Twelve-hour rhythms in the human dorsolateral prefrontal cortex (DLPFC) are abnormal in schizophrenia. Created with biorender.com. [Colleen A. McClung (CC-BY 4.0, https://creativecommons.org/licenses/by/4.0/)]

Researchers at the University of Pittsburgh School of Medicine have reported the first evidence of 12-hour cycles of gene activity in the human brain. The study, which evaluated gene expression in postmortem brain tissue, indicated that some of those 12-hour rhythms are missing or altered in the postmortem brains of patients with schizophrenia, when compared with brain tissue from individuals with no psychiatric diagnosis.

Colleen A. McClung, PhD, a co-author of the team’s published paper in PLOS Biology, said, “We find that the human brain has not only circadian (24 hour) rhythms in gene expression but also 12-hour rhythms in a number of genes that are important for cellular function and neuronal maintenance. Many of these gene expression rhythms are lost in people with schizophrenia, and there is a dramatic shift in the timing of rhythms in mitochondrial-related transcripts which could lead to suboptimal mitochondrial function at the times of day when cellular energy is needed the most.”

The researchers, led by Madeline R. Scott, PhD, reported on their results in a paper titled “Twelve-hour rhythms in transcript expression within the human dorsolateral prefrontal cortex are altered in schizophrenia,” in which they commented, “These findings indicate that 12 h rhythms in the brain are associated with processes necessary for essential cellular functions—and may be fundamental for timing processes to maximize resources and reserve energy when not needed … Future studies will determine the functional consequences of these findings to optimal brain health and the pathophysiology of brain disorders.”

Biological rhythms allow organisms ranging from bacteria to humans to anticipate and respond to changes in their environments across the light/dark cycle, the authors explained. “These rhythms occur on many scales, from seasons to days to hours, and the importance of circadian rhythms in health and disease has become increasingly clear over the past few decades, particularly in the context of psychiatric illnesses.”

However, virtually nothing is known about gene activity in the brain—healthy or not—for cycles that are shorter than the usual 24-hour rhythms. Twelve-hour (12 h) ultradian rhythms have long been observed in coastal marine animals, which have to align their behavior with the ocean tides. Recent studies have also identified 12 hour rhythms in the expression of genes among animals including the roundworm model organism, C. elegans, mice, and olive baboons, the team noted. “Various aspects of human behavior (sleep patterns, cognitive performance) and physiology (body temperature, blood pressure, migraine onset, circulating hormone levels) also exhibit 12 h rhythms,” they noted. However, no study has yet measured 12 h rhythms in the human brain, and it is unknown whether processes that demonstrate 12 h rhythms are regulated by molecular ultradian rhythms. “Far less is known about ultradian rhythms, including how prevalent they are in the human brain, and whether they are disrupted in subjects with psychiatric disorders,” the investigators stated. “Therefore, characterization of the human brain ultradian transcriptome will expand our understanding of transcript expression rhythms in the brain and their contribution to dysfunction in subjects with abnormalities in brain function.”

Schizophrenia (SZ) is a chronic neuropsychiatric illness that affects over 20 million people worldwide and is a leading cause of disability, they continued. Patients with schizophrenia, for example, are known to have disturbances in several types of 24-hour circadian body rhythms, including sleep/wake cycles, hormone levels, and gene activity in the prefrontal cortex of the brain. To search for 12-hour transcriptional rhythms in the postmortem brains of schizophrenia patients, the team used an approach known as time-of-death (TOD) analysis, in which gene expression data are organized across a 24 h clock based on the time of day of the subject’s death. This method can help to identify significant changes in gene expression rhythm patterns associated with specific brain regions. For their study the team focused on the dorsolateral prefrontal cortex (DLPFC), because this region of the brain is associated with cognitive symptoms and other abnormalities in gene expression rhythms that have been observed in schizophrenia.

Their studies found 12 h rhythms in transcripts that either peak at sleep/wake transitions (approximately 9 AM/PM) or static times (approximately 3 PM/AM) in the dorsolateral prefrontal cortex of the brain from individuals with no psychiatric diagnosis (NP). They identified numerous genes in this region of the brain that exhibited such 12-hour rhythms in activity. Among them, gene activity levels related to building connections between neurons peaked in the afternoon/night, while those related to mitochondrial function (and therefore cellular energy supply) peaked in the morning/evening.

In contrast, postmortem brains from patients with schizophrenia contained fewer genes with 12-hour activity cycles, and those related to neural connections were missing entirely. “… to our knowledge, this study is the first to identify 12 h rhythms in transcript expression in the human brain,” the team noted. “These rhythms are associated with fundamental cellular processes … However, in SZ, there is a strong reduction in the number of transcripts with 12 h rhythms … Subjects with schizophrenia (SZ) lose 12 h rhythms in genes associated with the unfolded protein response and neuronal structural maintenance.” Additionally, although the mitochondria-related genes in the schizophrenia brain samples did maintain a 12-hour rhythm, their activity did not peak at the normal times. In the schizophrenia brain, the team found, genes involved in mitochondrial function and protein translation, which normally peak at sleep/wake transitions, peaked instead at static times “… suggesting suboptimal timing of these essential processes.”

Whether these abnormal rhythms underly the behavioral abnormalities in schizophrenia, or whether they result from medications, nicotine use, or sleep disturbances should be examined in future studies, the team stated. “Our findings best align with the idea of a dedicated 12 h clock, but future work in cell and animal models will be necessary to confirm this.”

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