TY  - JOUR
A1  - Cline, Brandon H.
A1  - Costa-Nunes, Joao P.
A1  - Cespuglio, Raymond
A1  - Markova, Natalyia
A1  - Santos, Ana I.
A1  - Bukhman, Yury V.
A1  - Kubatiev, Aslan
A1  - Steinbusch, Harry W. M.
A1  - Lesch, Klaus-Peter
A1  - Strekalova, Tatyana
T1  - Dicholine succinate, the neuronal insulin sensitizer, normalizes behavior, REM sleep, hippocampal pGSK3 beta and mRNAs of NMDA receptor subunits in mouse models of depression
JF  - Frontiers in Behavioral Neuroscience
N2  - Central insulin receptor-mediated signaling is attracting the growing attention of researchers because of rapidly accumulating evidence implicating it in the mechanisms of plasticity, stress response, and neuropsychiatric disorders including depression. Dicholine succinate (DS), a mitochondrial complex II substrate, was shown to enhance insulin-receptor mediated signaling in neurons and is regarded as a sensitizer of the neuronal insulin receptor. Compounds enhancing neuronal insulin receptor-mediated transmission exert an antidepressant-like effect in several pre-clinical paradigms of depression; similarly, such properties for DS were found with a stress-induced anhedonia model. Here, we additionally studied the effects of DS on several variables which were ameliorated by other insulin receptor sensitizers in mice. Pre-treatment with DS of chronically stressed C57BL6 mice rescued normal contextual fear conditioning, hippocampal gene expression of NMDA receptor subunit NR2A, the NR2A/NR2B ratio and increased REM sleep rebound after acute predation. In 18-month-old C57BL6 mice, a model of elderly depression, DS restored normal sucrose preference and activated the expression of neural plasticity factors in the hippocampus as shown by Illumina microarray. Finally, young naive DS-treated C57BL6 mice had reduced depressive- and anxiety-like behaviors and, similarly to imipramine-treated mice, preserved hippocampal levels of the phosphorylated (inactive) form of GSK3 beta that was lowered by forced swimming in pharmacologically naive animals. Thus, DS can ameliorate behavioral and molecular outcomes under a variety of stress- and depression-related conditions. This further highlights neuronal insulin signaling as a new factor of pathogenesis and a potential pharmacotherapy of affective pathologies.
KW  - phosphorylated glycogen synthase kinase-3beta (pGSK-3beta)
KW  - hippocampal plasticity
KW  - sleep EEG
KW  - aging
KW  - NMDA receptor subunits NR2A and NR2B
KW  - dicholine succinate
KW  - insulin receptor
KW  - chronic stress
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143992
VL  - 9
IS  - 37
ER  - 
TY  - JOUR
A1  - Zannas, Anthony S.
A1  - Arloth, Janine
A1  - Carrillo-Roa, Tania
A1  - Iurato, Stella
A1  - Röh, Simone
A1  - Ressler, Kerry J.
A1  - Nemeroff, Charles B.
A1  - Smith, Alicia K.
A1  - Bradley, Bekh
A1  - Heim, Christine
A1  - Menke, Andreas
A1  - Lange, Jennifer F.
A1  - Brückl, Tanja
A1  - Ising, Marcus
A1  - Wray, Naomi R.
A1  - Erhardt, Angelika
A1  - Binder, Elisabeth B.
A1  - Mehta, Divya
T1  - Lifetime stress accelerates epigenetic aging in an urban, African American cohort: relevance of glucocorticoid signaling
JF  - Genome Biology
N2  - Background
Chronic psychological stress is associated with accelerated aging and increased risk for aging-related diseases, but the underlying molecular mechanisms are unclear.

Results
We examined the effect of lifetime stressors on a DNA methylation-based age predictor, epigenetic clock. After controlling for blood cell-type composition and lifestyle parameters, cumulative lifetime stress, but not childhood maltreatment or current stress alone, predicted accelerated epigenetic aging in an urban, African American cohort (n = 392). This effect was primarily driven by personal life stressors, was more pronounced with advancing age, and was blunted in individuals with higher childhood abuse exposure. Hypothesizing that these epigenetic effects could be mediated by glucocorticoid signaling, we found that a high number (n = 85) of epigenetic clock CpG sites were located within glucocorticoid response elements. We further examined the functional effects of glucocorticoids on epigenetic clock CpGs in an independent sample with genome-wide DNA methylation (n = 124) and gene expression data (n = 297) before and after exposure to the glucocorticoid receptor agonist dexamethasone. Dexamethasone induced dynamic changes in methylation in 31.2 % (110/353) of these CpGs and transcription in 81.7 % (139/170) of genes neighboring epigenetic clock CpGs. Disease enrichment analysis of these dexamethasone-regulated genes showed enriched association for aging-related diseases, including coronary artery disease, arteriosclerosis, and leukemias.

Conclusions
Cumulative lifetime stress may accelerate epigenetic aging, an effect that could be driven by glucocorticoid-induced epigenetic changes. These findings contribute to our understanding of mechanisms linking chronic stress with accelerated aging and heightened disease risk.
KW  - aging
KW  - DNA methylation
KW  - gene expression
KW  - glucocorticoids
KW  - psychological stress
KW  - aging-related disease
KW  - epigenetics
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149865
VL  - 16
IS  - 266
ER  -