Altered Expression of Phox2 Transcription Factors in the Locus Coeruleus in Major Depressive Disorder Mimicked by Chronic Stress and Corticosterone Treatment In Vivo and In Vitro

[Display omitted] •Protein levels of Phox2a, mRNA and protein levels of Phox2b were elevated in the locus coeruleus from brain donors of MDD.•CSD significantly increased Phox2a and Phox2b expression in the rat locus coeruleus.•Corticosterone administration increased Phox2b protein levels in the rat...

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Vydané v:Neuroscience Ročník 393; s. 123 - 137
Hlavní autori: Fan, Yan, Chen, Ping, Raza, Muhammad U., Szebeni, Attila, Szebeni, Katalin, Ordway, Gregory A., Stockmeier, Craig A., Zhu, Meng-Yang
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States Elsevier Ltd 21.11.2018
Predmet:
Animals
corticosterone
Corticosterone - metabolism
Corticosterone - pharmacology
Depressive Disorder, Major - metabolism
Gene Expression Regulation, Developmental - drug effects
Gene Expression Regulation, Developmental - physiology
Homeodomain Proteins - metabolism
locus coeruleus
Locus Coeruleus - drug effects
Locus Coeruleus - metabolism
major depressive disorder
Male
Nerve Tissue Proteins - metabolism
Norepinephrine - metabolism
Phox2 genes
postmortem
Rats, Inbred F344
RNA, Messenger - metabolism
stress
Transcription Factors - metabolism
PBS
stress
ir
DBH
MDD
q-PCR
locus coeruleus
CORT
TH
major depressive disorder
CSD
postmortem
LC
Phox2 genes
corticosterone
ISSN:0306-4522, 1873-7544, 1873-7544
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Shrnutí:[Display omitted] •Protein levels of Phox2a, mRNA and protein levels of Phox2b were elevated in the locus coeruleus from brain donors of MDD.•CSD significantly increased Phox2a and Phox2b expression in the rat locus coeruleus.•Corticosterone administration increased Phox2b protein levels in the rat locus coeruleus.•Corticosterone increased Phox2a and Phox2b expression in the SK-SY5Y cells.•Corticosterone-induced increase in Phox2 expression may be mediated through corticosteroid receptors. Phox2a and Phox2b are two homeodomain transcription factors playing a pivotal role in the development of noradrenergic neurons during the embryonic period. However, their expression and function in adulthood remain to be elucidated. Using human postmortem brain tissues, rat stress models and cultured cells, this study aimed to examine the alteration of Phox2a and Phox2b expression. The results show that Phox2a and Phox2b are normally expressed in the human locus coeruleus (LC) in adulthood. Furthermore, the levels of Phox2a protein and mRNA and protein levels of Phox2b were significantly elevated in the LC of brain donors that suffered from the major depressive disorder, as compared to age-matched and psychiatrically normal control donors. Fischer 344 rats subjected to chronic social defeat showed higher mRNA and protein levels of Phox2a and Phox2b in the LC, as compared to non-stressed control rats. In rats chronically administered oral corticosterone, mRNA and protein levels of Phox2b, but not Phox2a, in the LC were significantly increased. In addition, the corticosterone-induced increase in Phox2b protein was reversed by simultaneous treatment with either mifepristone or spironolactone. Exposing SH-SY5Y cells to corticosterone significantly increased expression of Phox2a and Phox2b, which was blocked by corticosteroid receptor antagonists. Taken together, these experiments reveal that Phox2 genes are expressed throughout the lifetime in the LC of humans and Fischer 344 rats. Alterations in their expression may play a role in major depressive disorder and possibly other stress-related disorders through their modulatory effects on the noradrenergic phenotype.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0306-4522
1873-7544
1873-7544
DOI:10.1016/j.neuroscience.2018.09.038