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

神经精神疾病，如焦虑症，是造成全球疾病负担的最大因素之一。这类疾病的特点往往是高合并症。因此，抑制过度恐惧的治疗策略是治疗焦虑和情绪障碍的核心。跨物种获得的实验数据表明，除了杏仁核，前额叶皮层和海马体在恐惧记忆的巩固和消除中起着关键作用，但分子基础才刚刚开始显现。现在人们普遍认为，复杂神经精神疾病的发病机制是由遗传和环境风险因素的可变组合驱动的。表观遗传机制是调控基因组-环境相互作用的关键过程，表观遗传机制的失调与复杂脑部疾病的发病机制有关。因此，靶向表观基因组作为神经精神疾病的一种新的治疗策略被讨论。在之前的资助期间，我发现海马表观遗传酶组蛋白去乙酰化酶1 （HDAC1）是小鼠恐惧记忆的关键调节因子。我还生成了初步数据，表明前额皮质中HDAC1的失调会导致神经精神表型。此外，我已经获得了初步证据，证明年轻时神经精神表型的表现会导致表观遗传变化，从而在衰老过程中加速记忆衰退，我建议在下一个资助期内继续研究这两个关键发现。我将以小鼠为模型生物，结合行为学、遗传学、电生理学和表观遗传学的方法，首次以细胞类型特异性的方式研究HDAC1在前额叶皮层-海马网络中的作用。为此，我将使用遗传HDAC1的功能增益和损失模型以及行为模型，如早期生活压力，并因此采用下一代测序进行细胞类型特异性表观基因组分析。此外，在先前资助期产生的数据的基础上，我将使用小鼠模型来验证一个假设，即与年轻时神经精神表型相关的认知灵活性受损会导致神经元的表观遗传变化，从而加速衰老过程中的记忆衰退。总之，这些数据将使我们对神经精神疾病和痴呆的分子机制有前所未有的了解，将建立新的方法标准，并将有助于识别生物标志物，从而为正确的患者群体开发治疗方法。

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.