Publikationsserver der Universitätsbibliothek Marburg

Titel:The absence of a functional thymus is associated with alterations in peripheral and central neurotransmitters and neurotrophins
Autor:Jouda, Jamela Aesa Kahdem
Weitere Beteiligte: Bauer, Uta-Maria (Prof. Dr. )
Veröffentlicht:2012
URI:https://archiv.ub.uni-marburg.de/diss/z2013/0001
URN: urn:nbn:de:hebis:04-z2013-00015
DOI: https://doi.org/10.17192/z2013.0001
DDC: Medizin, Gesundheit
Titel(trans.):The absence of a functional thymus is associated with alterations in peripheral and central neurotransmitters and neurotrophins
Publikationsdatum:2013-02-22
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
NA, NA, BDNF, Neurotrophins, Thymus, NGF, Neurotransmitters, Neurotrophins, Thymus, Neurotransmitters, BDNF, Unde mice, NGF, Unde mice

Summary:
Physiologische Wechselwirkungen zwischen neuronalem, endokrinem und Immunsystem sind inzwischen gut belegt. Diese Arbeit befasst sich mit Auswirkungen des Fehlens von funktionsfähigem Thymus auf Neurotransmitter- und Neurotrophin-Konzentrationen in der Milz sowie bestimmten Hirnregionen unter Verwendung homozygoter Foxn1nu Mäuse als Modell. Diese Spontanmutation führt zu einer fehlerhaften Entwicklung der Thymusanlage mit Ausbleiben der Entwicklung reifer T-Zellen. Der erste Teil der Arbeit zeigt bei Foxn1nu Mäusen 1) eine verstärkte sympathische Innervation der Milz, die auch im Erwachsenalter anhält; 2) Änderungen noradrenerger und serotonerger Neurotransmitter in bestimmten Hirnregionen, vergleichbar denen in der Milz; 3) eine erhöhte Dichte noradrenerger Fasern in Milz und Hypothalamus; 4) eine Erhöhung der Konzentrationen des Wachstumsfaktors „brain-derived nerve growth factor“ (BDNF) und von Neurotrophin-3 (NT-3) sowie von BDNF-Signalen in Milz und Hippocampus; 5) ausgeprägte anatomische Änderungen des Hippocampus und 6) erhöhte Kortikosteron-Blutwerte. Diese Änderungen verschwinden nach Rekonstitution der Foxn1nu Mäuse durch Thymustransplantation bei Geburt. Der zweite Teil geht der Frage nach, ob diese Änderungen in athymischen Mäusen grundsätzlicher bedeuten, dass das catecholaminerge System ursächlich mit der Neurotrophinbildung in Verbindung steht. Die Befunde zeigen, dass die Zerstörung noradrenerger Neurone nach Neurotoxinapplikation zu einer dauerhaften oder vorübergehenden Denervierung führt, begleitet von zu- oder abnehmenden Kortikosteron-Blutspiegeln sowie Neurotrophin-Konzentrationen in Milz und Gehirn, abhängig vom Alter der Denervierung. Zusammengenommen weisen die hier vorgelegten Ergebnisse darauf hin, dass die bei Foxn1nu Mäusen gefundenen Änderungen an Neurotransmittern und Neurotrophinen kein Epiphänomen darstellen, das zufällig mit dem Fehlen der Thymusfunktion einhergeht, sondern dass wahrscheinlich reife T-Zellen direkt oder indirekt eine inhibitorische Wirkung auf die Entwicklung der sympathischen Milzinnervation sowie auf catecholaminerge und serotonerge Mechanismen des zentralen Nervensystems entfalten. Die Ergebnisse liefern somit neue Belege, dass das Immunsystem nervale und endokrine Systeme beeinflussen kann.

Zusammenfassung:
It is at present well established that there are physiological interactions between the nervous, endocrine, and immune systems. This work focuses on the impact that the lack of a functional thymus has on neurotransmitter and neurotrophin concentrations in the spleen and in defined brain regions, using as a model homozygous Foxn1nu mice. This spontaneous mutation results in defective development of the thymus anlage, and therefore, in lack of mature T cells. The first part of this work shows that Foxn1nu mice have: 1) an increased splenic sympathetic innervation that is maintained during adult life; 2) alterations in noradrenergic and serotonergic neurotransmitters in defined brain regions comparable to those in the spleen; 3) increased density of noradrenergic fibers in the spleen and hypothalamus; 4) increased brain-derived nerve growth factor (BDNF) and neurotrophin-3 (NT-3) concentrations, and BDNF signals in the spleen and hippocampus; 5) marked alterations in the anatomy of the hippocampus; and 6) increased corticosterone blood levels. All these alterations are abolished in Foxn1nu mice reconstituted by thymus transplantation at birth. The second part studied whether the alterations detected in nude mice reflect a more general condition that causally relates the catecholaminergic system with the expression of neurotrophins. The results demonstrate that destruction of noradrenergic neurons by administration of a neurotoxin, results in a permanent or transient denervation that is paralleled by increased or decreased neurotrophin concentrations in the spleen and in the brain and in corticosterone blood levels, depending on the age at which mice are denervated. Taken together, the results reported here indicate that the alterations in neurotransmitters and neurotrophins observed in homozygous Foxn1nu mice are not just an epiphenomenon fortuitously associated with the absence of a functional thymus, but that most likely mature T cells, by acting either directly or indirectly, exert an inhibitory influence on the development of splenic sympathetic innervation and of catecholaminergic and serotonergic mechanisms in the central nervous system. In more general terms, these results provide new evidence that the immune system can affect the nervous and endocrine systems.

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