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Esbjörn Bergman
esbjorn.bergman@neuro.ki.se
Curriculum Vitae
Thesis
Current Research Program
and Abstracts
Full Publication List
Curriculum Vitae
MD at Karolinska Institutet, June 1994
PhD at Karolinska Institutet, December 1999
Thesis
Changes in Sensory Systems
During Aging
THESIS 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 (mechanoreceptive) 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 (p75NTR). Axotomy induce a further downregulation of all trk receptors
and a decrease in p75NTR 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 mRNA 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.
Keywords: aging, behavior, primary sensory neuron,
dorsal root ganglion, mystacial pad, sensory nerve ending, axon dystrophy,
neuropeptides, B4, RT97, CTB, neurotrophins, trk, p75NTR, GFRa, RET, protein,
mRNA.
ISBN 91-628-3900-4
The thesis is based on the following papers,
which will be referred to in the text by their roman numerals:
I.
Loss of primary
sensory neurons in the very old rat: Neuron number estimates using the disector
method and confocal optical sectioning.
Bergman, E. and B. Ulfhake; Journal of Comparative
Neurology; 1998; 396: 211-222.
II.
Structural changes in peripheral nerves and in
the central termination pattern of CTB and B4 labeled primary sensory neurons
of the aged rat.
Bergman, E. and B. Ulfhake
1999; Manuscript.
III.
Alterations
in mystacial pad innervation in the aged rat.
Fundin, BT., Bergman, E. and B. Ulfhake; Experimental
Brain Research; 1997; 117: 324-340.
IV.
Neuropeptides
and neurotrophin receptor mRNAs in primary sensory neurons of aged rats.
Bergman, E., Johnson, H., Zhang, X., Hökfelt
T. and B. Ulfhake
Journal of Comparative Neurology; 1996; 375:
303-320.
V.
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.
Bergman, E., Carlsson, K., Liljeborg, A., Manders,
E., Hökfelt, T. and B. Ulfhake
Brain Research; 1999; 832: 63-83.
VI.
Effects of aging
and axotomy on the expression of neurotrophin receptors in primary sensory
neurons.
Bergman, E., Fundin, B.T. and B. Ulfhake
Journal of Comparative Neurology; 1999; 410:
368-386.
VII.
Regulation
of NGF-family ligands and receptors in adulthood: correlation to degenerative
and regenerative changes in the cutaneous innervation in senescence.
Bergman, E., Ulfhake B. and B.T. Fundin
1999; Submitted.
VIII.
Reciprocal changes
in the expression of neurotrophin mRNAs in target tissues and peripheral nerves
of aged rats.
Ming, Y., Bergman, E., Edström, E. and B.
Ulfhake
Neuroscience Letters; 1999; 273: 187-190.
IX.
Upregulation
of GFRa-1 and c-ret in primary sensory neurons and spinal motoneurons of aged
rats.
Bergman, E., Kullberg, S., Ming, Y. and B. Ulfhake
Journal of Neuroscience Research; 1999; 57: 153-165.
X.
Evidence for
increased GDNF signaling in aged sensory and motor neurons.
Ming, Y., Bergman, E., Edström, E. and B.
Ulfhake
NeuroReport; 1999; 10: 1529-1535.
Current
Research Program and Abstracts
Loss of neurons in dorsal root ganglia of aged
rats.
Bergman, E., Nakagawa, S. and B. Ulfhake.
Neuroscience abstract (Stockholm), 1996. Abstract.
Alterations in mystacial pad innervation in the
aged rat.
Fundin, BT., Bergman, E. and B. Ulfhake.
Society for neuroscience, 1996. Abstract.
Effect of peripheral nerve injury on neuron
numbers and peptide expression in mouse dorsal root ganglia.
Shi, T-J., Tandrup, T., Bergman, E., Xu, Z-O., Kopp, U.C. and
T. Hökfelt.
Society for neuroscience, 1999. Abstract.
Changed expression of neurotrophins and
neurotrophin receptors in peripheral sensory pathways during aging.
