Researchers from the University of Pittsburgh School of Medicine, USA present the first evidence of 12-hour cycles of gene activity in the human brain. The study led by Madeline R. Scott, which was published Jan. 24 in the open access journal PLOS Biology, also reveals that some of those 12-hour rhythms are missing or altered in the postmortem brains of patients with schizophrenia.

Patients with schizophrenia are known to have disturbances in several types of 24-hour body rhythms, including sleep/wake cycles, hormone levels, and gene activity in the brain’s prefrontal cortex. However, virtually nothing is known about gene activity in the brain – healthy or not – for cycles shorter than the usual 24-hour circadian rhythm.

Because gene transcript levels cannot be measured in living brains, the new study used an analysis of time of death to look for 12-hour rhythms in gene activity in postmortem brains. They focused on the dorsolateral prefrontal cortex because this part of the brain is associated with cognitive symptoms and other abnormalities in gene expression rhythms seen in schizophrenia.

The researchers found numerous genes in the normal dorsolateral prefrontal cortex that have 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 thus cellular energy supply) peaked in the morning/evening.

In contrast, postmortem brains of patients with schizophrenia contained fewer genes with 12-hour activity cycles, and those related to neural connections were completely missing. In addition, although the mitochondria-related genes maintained a 12-hour rhythm, their activity did not peak at normal times. Whether these abnormal rhythms underlie the behavioral abnormalities in schizophrenia, or whether they result from medications, nicotine use, or sleep disturbances, needs to be explored in future studies.

Co-author Colleen A. McClung added: “We are discovering that the human brain has not only circadian (24-hour) rhythms in gene expression, but also 12-hour rhythms in a number of genes 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 that can lead to suboptimal mitochondrial function at times of the day when cellular energy is most needed.”

Magazine reference

  1. Scott MR, Zong W, Ketchesin KD, Seney ML, Tseng GC, Zhu B, et al. (2023) Twelve-hour rhythms in transcriptional expression in the human dorsolateral prefrontal cortex are altered in schizophrenia. PLoS Biol 21(1): e3001688. DOI: 10.1371/journal.pbio.3001688