AcScapeStress · Cell type-specific effects of HDAC1 on stress vulnerability, hippocampal gene regulation and genome-wide acetylation landscape

The discovery that broad spectrum histone deacetylase inhibitors (HDACi) can improve depression-related symptoms in humans and in corresponding mouse models in conjunction with the observation that stressors affect the epigenome by changing histone acetylation opened new avenues to a better understanding of the pathophysiology of stress-related disorders. Finding the essential molecular mechanisms of how single histone deacetylases (HDACs) contribute to or ameliorate stress-related pathologies will improve the efficacy of current antidepressant drugs through increased specificity.Aim of this study is to investigate whether and in which way the specific histone deacetylase (HDAC) 1 has an impact on anxiety and depression-like behaviour in adult mice under baseline, non-stressed and stressed conditions using a neuron and forebrain-specific ""loss-of-function"" mouse model (Hdac1 knockout mice). And, the study aims to determine effects of HDAC1 on gene expression and genome-wide acetylation signatures in the hippocamus to identify how the potential protective or detrimental role of HDAC1 in stress response is mediated. Moreover, it is important to understand if the findings are cell type-specific, since HDAC1 is expressed in neurons and glia. Finally, rescue experiments will test whether the phenotype is reversible, which is important for future therapeutic implications.The fellow has acquired the necessary expertise in Dr. Akbarian´s laboratory at UMASS Medical School (now: Mount Sinai School of Medicine). This includes: working with epigenetic mouse models, performing microarrays and especially chromatin immunoprecipitation (ChIP) specific for histone acetylation in conjunction with library preparation for next generation sequencing.The fellow will transfer this knowledge to the host institution, the Max Planck Institute of Psychiatry, which is renowned for the excellent depression and stress research and therefore the best place to conduct the proposed project.""