Diurnal alterations in gene expression across striatal subregions in psychosis

Background: Psychosis is a defining feature of schizophrenia and highly prevalent in bipolar disorder. Notably, individuals suffering with these illnesses also have major disruptions in sleep and circadian rhythms, and disturbances to sleep and circadian rhythms can precipitate or exacerbate psychotic symptoms. Psychosis is associated with the striatum, though no study to date has directly measured molecular rhythms and determined how they are altered in the striatum of subjects with psychosis. Methods: Here, we perform RNA-sequencing and both differential expression and rhythmicity analyses to investigate diurnal alterations in gene expression in human postmortem striatal subregions (NAc, caudate, and putamen) in subjects with psychosis relative to unaffected comparison subjects. Results: Across regions, we find differential expression of immune-related transcripts and a substantial loss of rhythmicity in core circadian clock genes in subjects with psychosis. In the nucleus accumbens (NAc), mitochondrial-related transcripts have decreased expression in psychosis subjects, but only in those who died at night. Additionally, we find a loss of rhythmicity in small nucleolar RNAs and a gain of rhythmicity in glutamatergic signaling in the NAc of psychosis subjects. Between region comparisons indicate that rhythmicity in the caudate and putamen is far more similar in subjects with psychosis than in matched comparison subjects. Conclusions: Together, these findings reveal differential and rhythmic gene expression differences across the striatum that may contribute to striatal dysfunction and psychosis in psychotic disorders. NAc, caudate, and putamen tissue samples were collected from schizophrenia (SCZ), bipolar disorder (BD), and unaffected comparison subjects obtained through the University of Pittsburgh Brain Tissue Donation Program and the NIH NeuroBioBank. Brain tissue was obtained, following consent from the next of kin, during autopsies conducted at the Allegheny County (Pittsburgh, PA) or Davidson County (Nashville, TN) Medical Examiner’s Office. All procedures were approved by the University of Pittsburgh Institutional Review Board for Biomedical Research and Committee for Oversight of Research and Clinical Training Involving Decedents. An independent committee of experienced clinical research scientists made consensus DSM-IV diagnoses for each subject using structured interviews with family members and review of medical records and toxicology results. The absence of psychiatric diagnoses was confirmed in comparison subjects using the same approach. Subjects were included based on three criteria: 1) known time of death (TOD) within a 4-hour window and meeting the criteria of rapid death; 2) age less than 65 years; 3) postmortem interval (PMI) less than 30 hours. A total of 60 unaffected comparison, 28 SCZ, and 28 BD subjects met these criteria. One subject (ID – 960; BD with psychosis) was removed due to low correlation with the other subjects. Another subject (ID – 1180; BD with psychosis) had low expression data in the NAc and therefore was removed from NAc-specific analyses. Given the high degree of overlap between SCZ and BD with psychosis at the symptomology, genomic, and transcriptomic levels (Gandal et al., 2018; Markota et al., 2018; Enwright and Lewis, 2021), we generated a psychosis cohort (n=36 in caudate and putamen; n=35 in NAc) consisting of SCZ subjects (n=28) and BD with psychosis subjects (n=8 in caudate and putamen; n=7 in NAc). An unbiased method is used to design a matched comparison cohort (n=36) matched to the 36 psychosis subject by sex, race, age, time of death, PMI, and pH.