Identification of molecular rhythm changes in postmortem tissue from individuals with psychiatric illness.

摘要 昼夜节律和睡眠中断是双相情感障碍等精神障碍的一个明显特征 (BP)、精神分裂症(SCZ)和严重抑郁障碍(MDD)。这些对正常节律的干扰 包括睡眠/清醒周期的改变、激素水平的昼夜模式以及昼夜节律基因的表达 外周样本。此外，对正常睡眠/清醒周期的干扰通常会导致情绪和 精神病发作，并可能导致认知功能障碍。精神病患者的一些治疗方法 紊乱可以通过稳定或放大大脑中的分子节律来发挥疗效。 然而，精神疾病受试者大脑中发生的分子节律变化仍然存在。 很大程度上是未知的。测量人类大脑中有节奏的基因表达现在是可能的。最近的两个 研究，包括我们小组的一项，证明了全基因组范围内的分子节律性。 使用“死亡时间”分析来对24小时周期内的人脑样本进行排序。这个 李等人的第一个研究。发现MDD受试者在六种不同的分子节律上有重大的干扰 大脑区域，包括前额叶皮质(PFC)区46和膝下扣带回(SGC)区25，比较 与比较对象进行比较。在146名对照受试者(年龄从16岁到16岁)中使用相同的方法 到96岁)，我们发现两个PFC区域表现出非常显著的节律性基因表达模式。 此外，我们发现，正常衰老与许多脑部疾病的节律性显著丧失有关。 成绩单和其他人的节奏性令人惊讶的增长。在这里，我们计划研究精神疾病人群。 在对患有SCZ和BP的受试者的初步研究中，我们发现SCZ与显著的 核心时钟基因在PFC区46的分子节律，而BP与 这一区域的节律。此外，我们测量了分离的细胞类型(锥体细胞和 含有小白蛋白(PV)的细胞)从对照组和高血压患者的特定皮质层(3和5) SCZ.我们的数据表明，在这些节律基因的特性和时间上存在着显著的差异 对照受试者的单个细胞类型。此外，患有SCZ的受试者不仅仅是缺乏节律性。 这些细胞，但有完全不同的节律曲线，这表明在 调控这些细胞的分子节律性的转录复合体。在这项研究中，我们将确定 与精神病诊断或特定临床特征相关的分子节律的变化，如 在第46区和第25区中，精神病、情绪和自杀与诊断无关(目标1)。然后我们将确定 这些受试者PFC改变的层次和细胞类型特异性(目标2)。然后我们将测试 特定细胞类型中这些分子节律的破坏与小鼠模型中的行为的功能相关性 (目标3)。这些对人脑分子节律性的开创性研究将是我们 了解节律紊乱如何以如此深刻的方式与精神疾病联系在一起。

Abstract Circadian rhythm and sleep disruptions are a defining feature of psychiatric disorders like Bipolar disorder (BP), schizophrenia (SCZ) and major depressive disorder (MDD). These disruptions to normal rhythmicity include altered sleep/wake cycles, diurnal patterns of hormone levels, and circadian gene expression in peripheral samples. Moreover, disruptions to the normal sleep/wake cycle often precipitate mood and psychotic episodes, and may contribute to deficits in cognitive function. A number of treatments for psychiatric disorders may derive their efficacy through stabilization or amplification of molecular rhythms in the brain. However, the molecular rhythm changes that occur in human brain in subjects with psychiatric diseases remain largely unknown. Measurement of rhythmic gene expression in the human brain is now possible. Two recent studies, including one from our group, demonstrated molecular rhythmicity on a genome-wide scale by employing a “time of death” analysis to order postmortem human brain samples around a 24-hour cycle. The first study by Li et al. found that MDD subjects had major disruptions in molecular rhythms across six different brain regions, including prefrontal cortex (PFC) area 46 and subgenual cingulate (SGC) area 25, compared with comparison subjects. Using the same approach in a cohort of 146 control subjects (ranging in age from 16 to 96 years), we found that two PFC regions exhibited highly significant patterns of rhythmic gene expression. Moreover, we found that normal aging was associated with a significant loss of rhythmicity in a number of transcripts and a surprising gain of rhythmicity in others. Here we plan to study psychiatric disease populations. In preliminary studies of subjects with SCZ and BP we find that SCZ is associated with a marked loss of molecular rhythms of core clock genes in PFC area 46, whereas BP is associated with a phase advance in rhythms in this region. Moreover, we measured molecular rhythms in isolated cell types (pyramidal cells and parvalbumin (PV) containing cells) from specific cortical layers (3 and 5) of control subjects and subjects with SCZ. Our data suggests that there are striking differences in the identity and timing of rhythmic genes in these individual cell types in control subjects. Moreover, subjects with SCZ do not simply have a loss of rhythmicity in these cells, but have a totally different rhythmic profile, suggesting that there are differences in the transcriptional complex that governs molecular rhythmicity in these cells. In this study we will determine changes in molecular rhythms associated with psychiatric diagnoses or specific clinical features such as psychosis, mood and suicide independent of diagnosis in areas 46 and 25 (Aim #1). We will then determine the layer and cell type specificity of changes in the PFC in these same subjects (Aim #2). Then we will test the functional relevance of these molecular rhythms disruptions in specific cell types to behavior in mouse models (Aim #3). These pioneering studies of molecular rhythmicity in the human brain will be central to our understanding of how rhythm disruptions are connected in such a profound way to psychiatric diseases.