Bergman, E., Fundin, B.T., Ming, Y., Edström, E. and B.
Ulfhake.
Society for neuroscience, 1999. Abstract.
Evidence for decreased neurotrophin-trk
signaling in aged motoneurons.
Edström, E., Johnson, H., Ming, Y., Bergman, E. and B.
Ulfhake.
Society for neuroscience, 1999. Abstract.
Evidence for increased GDNF-GFR?-1/RET signaling
in aged sensory and motor neurons.
Ming, Y., Bergman, E., Edström, E., Kullberg, S. and B.
Ulfhake.
Society for neuroscience, 1999. Abstract.
Phenotypic changes and alterations in trophin
signaling in aged sensory neurons.
Ulfhake, B. and E. Bergman.
Society for neuroscience, 1999. Abstract.
Full
Publication List
Evidence
for loss of myelinated input to the spinal cord in senescent rats.
Bergman E, Ulfhake B.
Neurobiol Aging 2002 Mar-Apr;23(2):271-86. PubMed
Retrograde
labeling of primary sensory neurons with fluorescent latex microspheres: a
useful tool for long term tagging of neurons.
Altun M, Bergman E, Ulfhake B.
J Neurosci Methods. 2001 Jul 15;108(1):19-24. PubMed
Effect
of peripheral nerve injury on dorsal root ganglion neurons in the C57 BL/6J
mouse: marked changes both in cell numbers and neuropeptide expression.
Shi TS, Tandrup T, Bergman E, Xu ZD, Ulfhake B, Hokfelt T.
Neuroscience. 2001;105(1):249-63. PubMed,
Elsevier
Regulation
of neurotrophin signaling in aging sensory and motoneurons. Dissipation of
target support?
Ulfhake B, Bergman E, Edstrom E, Fundin BT, Johnson H, Kullberg S,
Ming Y.
Mol Neurobiol 2000 Jun;21(3):109-35. PubMed
Regulation
of NGF-family ligands and receptors in adulthood and senescence: correlation
to degenerative and regenerative changes in cutaneous innervation.
Bergman E, Ulfhake B, Fundin BT
Eur J Neurosci 2000 Aug;12(8):2694-706. PubMed
Evidence
for increased GDNF signaling in aged sensory and motor neurons.
Ming Y, Bergman E, Edstrom E, Ulfhake B
Neuroreport 1999 May 14;10(7):1529-35. PubMed
Reciprocal
changes in the expression of neurotrophin mRNAs in target tissues and peripheral
nerves of aged rats.
Ming Y, Bergman E, Edstrom E, Ulfhake B
Neurosci Lett. 1999 Oct 8;273(3):187-90. PubMed
Effects
of aging and axotomy on the expression of neurotrophin receptors in primary
sensory neurons.
Bergman E, Fundin BT, Ulfhake B
J Comp Neurol 1999 Aug 2;410(3):368-86. PubMed,
InterScience
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.
Bergman E, Carlsson K, Liljeborg A, Manders E,
Hokfelt T, Ulfhake B
Brain Res 1999 Jun 19;832(1-2):63-83. PubMed
Upregulation
of GFRalpha-1 and c-ret in primary sensory neurons and spinal motoneurons
of aged rats.
Bergman E, Kullberg S, Ming Y, Ulfhake B
J Neurosci Res 1999 Jul 15;57(2):153-65. PubMed,
InterScience
Loss
of primary sensory neurons in the very old rat: neuron number estimates using
the disector method and confocal optical sectioning.
Bergman E, Ulfhake B
J Comp Neurol 1998 Jun 29;396(2):211-22. PubMed,
InterScience
Alterations
in mystacial pad innervation in the aged rat.
Fundin BT, Bergman E, Ulfhake B
Exp Brain Res 1997 Nov;117(2):324-40. PubMed,
Springer
Neuropeptides
and neurotrophin receptor mRNAs in primary sensory neurons of aged rats.
Bergman E, Johnson H, Zhang X, Hökfelt T,
Ulfhake B
J Comp Neurol 1996 Nov 11;375(2):303-19. PubMed
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