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

ABSTRACT Circadian rhythm and sleep disruptions are prevalent in nearly all psychiatry disorders including major depression (MDD), bipolar disorder (BP), and schizophrenia (SZ). Each cell in the brain has its own molecular clock which regulates the rhythmic expression of many different genes, allowing cells to maximize efficiency at times of day in which they are most needed. Importantly, while the core clock does not change from cell to cell, the genes that the clock regulates can be very different in each cell type and the timing in which genes peak can also be highly variable, even with some cells having a completely opposite phases of gene expression. Previous studies by our group and others have established that gene expression rhythms can be reliably measured in human postmortem brain and that molecular rhythms are highly irregular or disrupted in subjects with psychiatric disease. In the first funding cycle, we assessed molecular rhythms in tissue homogenates taken from specific cortical and striatal regions in subjects with major depressive disorder (MDD), bipolar disorder (BP), schizophrenia (SZ), or unaffected comparison subjects. Using mouse models, we also established that molecular rhythms in these regions are important in the regulation of behavior. We also found that particular rhythmic signatures are associated with features like psychosis independent of clinical diagnosis. In this next funding cycle, we will dive deeper to determine the rhythmic signatures of individual cell types and how these work in harmony with others around them to synchronize the brain. We will also determine how these rhythms differ in subjects with MDD, BP, and SZ. We will perform additional analysis to determine if clinical features across diagnosis are related to specific rhythmic patterns and assess ultradian and seasonal rhythms. We will focus on one particular circuit, the subgenual anterior cingulate cortex (sgACC) to nucleus accumbens (NAc), since this circuit is known to be important in the regulation of reward-related decision making, mood, impulsivity, and motivation and compare these regions to the motor cortex. To determine the functional relevance of these molecular rhythm changes in specific cell types we will use mouse models with cell-type specific manipulations of the core molecular clock and rhythms in selected transcripts to determine the impact on both cellular activity and behavior. Taken together, these studies will extend and expand the results obtained during the first funding cycle to give us important insight into rhythm disruptions associated with major psychiatric disease.