.1B is a scaffolding molecule involved in stabilizing protein complexes at sites of cell adhesion. We identified two 4.1B genes in the zebrafish genome, 4.1B-a and 4.1B-b, which are differentially expressed and have evolved divergent functions. 4.1B-a is expressed within the central nervous system, specifically within primary motor neurons. Knockdown studies show a reduction in the number of synapses and altered kinetics of touch evoked-responses, suggesting a role in synaptic stabilization. In contrast, 4.1B-b is primarily expressed in muscle cells. Knockdown of 4.1B-b results in severe muscle fiber disorganization as well as altered locomotor behaviors. Together, these data suggest the basic functions of 4.1B are evolutionarily conserved, with new roles described in the development of synapses and muscle fibers. To determine the mechanisms that underlie protein recruitment to newly forming synapses, we examined the recruitment of three distinct transport packets in the zebrafish spinal cord. During presynaptic assembly, we found synaptic vesicle protein transport vesicles preceded piccolo-containing active zone precursor transport vesicles, which in turn preceded synapsin transport vesicles. We identified the last transport packet as a unique and independent mechanism for the recruitment of synapsin, a protein involved in regulating the reserve pool of synaptic vesicles. Importantly, we found cyclin-dependent kinase 5 regulated the late recruitment of synapsin transport packets to synapses, thus identifying kinases as a key signaling molecule in the formation of synaptic contacts. Together, this work provides new insight into the mechanisms that underlie synaptogenesis. This dissertation includes both previously published and unpublished co-authored material.

Thesis (Ph. D.)--University of Chicago, Dept. of Molecular Genetics and Cell Biology, 2001. / Includes bibliographical references. Also available on the Internet.

published_or_final_version / Paediatrics and Adolescent Medicine / Doctoral / Doctor of Philosophy

Systemic Lupus Erythematosus (SLE) is an autoimmune disease which is characterized by high level of autoantibody detected in the body. This disease is female predominant with a male to female ratio 1: 9. SLE could cause damage to different organ systems and central nervous system is one of them. Patients diagnosed with SLE could suffer from psychiatric problems like cognitive dysfunction, depression and anxiety. Neurogenesis refers to the process by which new neurons are generated. Although it has been widely reported that neurogenesis could be enhanced under pathological conditions such as stroke, Huntington’s disease and epilepsy, study focusing on the relationship between neurogenesis and SLE remains limited. In the present study, by using NZB/W F1 mice as the animal model of SLE, we could demonstrate that there was dramatic increase of neuronal precursor cells at the corpus callosum after the onset of SLE symptoms. Meanwhile, as IBA-1 positive cells and GFAP positive cells also increased significantly there, this suggested inflammation has taken place. I hypothesized there were upregulation of immunological factors after the onset of SLE symptoms and those factors were responsible for the neurogenesis. In my in vitro study, cytokine- interferon gamma (IFN gamma) has been shown to promote neuronal progenitor cells (NPCs) to differentiate into neuronal linage but it did not obviously affect the cell proliferation and migration. For the other cytokine and chemokines, including interleukin-10 (IL-10), interleukin-8 (IL-8), macrophage-derived chemokine (MDC), stromal cell-derived factor 1 alpha (SDF-1alpha) and thymus and activation regulated chemokine (TARC), all of them had no effect on NPC proliferation and differentiation. As far as we know, this is the first study to report SLE could enhance neurogenesis. Concerning the role of inflammation and IFN gamma on the neurogenesis in our case, it should be worth for further investigation, which will benefit future development of novel treatment targeting psychiatric symptoms in SLE. / published_or_final_version / Anatomy / Master / Master of Philosophy