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Séminaire - Vincent Vialou∆FosB in the limbic brain, resilience and susceptibility to stress

Abstract :

The ability to cope with stressful situations—resilience—depends upon active neural and behavioral adaptations that successfully oppose the deleterious effects of chronic stress. Such adaptations could provide pathways for the development of novel antidepressant treatments. Using a chronic social defeat stress paradigm, an ethologically valid approach, we identified persistent molecular adaptations occurring in the limbic brain in particular the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc) driving such motivational states.

We first quantified by immunohistochemistry levels of ∆FosB, a protein implicated in the persistent neuronal alterations induced by chronic exposure to stress. We previously showed that induction of the transcription factor ∆FosB in the NAc in response to chronic social defeat stress is both necessary and sufficient for resilience. ∆FosB produces these effects through the induction of the GluR2 AMPA glutamate receptor subunit, which decreases the responsiveness of NAc neurons to glutamate.

Here we show that ∆FosB is induced in the mPFC of susceptible mice. Such induction increased social avoidance induced by social stress and increased time of immobility in the forced swim test. A potential molecular mechanism underlying the susceptible phenotype could be the release of cholecystokinin (CCK) in the mPFC, which has been shown to be released during social stress and to mediate an anxiogenic response. Overexpression of ∆FosB in the mPFC increased cholecystokinin receptor (CCK-B) levels suggesting that it might mediate the behavioral effects of ∆FosB. To test a role for CCK-B in social stress, we infused CI-988 in the mPFC of susceptible mice. We further tested the involvement cortical projections to the amygdala and NAc in this behavioral adaptation using a combined pharmacological and optogenetic approach.

Long-term alterations in the limbic brain contribute to the behavioral abnormalities observed after social defeat. These experiments will provide a better understanding of the role of ΔFosB in the pathophysiology of depression and its treatment.

Selected publications

Vialou V, Feng J, Robison AJ, Nestler EJ.Epigenetic mechanisms of depression and antidepressant action. Annu Rev Pharmacol Toxicol. 2013 Jan 6;53:59-87. doi: 10.1146/annurev-pharmtox-010611-134540. Epub 2012 Sep 27.

Vialou V, Feng J, Robison AJ, Ku SM, Ferguson D, Scobie KN, Mazei-Robison MS, Mouzon E, Nestler EJ. Serum response factor and cAMP response element binding protein are both required for cocaine induction of ΔFosB. J Neurosci. 2012 May 30;32(22):7577-84. doi: 10.1523/JNEUROSCI.1381-12.2012.

Vialou V, Cui H, Perello M, Mahgoub M, Yu HG, Rush AJ, Pranav H, Jung S, Yangisawa M, Zigman JM, Elmquist JK, Nestler EJ, Lutter M. A role for ΔFosB in calorie restriction-induced metabolic changes. Biol Psychiatry. 2011 Jul 15;70(2):204-7. doi: 10.1016/j.biopsych.2010.11.027. Epub 2011 Jan 7.

Vialou V, Maze I, Renthal W, LaPlant QC, Watts EL, Mouzon E, Ghose S, Tamminga CA, Nestler EJ. Serum response factor promotes resilience to chronic social stress through the induction of DeltaFosB. J Neurosci. 2010 Oct 27;30(43):14585-92. doi: 10.1523/JNEUROSCI.2496-10.2010.

Vialou V. [Histone acetylation, gene regulation and depression]. Med Sci (Paris). 2010 May;26(5):465-7. doi: 10.1051/medsci/2010265465. French.

Vialou V, Robison AJ, Laplant QC, Covington HE 3rd, Dietz DM, Ohnishi YN, Mouzon E, Rush AJ 3rd, Watts EL, Wallace DL, Iñiguez SD, Ohnishi YH, Steiner MA, Warren BL, Krishnan V, Bolaños CA, Neve RL, Ghose S, Berton O, Tamminga CA, Nestler EJ. DeltaFosB in brain reward circuits mediates resilience to stress and antidepressant responses. Nat Neurosci. 2010 Jun;13(6):745-52. doi: 10.1038/nn.2551. Epub 2010 May 16. PubMed PMID: 20473292;

Etienne Herzog (etienne.herzog @