Date of Award

12-1-2012

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Abstract

While it is well-known that ciliary neurotrophic factor (CNTF) promotes the survival of a myriad of neuronal phenotypes, little is understood on the specific CNTF-induced neuroprotective mechanisms in the central nervous system (CNS). Elucidation of these mechanisms may provide insight that would assist in the development of future therapeutic strategies. Therefore, the goal of my research is to determine the mechanisms underlying the neuroprotective effects of CNTF within the rat magnocellular neurosecretory system. The central hypothesis of my research is that CNTF acts as both a neuronal survival and sprouting factor for hypothalamic magnocellular neurons in vitro and in vivo. In order to determine the neuroprotective mechanisms that CNTF utilizes, we performed extensive animal work including, in vivo stereotaxic surgeries and in vitro organotypic explant cultures, in addition to Western blot and immunohistochemical analyses. Our analyses demonstrated that following injury to the magnocellular neurosecretory system, CNTF is up-regulated in the supraoptic nucleus (SON) that undergoes a collateral sprouting response and this increase is not due to heightened neurosecretory activity. Moreover, we demonstrated a reduction in the protein levels of the CNTF specific receptor, CNTFRa, in the mature SON. Thus, we believe that the inability of the mature rat to elicit the sprouting response is due to a deficit in CNTF signaling. CNTF has been demonstrated to promote survival and potentiate process outgrowth of magnocellular neurons. Utilizing hypothalamic organotypic cultures, we demonstrated that the Jak-STAT and MAPK-ERKV2 pathways are necessary for CNTF to mediate its pro-survival effects on oxytocinergic neurons. Conversely, we demonstrated that the PI3K-AKT pathway is necessary to promote CNTF- induced process outgrowth. Interestingly, our results show that the p38, JNK, and mTOR signaling components appear to mediate the post-axotomy apoptotic cascade that results in the significant loss of oxytocinergic neurons following the organotypic culture preparation. Altogether, these novel data provide evidence of the mechanisms that CNTF utilizes to elicit its neuroprotective actions. We submit that gaining a greater understanding of these mechanisms will lead to the development of future therapeutic strategies that will target nervous system injuries or disorders that result in neurodegenerative processes.

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