This application combines the expertise of three established laboratories in sensory biology to investigate the cellular, molecular and physiological aspects of age-related changes in the somatosensory system. The experiments address the goals of the Program Announcement (99-123) titled The Aging Senses: Relationships Among Multiple Sensory Systems. The long-term goal of this research is to identify the cellular mechanisms that lead to degeneration of sensory neurons and their end organs and determine whether modulating the level of trophic support provided by the skin can alleviate the onset and progression of age-related deficits in sensation. Sensations of touch, pain and temperature are transmitted by a variety of morphologically and electrophysiologically distinct mechanosensory endings located in the skin. These endings are comprised of sensory neurons and specialized end organs, e.g., Merkel complexes, Meissner corpuscles, that undergo degeneration as a consequence of aging. The loss of innervation causes reduced tactile sensitivity that can have significant impact on job performance and the quality of life for elderly individuals. Studies have shown that atrophy in the PNS is characterized by decreased neuron sensitivity and reduction in the integrity and/or number of peripheral terminals. We hypothesize these degenerative changes are related to growth factor signaling, in particular for the neurotrophins NT3 and BDNF. Studies of transgenic mice that overexpress NT3 or BDNF in the skin have shown they act in very specific manners to enhance sensory ending development, maintenance and physiological properties. In this project we propose to identify how NT3 and BDNF affect the morphological, cellular and physiological properties of sensory neurons using an ex vivo skin/nerve/spinal cord preparation. This preparation will be used to identify the physiological properties and chemical phenotype of cutaneous neurons of young and old mice and mice that overexpress either NT3 or BDNF in the skin. In this way we will define differences in sensitivity and response properties in relation to neuron phenotype and age, and determine how trophic factors alter these properties. To explore why neurons lose sensitivity in the aging system, we will analyze the expression of channel receptor proteins thought to mediate mechanosensation in physiologically characterized neurons of young and old mice and determine whether their expression is modulated in response to elevation in NT3 or BDNF expression. The experimental design will use immunocytochemistry, immunoblotting, RT-PCR and in situ hybridization to analyze RNA and protein expression, an ex vivo skin/nerve/spinal cord preparation for physiological analysis and transgenic mice that either constitutively or inducibly express increased levels of NT3 nr BDMF in the skin.
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