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

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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.