Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 339 (6117): 335-339

Copyright © 2013 by the American Association for the Advancement of Science

Adolescent Stress–Induced Epigenetic Control of Dopaminergic Neurons via Glucocorticoids

Minae Niwa1,2,3, Hanna Jaaro-Peled2, Stephanie Tankou2, Saurav Seshadri2, Takatoshi Hikida2,4, Yurie Matsumoto1,3, Nicola G. Cascella2, Shin-ichi Kano2, Norio Ozaki3, Toshitaka Nabeshima1,5,6,*, and Akira Sawa2,*

1 Department of Chemical Pharmacology, Meijo University Graduate School of Pharmaceutical Sciences, Nagoya 468-8503, Japan.
2 Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
3 Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya 464-8601, Japan.
4 Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
5 Academic Frontier Project for Private University, Comparative Cognitive Science Institution, Meijo University, Nagoya 468-8503, Japan.
6 Department of Regional Pharmaceutical Care and Science, Meijo University, Nagoya 468-8503, Japan.


Figure 1
View larger version (19K):
[in this window]
[in a new window]

 
Fig. 1. The GXE mouse model: Behavioral abnormalities in DISC1-DN-Tg-PrP after exposure to adolescent isolation stress for 3 weeks. (A) Deficits in PPI. (B) Impaired performance in the forced swim test. (C) Aberrant locomotor activity. CTL, wild type without isolation; E, wild type with isolation; G, DISC1-DN-Tg-PrP without isolation; GXE, DISC1-DN-Tg-PrP with isolation. Values are means ± SE; **P < 0.01, *P < 0.05. Numbers of animals and statistical information are described in tables S1 and S2.

 

Figure 2
View larger version (31K):
[in this window]
[in a new window]

 
Fig. 2. Dopaminergic disturbances in the GXE model. (A) Levels of total content of monoamines [dopamine (DA), norepinephrine (NE), and serotonin (5-HT)]. (B) Levels of extracellular basal DA in the Fc. (C) Levels of total content of monoamines in the CPu. (D) Levels of TH in the Fc. (E) Levels of TH in the NAc. (F) Extracellular DA levels upon METH challenge in the Fc. (G) Extracellular DA levels upon METH challenge in the NAc. Total and extracellular levels of neurotransmitters were measured by high-performance liquid chromatography and in vivo microdialysis, respectively. Values are means ± SE; **P < 0.01, *P < 0.05.

 

Figure 3
View larger version (42K):
[in this window]
[in a new window]

 
Fig. 3. Influence of glucocorticoids on neurochemical and behavioral abnormalities in the GXE model. (A) Levels of plasma corticosterone after behavioral tests. (B) Effects of the GR antagonist RU38486 on levels of extracellular basal DA in the Fc. (C) Effects of RU38486 on levels of extracellular DA upon METH challenge in the NAc. (D to F) Effects of RU38486 on performance of PPI (D), forced swim test (E), and locomotor activity (F). Veh, treated with vehicle; RU, treated with RU38486. Values are means ± SE; **P < 0.01, *P < 0.05.

 

Figure 4
View larger version (52K):
[in this window]
[in a new window]

 
Fig. 4. Distinct influence of glucocorticoids on epigenetic modification of the Th genes between mesocortical and mesolimbic dopaminergic projections in the GXE model. (A) Confocal images of TH-immunopositive cells in the VTA (blue), which are also labeled with retrogradely transported beads in mesocortical neurons (green) and those in mesolimbic neurons (red), respectively. Scale bars, 20 and 10 μm for upper and lower panels, respectively. (B) Graphic representation of the bisulfite-sequenced region in the promoter of the Th gene. The 11 CpG sites inside the island are indicated by open circles. The transcription start site (arrow), first exon (white box), and translation start site (ATG) are shown. (C) DNA methylation pattern of the Th promoter in the VTA neurons projected to the Fc. (D) DNA methylation pattern of the Th promoter in the VTA neurons projected to the NAc. (E) Effects of RU38486 on increased DNA methylation of the Th promoter in the VTA neurons projected to the Fc. (F) Long-lasting change in the DNA methylation of the Th promoter in the VTA neurons projected to the Fc. GXE-G, GXE returned to group housing from 8 to 20 weeks. The columns and rows represent the 11 CpG sites and the sequenced clones, respectively. Black and white squares indicate methylated and unmethylated CpG sites, respectively. Results were obtained from at least three independent experiments. In right panels of (C) to (F), values are means ± SE; **P < 0.01, *P < 0.05.

 


To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882