Changes in sensory systems during aging : an experimental study in the rat

Sammanfattning: Aging is associated with sensorimotor disturbances, including increased proprioceptive thresholds. The present study aimed to clarify the occurrence of structural and biochemical alterations in sensory systems of behaviorally characterized aged rats. By applying stereological cell counting techniques, it was shown that aged rats of both sexes only suffer from a small decrease (~12%) in the number of dorsal root ganglion (DRG) neurons and, furthermore, that no correlation is present between the degree of neuron loss and the extent of behavioral deficits. Analysis of B4 and RT97, used as markers for small unmyelinated and large myelinated primary afferent neurons, respectively, clearly indicate that DRG neuron loss is unselective with regard to neuron subpopulations, but that a selective cell body atrophy is manifest among myelinated DRG neurons during aging. While the moderate decrease (~13%) in myelinated axons in the saphenous nerve of aged rats is fully consistent with the small loss of DRG neurons, morphological changes, including myelin aberrations, axon dystrophy as well as axon and Schwann cell degeneration, are abundant in peripheral nerves of aged rats. These alterations are more pronounced in myelinated than unmyelinated axons and, moreover, a good correlation is found between the severity of axon lesions and behavioral impairments. Following peripheral nerve injections of tracer substances, aged rats disclose a dramatic decrease in the transganglioniC transport of CTB, but not B4. This suggests a substantial aging-related decrease in the density of myelinated, but not unmyelinated, primary afferents terminals in the spinal cord. The impact of aging on the peripheral innervation pattern was examined in the mystacial pad model, and reveal extensive degenerative changes, but also some signs of regenerative processes. The degenerative events are characteristically more widespread among myelinated (mcchanoreceptive) than unmyelinated (nociceptive) populations of cutaneous receptors and sensory fibers. Thus, several lines of evidence suggest that aging has a more deleterious effect on myelinated primary afferents than their unmyelinated counterparts, and that these aging-related regressive events primarily are confined to the distal axonal domains of primary sensory neurons. The DRG neuropeptide phenotype show pronounced alterations in senescence, including a dramatic decrease in calcitonin gene-related peptide (CGRP), a moderate reduction in substance P and a substantial increase in neuropeptide tyrosine (NPY). These findings were moreover confirmed with regard to the distribution of neuropeptides in the dorsal horn. The changes in CGRP and SP are consistent with some of the functional deficits characterizing elderly individuals, such as increased nociceptive thresholds and impaired inflammatory and reparative responses. Against the background that neurotrophic signaling play important roles in the functional maintenance of sensory neurons in adulthood, the regulation of the nerve growth factor (NGF) and glial cell-line derived neurotrophic factor (GDNF) families of ligands and receptors in senescence was examined. The neurotrophin receptors trkA, trkB and trkC are decreased in primary sensory neurons in senescent animals, while a small increase is observed with regard to the p75 neurotrophin receptor (p75 NTR) . Axotomy induce a further downregulation of all trk receptors and a decrease in p75 NTR expression in aged rats. In accordance with the view that neurotrophin receptor expression is regulated by the availability of their cognate ligands, a decreased expression of NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3) and neurotrophin-4 (NT4) mRNA is observed in muscle tissue of aged rats. Moreover, pronounced and site-specific reductions of neurotrophin mRNAs are detected in the mystacial pad during aging. These aging-related changes clearly suggest an attenuated neurotrophin signaling in senescence, possibly relating to a breakdown in the trophic relations between neurons and their targets. This may, at least in part, explain characteristics of senescent sensory neurons, including neuronal atrophy, an altered neuropeptide phenotype and an impaired maintenance and plasticity of nerve terminals. In contrast, a dramatic upregulation of GDNF rnRNA is detected in target muscles and to a lesser extent also in peripheral supportive tissues during aging. A parallel increase of the preferred receptors in primary sensory neurons strongly indicates an enhanced GDNF signaling in senescence. Since GDNF has been suggested to act primarily on unmyelinated DRG neurons, an increased GDNF signaling may explain why unmyelinated primary afferents are better preserved in senescence.