Date

December 2010

Document Type

Dissertation

Degree Name

Ph.D.

Institution

Oregon Health & Science University

Abstract

Cardiorespiratory reflexes are essential to life, maintaining key physiological functions such as breathing and blood pressure. However, the characteristics of these reflexes at birth differ significantly from the characteristics in adults, suggesting a period to refine reflex circuitry. Mechanisms that guide maturation in these pathways are virtually unknown. This lack of understanding is an impediment to discovering the underlying causes of developmental disorders, such as Sudden Infant Death Syndrome, the leading cause of death during the first year of life. Brain-derived neurotrophic factor (BDNF) is one candidate mediator of development in cardiorespiratory pathways and is known to mediate activity-dependent maturation throughout the central nervous system. However, its functional role in developing cardiorespiratory pathways is unknown. My overall hypothesis is that BDNF in cardiorespiratory afferents drives activity-dependent maturation of circuitry in the brainstem Nucleus Tractus Solitarius (NTS). The studies in this dissertation support this overall hypothesis. I first characterize BDNF protein distribution and release in the sensory portion of a model cardiorespiratory reflex, the aortic baroreceptor reflex. Then, I assess one possible maturational function of BDNF, dendritogenesis of neurons in the NTS. Immunoreactivity to BDNF is present in the cell bodies of baroreceptor neurons in the nodose ganglion (NG), their central projections in the solitary tract, and terminal-like structures in the lower brainstem NTS. In addition, native BDNF is released in an activity-dependent manner from cultured newborn NG neurons in response to patterns that mimic the in vivo activity of baroreceptor afferents. Thus, these studies show that BDNF is poised to mediate activity-dependent maturation through the release of BDNF from aortic baroreceptors onto their targets in the NTS. Coinciding with the maturation of cardiorespiratory reflexes, many structural and functional changes occur within the NTS, including the extension and elaboration of dendritic arbors. The mechanisms guiding dendritic elaboration in the NTS, however, are unknown. Using a dissociate culture model of the NTS, I tested the hypothesis that BDNF mediates dendritic outgrowth and complexity of NTS neurons. Unexpectedly, I discovered a significant contribution of glia in regulating BDNF-mediated dendritic growth. In mixed neuron-glia cultures, BDNF promotes dendritic outgrowth and complexity. However, depleting glia changes the direction of BDNF-mediated effects from promoting to inhibiting NTS dendritogenesis. In addition, I show that the number of glia alone influences dendritic growth of NTS neurons and provide evidence that an unidentified astrocyte-derived diffusible factor inhibits NTS dendritic growth. These findings have important implications for dendritogenesis in the NTS in vivo, providing evidence for a functional role of BDNF and showing an unappreciated role of glia in guiding dendritogenesis. Together, these studies further our understanding of maturation in cardiorespiratory pathways and point to BDNF, together with glia, as a significant contributor in guiding these events.

Identifier

doi:10.6083/M43J39ZP

Division

Neuroscience Graduate Program

School

School of Medicine

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