The role of hippocampal actin dynamics and epigenetic gene-expression during the extinction of fear memories

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Neuropsychiatric diseases such as anxiety disorders are amongst the largest contributors to the global burden of disease. Such diseases are often characterized by high comorbidity. Thus, therapeutic strategies to inhibit excess fear are central for the treatment of anxiety and mood disorders. Experimental data obtained across species demonstrated that in addition to the amygdala, the prefrontal cortex and the hippocampus play critical roles in the consolidation and extinction of fear memories but the molecular underpinnings are only beginning to emerge. It is now commonly accepted that the pathogenesis of complex neuropsychiatric diseases is driven by variable combinations of genetic and environmental risk factors. Epigenetic mechanisms are key processes that regulate such genome-environment interactions and deregulation of epigenetic mechanisms has been linked to the pathogenesis of complex brain diseases. Targeting the epigenome is therefore discussed as a novel therapeutic strategy for neuropsychiatric diseases. In the previous funding period I found that the hippocampal epigenetic enzyme histone-deacetylase 1 (HDAC1) is a key regulator of fear memories in mice. I also generated preliminary data suggesting that deregulation of HDAC1 in the prefrontal cortex leads to neuropsychiatric phenotypes. In addition I have obtained preliminary evidence that the manifestation of neuropsychiatric phenotypes at young age causes epigenetic changes that accelerate memory decline during aging and I suggest to follow up on these two key findings during the next funding period. I will employ the mouse as model organism and use a combination of behavioral, genetic, electrophysiological and epigenetic approaches to study, for the first time, the role of HDAC1 in the prefrontal cortex-hippocampal network in a cell type specific manner. To this end I will use genetic HDAC1 gain and loss of function models as well as behavioral models such as early life stress and consequently employ next-generation-sequencing for cell-type specific epigenome profiling. In addition, on the basis of data generated in the previous funding period I will use mouse models to test the hypothesis that impaired cognitive flexibility linked to neuropsychiatric phenotypes at young age induces epigenetic changes to neurons that will accelerate memory decline during aging. In conclusion this data will allow unprecedented insight to the molecular mechanisms underlying neuropsychiatric diseases and dementia, will set novel methodological standards and shall help to identify biomarker that allow the development of therapeutic approaches for the correct patient population.