Schizophrenia (SCZ) is a debilitating psychiatric disorder affecting more than 20 million people worldwide and is a leading cause of disability. Notably, a prominent feature of SCZ is disturbances in circadian rhythms, including altered sleep/wake cycles and disrupted peripheral gene expression and hormone rhythms. While altered peripheral and behavioral rhythms have been implicated in SCZ, it is currently unknown whether molecular rhythms are altered in the human brain, particularly in regions of the cortex and striatum thought to be associated with core symptoms of the disease. Recent studies from our group and others have demonstrated circadian rhythms in gene expression in the human brain by utilizing a ?time of death? (TOD) analysis of postmortem brain tissue, in which gene expression data is organized across a 24-hour clock based on the subject?s time of death. Li and colleagues (2013) performed a TOD analysis of microarray data and found subjects with major depressive disorder show altered rhythms in a variety of cortical and limbic regions. Using a similar approach, our group identified significant gene expression rhythms in the human prefrontal cortex (PFC) and discovered changes in rhythmicity that occur with aging. Preliminary studies from our group have recently extended these findings into psychiatric disease cohorts. Using a TOD analysis of RNA sequencing data from the dorsolateral PFC, we find SCZ subjects have completely different sets of rhythmic genes and a distinct pattern of rhythmic transcripts compared to controls. In this proposal, I aim to study molecular rhythms in two regions of the striatum, the dorsal striatum (DS) and nucleus accumbens (NAc). Alterations in dopamine functioning in the striatum are associated with positive symptoms and psychosis in SCZ. Notably, dopamine acts via striatal dopamine receptors to regulate rhythmic expression of core circadian clock genes in the striatum, suggesting that altered dopamine signaling in SCZ could influence molecular rhythms in the striatum, which may play a role in the circadian abnormalities observed in SCZ. In this proposal, I will first use human postmortem brain tissue to compare gene expression rhythms in the DS and NAc of SCZ versus healthy control subjects. Mice will then be used as an experimental system to determine the functional relevance of molecular rhythms in each of these regions. Given the role of dopamine in regulating striatal rhythmicity, I hypothesize that SCZ subjects will exhibit significant disruptions in molecular rhythms in the DS and NAc compared to control subjects. In mice, I hypothesize that disrupting striatal rhythms will promote SCZ-relevant behaviors. Together, these studies will be the first to measure molecular rhythms in the human striatum of SCZ subjects and are central to understanding how rhythm disruptions in the striatum are linked to disease state. A better understanding of the role of molecular rhythms in SCZ may lead to novel targets for future drug development.
Schizophrenia is a debilitating psychiatric disease affecting more than 20 million people worldwide. This proposal will help uncover changes in molecular rhythms in the human brain that may contribute to the pathophysiology of the disease. A better understanding of these molecular changes may lead to novel targets for future drug development.
