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疾病的定义特征 (BP)、精神分裂症（SCZ）和重度抑郁症（MDD）。这些对正常节律的破坏 包括改变的睡眠/觉醒周期，激素水平的昼夜模式， 外周样本此外，正常睡眠/觉醒周期的中断通常会引发情绪， 精神病发作，并可能导致认知功能缺陷。一些精神病治疗 疾病可以通过稳定或放大脑中的分子节律来获得它们的功效。 然而，在患有精神疾病的受试者中发生在人脑中的分子节律变化仍然存在， 大部分未知。测量人类大脑中的节律基因表达现在是可能的。最近的两 包括我们小组的一项研究在内，通过以下方式证明了全基因组范围内的分子节律性： 采用“死亡时间”分析，以24小时为周期对死后人脑样本进行排序。的 Li等人的第一项研究发现，MDD受试者在六种不同的分子节律中存在重大干扰， 大脑区域，包括前额叶皮层（PFC）46区和膝下扣带回（SGC）25区， 对比对象。在146名对照受试者（年龄从16岁到18岁不等）中使用相同的方法。 到96岁），我们发现两个PFC区域表现出高度显着的节奏基因表达模式。 此外，我们发现，正常衰老与许多人的节律性显著丧失有关。 另一些则有惊人的节奏感。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 PFC区46的核心时钟基因的分子节律，而BP与PFC区46的相位提前相关。 该地区的节奏。此外，我们测量了孤立细胞类型（锥体细胞和 来自对照受试者和患有以下疾病的受试者的特定皮质层（3和5）的含有小清蛋白（PV）的细胞） SCZ。我们的数据表明，在这些细胞中，节律基因的身份和时间存在着惊人的差异。 单个细胞类型。此外，患有SCZ的受试者不仅仅是节奏性丧失， 这些细胞，但有一个完全不同的节奏，这表明有差异，在 在这些细胞中控制分子节奏的转录复合物。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变化， 在第46和25区，精神病、情绪和自杀与诊断无关（目标1）。然后我们将决定 这些相同受试者PFC变化的层和细胞类型特异性（目标#2）。然后我们将测试 在小鼠模型中，特定细胞类型中的这些分子节律破坏与行为的功能相关性 (Aim#3）。这些关于人类大脑分子节律性的开创性研究将是我们研究的核心。 了解节律紊乱是如何以如此深刻的方式与精神疾病联系在一起的。

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.