In the elderly, gastrointestinal (GI) disorders are common, often either complicate or are complicated by other diseases, and can be debilitating. Research over the last decade has established that aging-related GI disorders are correlated with dramatic losses (~40 - 50%) of neurons in the autonomic, or enteric, plexuses of the digestive tract. The past research is very limited, however, and has been focused almost exclusively on establishing that losses occur. Too little is presently known to specify underlying mechanisms, to establish causal relationships, or to formulate rational therapeutic interventions. More specifically, too little information is available on which GI regions are compromised, on the neurochemical phenotypes of either the neurons that die or those that survive, and on the temporal patterning of the dissolution. The neuroscience of the aging GI tract has largely focused on the myenteric plexus in a few intestinal regions, while ignoring some organs (e.g., the stomach), some enteric elements (e.g., the submucosal plexus), and the extensive extrinsic motor and sensory innervation (e.g., vagal and sympathetic projections) that links the gut to the central nervous system. The present proposal's long-term objective, which unifies its four specific aims, is to characterize the regional, temporal and neurochemical patterns of neuronal aging in the GI tract.
Aim 1 will specify the neurochemical phenotypes of enteric neurons throughout the gut that undergo age-related neurodegeneration. The evolution of such losses over the lifespan will also be delineated.
Aim 2 will analyze age-related axonopathies of the extrinsic innervation of the GI tract and determine the temporal patterns by which those pathologies develop.
Aim 3 will correlate aging-associated changes in GI motility and nutrient handling with the different specific neuropathies characterized in Aims 1 and 2.
Aim 4 will begin to evaluate two particularly promising hypotheses identifying cellular mechanisms underlying the neuronal losses and axonopathies of aging. The four aims will be addressed using a battery of immunohistochemical protocols, anterograde tracing techniques, and functional assays of gut motility patterns employing recently developed spatio-temporal mapping algorithms. These analyses will be done primarily with animal models of aging established by the National Institute on Aging. Taken together, the proposed observations on the aging the GI tract will specify the vulnerable regions, neuronal phenotypes, timepoints, and cellular processes to which therapeutic interventions should be targeted.
The proposed understanding of the spatial, temporal and neurochemical patterns of neural losses in the GI tract with aging will provide a much-needed foundation for rational strategies for clinical interventions or management of some of the homeostatic and digestive disorders that affect appetite, ingestion, digestion, and motility, as well ultimately, nutrition and health, in the elderly.
|Powley, Terry L; Hudson, Cherie N; McAdams, Jennifer L et al. (2014) Organization of vagal afferents in pylorus: mechanoreceptors arrayed for high sensitivity and fine spatial resolution? Auton Neurosci 183:36-48|
|Phillips, Robert J; Billingsley, Cherie N; Powley, Terry L (2013) Macrophages are unsuccessful in clearing aggregated alpha-synuclein from the gastrointestinal tract of healthy aged Fischer 344 rats. Anat Rec (Hoboken) 296:654-69|
|Powley, Terry L; Baronowsky, Elizabeth A; Gilbert, Jared M et al. (2013) Vagal afferent innervation of the lower esophageal sphincter. Auton Neurosci 177:129-42|
|Powley, Terry L; Mittal, Ravinder K; Baronowsky, Elizabeth A et al. (2013) Architecture of vagal motor units controlling striated muscle of esophagus: peripheral elements patterning peristalsis? Auton Neurosci 179:90-8|
|Phillips, Robert J; Hudson, Cherie N; Powley, Terry L (2013) Sympathetic axonopathies and hyperinnervation in the small intestine smooth muscle of aged Fischer 344 rats. Auton Neurosci 179:108-21|
|Phillips, R J; Martin, F N; Billingsley, C N et al. (2013) Alpha-synuclein expression patterns in the colonic submucosal plexus of the aging Fischer 344 rat: implications for biopsies in aging and neurodegenerative disorders? Neurogastroenterol Motil 25:e621-33|
|Phillips, Robert J; Powley, Terry L (2012) Macrophages associated with the intrinsic and extrinsic autonomic innervation of the rat gastrointestinal tract. Auton Neurosci 169:12-27|
|Powley, T L; Phillips, R J (2011) Vagal intramuscular array afferents form complexes with interstitial cells of Cajal in gastrointestinal smooth muscle: analogues of muscle spindle organs? Neuroscience 186:188-200|
|Powley, Terry L; Spaulding, Ryan A; Haglof, Stanley A (2011) Vagal afferent innervation of the proximal gastrointestinal tract mucosa: chemoreceptor and mechanoreceptor architecture. J Comp Neurol 519:644-60|
|Phillips, Robert J; Walter, Gary C; Powley, Terry L (2010) Age-related changes in vagal afferents innervating the gastrointestinal tract. Auton Neurosci 153:90-8|
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