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Susanna Kullberg
susanna.kullberg@neuro.ki.se
Curriculum Vitae
Thesis
Publications
Curriculum Vitae
1.Läkarexamen, KI 970613
2.Leg. läkare, KI 2002
3.Med. Dr, KI 2002-08-30
Thesis
On Age Related Changes in Axons and Glia of the Central
Nervous System
THESIS ABSTRACT
A growing body of evidence shows that phenotypic changes including axon
aberrations, rather than loss of neurons, account for behavioral impairments
during aging. The present thesis was undertaken to investigate the occurrence
of axon aberrations in relation to transmitter identity, glial reaction
and sensorimotor disturbances. To shed light on possible underlying mechanisms,
signs of oxidative stress and inflammation were also examined. The studies
were performed on behaviorally defined aged (30 months old) and young adult
(2-3 months old) Sprague Dawley rats, by using electron microscopy, immunohistochemistry,
in situ hybridization and reverse transcriptase-polymerase chain reaction.
The results show that many aged motoneurons lose a significant portion
of their bouton covering, due to a decreased number of apposing boutons.
Consistent with the more pronounced sensorimotor disturbances observed
in the hind- in comparison with the forelimbs, lumbar motoneurons appeared
more severely affected than cervical motoneurons. In the neuropil of the
motor nucleus, aberrant axons were encountered. Ultrastructural analysis
of aberrant axons in relation to content of amino acid neurotransmitters
and the free radical scavenger glutathione (GSH) revealed that many of
the aberrant axons contained high levels of glutamate-immunoreactivity
(-IR) and were often enriched with GSH-IR. Increased levels of GSH-IR were
also encountered in glutamate-IR terminals with a preserved ultrastructure,
suggesting that a changed redox status may be mechanistic in the development
of axon aberrations. GABA- and glycine-IR terminals were more rarely affected,
suggesting that excitatory and inhibitory pathways are differentially affected.
In the aged rats, immunohistochemistry showed a reduced fiber density
and axon aberrations of cholinergic and monoaminergic axons in both the
spinal cord and the hippocampus. In contrast, the innervation of ?-motoneurons
by C boutons was preserved in senescence. However, the C boutons showed
a decreased labeling for cholinergic markers. Regions disclosing axon terminal
loss and aberrations showed increased expression of glial fibrillary acidic
protein (GFAP, the main intermediate filament of astrocytes).
Using Marchi staining on spinal cord sections, the outer parts of the
white matter showed signs of a changed myelin metabolism and/or dysmyelination
in aged rats. In the same regions, astro- and microglial cells showed conspicuous
signs of activation, most pronounced in rats disclosing the most severe
sensorimotor disturbances. The glial reaction appeared less pronounced
in brain white matter compared to the spinal cord white matter.
The spinal cord white matter of aged rats also disclosed a changed
expression of several cytokines, while the majority of investigated cytokines
were unaltered in the hippocampus. One of the most prominent changes was
an upregulation of the proinflammatory cytokine IFN- ?, encountered in
both the hippocampus and the spinal cord. There was a robust upregulation
of TGF?-1 and IL1-? in astroglia of spinal cord white matter, while no
change was evident in the hippocampus. CNTF levels were unaltered in aged
rats, however, IR appeared reduced in oligodendroglia-like cells, while
it seemed increased in astroglia of the spinal cord white matter. IGF-1,
a molecule with similar effects as CNTF, was upregulated in hippocampus
but not in the spinal cord.
Keywords: aging, synaptic input, spinal cord, hippocampus, amino acid
neurotransmitters, astrocyte, microglia, oligodendroglia, C bouton, cholinergic,
monoaminergic, cytokine
© Susanna Kullberg, 2002
ISBN 91-7349-271-X
Publications
Microglial
activation, emergence of ED1-expressing cells and clusterin upregulation
in the aging rat CNS, with special reference to the spinal cord.
Kullberg S, Aldskogius H, Ulfhake B.
Brain Res 2001 Apr 27;899(1-2):169-86. PubMed
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
Increased
glutathione levels in neurochemically identified fibre systems in the aged
rat lumbar motor nucleus.
Vania Ramírez-León, Susanna Kullberg, Ole-Petter Hjelle,
Ole-Petter Ottersen, Brun Ulfhake.
Eur J Neurosci 1999 Aug;11(8): 2935-48
Upregulation
of GFRa-1 and c-ret in primary sensory neurons and spinal motoneurons of
aged rats.
Esbjörn Bergman, Susanna Kullberg, Yu Ming, Brun Ulfhake
J Neurosci Res 1999 Jul 15;57(2):153-65
Decreased
axosomatic input to motoneurons and astrogliosis in the spinal cord of
aged rats.
Susanna Kullberg, Vania Ramírez-León, Hans Johnson, Brun
Ulfhake.
J Gerontol A Biol Sci Med Sci 1998 Sep;53(5): B369-79
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