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): 332-335

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

Chronic Stress Triggers Social Aversion via Glucocorticoid Receptor in Dopaminoceptive Neurons

Jacques Barik1,2,3,4,*, Fabio Marti3,4,5, Carole Morel3,4,5, Sebastian P. Fernandez3,4,6, Christophe Lanteri2,3,7, Gérard Godeheu2,3,7, Jean-Pol Tassin2,3,7, Cédric Mombereau3,4,8, Philippe Faure3,4,5, and François Tronche1,2,3,4,*

1 Molecular Genetics, Neurophysiology and Behavior Group, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 7224, 75005 Paris, France.
2 Institut National de la Santé et de la Recherche Médicale (INSERM) U952S, 75005 Paris, France.
3 Université Pierre et Marie Curie, 75005 Paris, France.
4 Laboratory of Excellence (Labex) Biological Psychiatry Laboratory, 75005 Paris, France.
5 Neurophysiology and Behavior Group, CNRS UMR7102, 75005 Paris, France.
6 Neurotransmission and Development Group, INSERM U839, 75005 Paris, France.
7 Physiopathology of Addiction and Relapse Group, CNRS UMR7224, 75005 Paris, France.
8 Molecular and Cellular Mechanisms of Cortical Development Group, INSERM U839, 75005 Paris, France.


Figure 1
View larger version (25K):
[in this window]
[in a new window]

 
Fig. 1. GR in dopaminoceptive neurons, but not in DA neurons, selectively drives social aversion triggered by chronic social stress. (A) Undefeated control (gray) and GRDATCre mice (white) spent more time in the virtual interacting zone when a mouse was contained in a box present in the open field (Target+) than when no mouse was introduced (Target–). In contrast, defeated control and GRDATCre mice displayed social aversion (interaction defeat x target, F1,44 = 19.5, P < 0.0001) but no genotype effect (no interaction defeat x target x genotype, F1,44 = 0.3, P > 0.05). (B) Undefeated control (gray) and GRD1Cre (black) mice displayed expected social interactions. Defeated control animals exhibited social aversion, whereas defeated GRD1Cre mice exhibited social interaction (interaction defeat x target x genotype, F1,44 = 9.7, P < 0.01). (C and D) The numbers of contacts (C) and time spent in physical contact with the box (D) by defeated GRD1Cre mice were higher than in defeated controls but similar to undefeated control mice [interaction genotype x defeat, F1,44 = 4.3, P < 0.05 (C); F1,44 = 7.3, P < 0.01 (D)]. n = 12 per group; *P < 0.05, **P < 0.01 (post hoc Bonferroni test).

 

Figure 2
View larger version (22K):
[in this window]
[in a new window]

 
Fig. 2. GR in dopaminoceptive neurons is dispensable for emotional behavior and HPA axis reactivity subsequent to chronic social stress. (A) Levels of plasma corticosterone differed neither in naïve nor in chronically defeated control and GRD1Cre mice under basal conditions or after an additional acute social defeat episode. Effect of acute stress (F1,36 = 314.9, P < 0.0001) with no genotype (F1,36 = 1.3, P > 0.05) or defeat (F1,36 = 0.14, P > 0.05) effect. Circulating GC levels in control and defeated GRD1Cre mice (black) and control littermates (gray) are shown under basal conditions or after an acute defeat. (B) Anxiety was measured within an elevated zero-maze in undefeated and defeated animals. After chronic defeat stress in control and GRD1Cre mice, the latency to enter (right panel) and the time spent (left panel) in the open arms was equally increased and decreased, respectively. Effect of defeat (time in open arms F1,44 = 63.3, P < 0.001; latency F1,44 = 43.3, P < 0.001), no effect of genotype (time in open arms F1,44 = 0.8, P > 0.05; latency F1,44 = 0.5, P > 0.05). (C) Quantification of freezing behavior in control and GRD1Cre mice reexposed to the conditioning context 24 hours after conditioning with footshocks (unpaired t test, P > 0.05). n = 5 to 7 mice per group (A), n = 12 mice per group [(B) and (C)]; **P < 0.01, ***P < 0.001 (post hoc Bonferroni test).

 

Figure 3
View larger version (27K):
[in this window]
[in a new window]

 
Fig. 3. Increase of in vivo firing of VTA neurons is required for the expression of social aversion. (A) An acute social defeat stress (arrow) fails to induce significant DA overflow, as measured by microdialysis, in the NAc of GRD1Cre mice relative to control littermates (interaction defeat x genotype F10,130 = 4.7, P < 0.0001). Stress versus respective baseline: ***P < 0.001. Control versus mutant: °°P < 0.01, °°°P < 0.0001. n = 7 to 8 mice per group. (B) Firing rate (left panel) and percentage of spikes within bursts (right panel) of VTA DA cells in undefeated or defeated control and GRD1Cre mice in vivo. Numbers indicate the number of DA cells in corresponding groups; n = 24 to 34 neurons from 6 to 8 mice per group. (C) Representative recordings obtained from control and GRD1Cre mice after repeated social defeat. (D) An acute quinpirole injection to defeated control mice prior to the social interaction test reverses social aversion, whereas saline fails to do so. Left panel: Quantification of the time spent in the interacting zone by defeated mice injected with saline (white bars) or quinpirole (0.03mg/kg, black shaded bars) in the presence of an empty box (Target–) or containing a mouse (Target+). Right panel: Representative trackings of defeated mice after either saline or quinpirole administration (interaction target x treatment F1,38 = 7.4, P < 0.01). n = 10 to 11 mice per group. *P < 0.05, **P < 0.01, ***P < 0.001 (post hoc Bonferroni test).

 


To Advertise     Find Products


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