Epigenetic involvement in socio-emotional behavior studied by PET- MRI

摘要 组蛋白去乙酰化酶（HDAC），通过去乙酰化抑制基因转录的酶家族， 这是环境影响基因表达的机制之一。临床前研究 已经反复证明，表观遗传酶HDAC对正常的大脑功能起着关键作用， 包括社会情感技能。动物和人类的体内和死后研究表明， HDAC在精神疾病中的表达水平异常。然而，迄今为止，人们对 体内HDAC表观遗传酶表达与人类行为之间的关联。研究这一 考虑到[11 C]Martinostat（一种正电子发射断层扫描（PET））的最新发展， 成像探针允许HDAC脑表达的体内评估。 与情绪调节、社交技能、焦虑、有能力或无能力相关的神经心理特征 （快感缺乏）体验快乐，和敏感的奖励是常见的，并不断分布在 一般人口。利用这种正常变化，我们将研究 HDAC表达和神经心理学特征。我们建议研究HDAC之间的关联 通过PET成像和神经心理学特征确定健康男性和女性年轻人中的表达 (Aim 1）。我们还将研究在年轻人中HDAC脑表达是否存在区域性别差异， 成人（目标2）。此外，使用同步PET-功能磁共振成像（fMRI），我们将 确定HDAC表达和大脑激活之间的关系，以响应社会情绪和 奖励fMRI任务（目标3）。 总之，这项研究将提供对健康男性和健康女性中HDAC的体内表观遗传景观的见解。 女性成年人，以及它与神经心理特征和大脑激活的关系。如果区域HDAC 表达是性别特异性的，它可能有助于疾病易感性和疾病的已知差异， 男性和女性的患病率。更好地了解正常的表观遗传变异及其关联 与人类行为表型是神经表观遗传学领域的重要第一步， 对未来研究精神疾病表观遗传失调的影响。

ABSTRACT Histone deacetylases (HDACs), a family of enzymes that repress gene transcription through deacetylation, represent one of the mechanisms through which environment can affect gene expression. Preclinical studies have repeatedly demonstrated that the epigenetic enzymes HDACs play a key role for normal brain function, including socio-emotional skills. In vivo and postmortem work in animals and humans has implicated regional abnormalities in HDAC expression levels in psychiatric disorders. However, to date, little is known in terms of the association between in vivo HDAC epigenetic enzymes expression and human behavior. The study of this association is possible given the recent development of [11C]Martinostat, a positron emission tomography (PET) imaging probe allowing the in vivo assessment of HDAC brain expression. Neuropsychological traits associated with emotion regulation, social skills, anxiety, the ability or inability (anhedonia) to experience pleasure, and sensitivity to reward are common and continuously distributed in the general population. Taking advantage of this normal variation, we will investigate the relationships between HDAC expression and neuropsychological profile. We propose to study the association between HDACs expression determined by PET imaging and neuropsychological traits in healthy male and female young adults (Aim 1). We will also investigate whether there are regional sex differences in HDAC brain expression in young adults (Aim 2). Furthermore, using simultaneous PET- functional magnetic resonance imaging (fMRI), we will determine the relationship between HDAC expression and brain activation in response to socio-emotional and reward fMRI tasks (Aim 3). In summary, this study will provide insights into the in vivo epigenetic landscape of HDACs in healthy male and female adults, and its association with neuropsychological traits and brain activation. If regional HDACs expression is sex-specific, it may contribute to known differences in disease susceptibility and disease prevalence in males and females. A better understanding of normal epigenetic variations and their association with behavioral phenotype in humans is an essential first step for the field of neuroepigenetics, and will have implications for future studies investigating epigenetic dysregulation in psychiatric diseases.