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

摘要 组蛋白脱乙酰酶(HDACs)是一类通过脱乙酰基抑制基因转录的酶， 代表了环境影响基因表达的机制之一。临床前研究 反复证明，表观遗传酶HDAC对正常的大脑功能起着关键作用， 包括社交情感技能。在动物和人类体内和身体上的研究表明 精神障碍中HDAC表达水平的异常。然而，到目前为止，人们对 体内HDAC表观遗传酶表达与人类行为的关系。对此的研究 考虑到正电子发射断层扫描(PET)[11C]Martinostat的最新发展，关联是可能的 成像探针允许在体内评估HDAC脑表达。 与情绪调节、社交技能、焦虑、能力或无能相关的神经心理特征 (快感缺乏症)体验快乐和对奖励的敏感性是常见的，并持续分布在 普通人口。利用这种正态变化，我们将研究 HDAC的表达和神经心理特征。我们建议研究HDAC之间的关联 健康男女青年的PET影像表现及神经心理学特征 (目标1)。我们还将调查青少年HDAC脑表达是否存在地区性性别差异 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 奖励fMRI任务(目标3)。 综上所述，这项研究将为了解健康男性和女性体内HDAC的表观遗传格局提供见解。 成年女性，及其与神经心理特征和大脑激活的关系。如果地区性HDAC 表达是性别特有的，它可能有助于已知疾病易感性和疾病的差异 在男性和女性中的患病率。更好地理解正常的表观遗传变异及其关联 人类的行为表型是神经表观遗传学领域必不可少的第一步，并将具有 对未来精神疾病表观遗传失调研究的启示。

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.