edgments We thank Dr. MJ Spencer, Dr. RL Mellgren and Dr. G Butler-Browne for useful comments and critical examination of the manuscript. We thank Dr. AC Vertegaal for technical advice and critical reading of the manuscript. We are grateful to Dr. JM Daniel for providing us with the bGalactosidase-GFP fusion constructs. We thank G Roukens for supplying the SUMO and PIAS expression constructs. We also thank Dr. K Busby Institute of Human Genetics, International Centre for Life and Dr. R Charlton, Freeman Hospital, Newcastle-upon-Tyne, UK for providing us with muscle cryosections. Author CHIR 99021 site Contributions Conceived and designed the experiments: AdM DLH AvR PACH SMvdM. Performed the experiments: AdM DLH AI HHHBMvH PdG AvR PACH. Analyzed the data: AdM DLH AI PACH SMvdM. Wrote the paper: AdM GJBvO RRF SMvdM. August A Calpain August Environmental Enrichment Induces Behavioral Recovery and Enhanced Hippocampal Cell Proliferation in an Antidepressant-Resistant Animal Model for PTSD Hendrikus Hendriksen, Jolanda Prins, Berend Olivier, Ronald S. Oosting Department of Pharmacology, Utrecht 
Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands Abstract Background: Post traumatic stress disorder can be considered the result of a failure to recover after a traumatic experience. Here we studied possible protective and therapeutic aspects of environmental enrichment in Sprague Dawley rats exposed to an inescapable foot shock procedure. Methodology/Principal Findings: IFS induced long-lasting contextual and non-contextual anxiety, modeling some aspects of PTSD. Even Citation: Hendriksen H, Prins J, Olivier B, Oosting RS Environmental Enrichment Induces Behavioral Recovery and 11325787 Enhanced Hippocampal Cell Proliferation in an Antidepressant-Resistant Animal Model for PTSD. PLoS ONE Introduction sensory stimulation as compared to standard housing. The availability of a running wheel results in more voluntary exercise, while providing tunnels and shelters and repeated introduction of novel objects leads to more opportunities to experience new sensory information. Environmental enrichment leads to beneficial effects on learning and memory, anxiety and depression like behaviors and stimulates recovery after brain lesions or cerebral ischemia. At the cellular level, environmental enrichment enhances neurogenesis in the dentate gyrus and stimulates dendritic branching and spine forming in the CAAugust EE-Induced Recovery Both are core symptoms of PTSD. We applied an inescapable foot shock paradigm that induces both longlasting contextual and non-contextual anxiety and alterations in emotional reactivity measured as a blunted light-enhanced startle. We used reduced locomotion and immobility in an open field test as a measure for anxiety. We show, in agreement with the limited pharmacological treatment possibilities in patients, that imipramine and escitalopram do not improve the behavioral effects induced by IFS. As EE improves depression-like behaviors, we expected an improvement of the behavior of shocked rats after EE. Furthermore we expected more resilience to the shocks in animals that were exposed to EE two weeks before IFS since the molecular processes that are held responsible for the antidepressant effect of EE, for example neurogenesis and the expression of neurotrophic factors are also enhanced in ��healthy��control animals and thus could form a protective buffer against the IFS. Also, we tested inhibition of HDAC-dependent chroma
