Changes in sensory systems during aging : an experimental study in the rat
Author: Bergman, Esbjörn
Date: 1999-12-17
Location: Farmakologens föreläsningssal, Nanna Svartz väg 2
Time: 9.00
Department: Institutionen för neurovetenskap / Department of Neuroscience
Abstract
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.
List of papers:
I. Bergman E, Ulfhake B (1998). "Loss of primary sensory neurons in the very old rat: neuron number estimates using the disector method and confocal optical sectioning" J Comp Neurol 396(2): 211-222
Pubmed
II. Bergman E, Ulfhake B (1999). "Structural changes in peripheral nerves and in the central termination pattern of CTB and B4 labeled primary sensory neurons of the aged rat" (Manuscript)
III. Fundin BT, Bergman E, Ulfhake B (1997). "Alterations in mystacial pad innervation in the aged rat" Exp Brain Res 117(2): 324-340
Pubmed
IV. Bergman E, Johnson H, Zhang X, Hökfelt T, Ulfhake B (1996). "Neuropeptides and neurotrophin receptor mRNAs in primary sensory neurons of aged rats" J Comp Neurol 375(2): 303-319
Pubmed
V. Bergman E, Carlsson K, Liljeborg A, Manders E, Hökfelt T, Ulfhake B (1999). "Neuropeptides, nitric oxide synthase and GAP-43 in B4-binding and RT97 immunoreactive primary sensory neurons: normal distribution pattern and changes after peripheral nerve transection and aging" Brain Res 832(1-2): 63-83
Pubmed
VI. Bergman E, Fundin BT, Ulfhake B (1999). "Effects of aging and axotomy on the expression of neurotrophin receptors in primary sensory neurons" J Comp Neurol 410(3): 368-386
Pubmed
VII. Bergman E, Ulfhake B, Fundin BT (1999). "Regulation of NGF-family ligands and receptors in adulthood: correlation to degenerative and regenerative changes in the cutaneous innervation in senescence" (Submitted)
VIII. Ming Y, Bergman E, Edstrom E, Ulfhake B (1999). "Reciprocal changes in the expression of neurotrophin mRNAs in target tissues and peripheral nerves of aged rats" Neurosci Lett 273(3): 187-190
Pubmed
IX. Bergman E, Kullberg S, Ming Y, Ulfhake B (1999). "Upregulation of GFRalpha-1 and c-ret in primary sensory neurons and spinal motoneurons of aged rats" J Neurosci Res 57(2): 153-165
Pubmed
X. Ming Y, Bergman E, Edstrom E, Ulfhake B (1999). "Evidence for increased GDNF signaling in aged sensory and motor neurons" Neuroreport 10(7): 1529-1535
Pubmed
I. Bergman E, Ulfhake B (1998). "Loss of primary sensory neurons in the very old rat: neuron number estimates using the disector method and confocal optical sectioning" J Comp Neurol 396(2): 211-222
Pubmed
II. Bergman E, Ulfhake B (1999). "Structural changes in peripheral nerves and in the central termination pattern of CTB and B4 labeled primary sensory neurons of the aged rat" (Manuscript)
III. Fundin BT, Bergman E, Ulfhake B (1997). "Alterations in mystacial pad innervation in the aged rat" Exp Brain Res 117(2): 324-340
Pubmed
IV. Bergman E, Johnson H, Zhang X, Hökfelt T, Ulfhake B (1996). "Neuropeptides and neurotrophin receptor mRNAs in primary sensory neurons of aged rats" J Comp Neurol 375(2): 303-319
Pubmed
V. Bergman E, Carlsson K, Liljeborg A, Manders E, Hökfelt T, Ulfhake B (1999). "Neuropeptides, nitric oxide synthase and GAP-43 in B4-binding and RT97 immunoreactive primary sensory neurons: normal distribution pattern and changes after peripheral nerve transection and aging" Brain Res 832(1-2): 63-83
Pubmed
VI. Bergman E, Fundin BT, Ulfhake B (1999). "Effects of aging and axotomy on the expression of neurotrophin receptors in primary sensory neurons" J Comp Neurol 410(3): 368-386
Pubmed
VII. Bergman E, Ulfhake B, Fundin BT (1999). "Regulation of NGF-family ligands and receptors in adulthood: correlation to degenerative and regenerative changes in the cutaneous innervation in senescence" (Submitted)
VIII. Ming Y, Bergman E, Edstrom E, Ulfhake B (1999). "Reciprocal changes in the expression of neurotrophin mRNAs in target tissues and peripheral nerves of aged rats" Neurosci Lett 273(3): 187-190
Pubmed
IX. Bergman E, Kullberg S, Ming Y, Ulfhake B (1999). "Upregulation of GFRalpha-1 and c-ret in primary sensory neurons and spinal motoneurons of aged rats" J Neurosci Res 57(2): 153-165
Pubmed
X. Ming Y, Bergman E, Edstrom E, Ulfhake B (1999). "Evidence for increased GDNF signaling in aged sensory and motor neurons" Neuroreport 10(7): 1529-1535
Pubmed
Issue date: 1999-11-26
Publication year: 1999
ISBN: 91-628-3900-4
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