The body anticipates regular environmental changes – such as the alternation of day and night. This process is controlled by the circadian system – internal biological clocks that coordinate the activity of cells, tissues, and organs throughout the day. In addition, the body must respond to environmental threats – injuries and pathogen exposure. This role is carried out by the immune system, which protects the body from infections and helps maintain tissue homeostasis.
Circadian rhythms are closely linked to immunity. In humans, chronic circadian disruption is associated with an increased risk of inflammatory and autoimmune diseases, as well as diabetes, cardiovascular disease, and cancer. Animal experiments show that disruption of circadian rhythms alters immune responses and may accelerate disease progression.
One brain region that contains molecular circadian clocks is the olfactory bulb. This region is responsible for odor processing. It is located adjacent to the nasal cavity and therefore remains in constant contact with substances from the external environment. Certain viruses – including poliovirus, influenza A virus, and herpes simplex virus – can enter the brain through this route.
The molecular clocks in the olfactory bulb alter neuronal activity with the time of day. In addition, the timing of exposure to a neurotropic virus entering through the nose significantly affects infection severity.
American scientists demonstrated that immune activity in the olfactory bulb changes throughout the day, even in the absence of infection. Genes associated with immune processes show different patterns of activity at different times of day, and microglial activity – the activity of the brain’s immune cells – also fluctuates. In mice, many immune-related genes reached peak activity at the onset of the dark phase, indicating coordinated daily tuning of the immune system.
The researchers also investigated how time of day affects the brain’s response to a virus-like stimulus – intranasal poly(I:C), a substance that mimics viral RNA. When exposure occurred at the beginning of the dark phase, the type I interferon (IFN) response was activated more rapidly than at the beginning of the light phase.
Thus, daily fluctuations in immune activity may precondition the olfactory bulb for potential encounters with viruses.
Circadian Rhythms Coordinate Immune Processes in the Olfactory Bulb
The researchers investigated whether the activity of genes associated with neuroinflammation changes in the mouse olfactory bulb throughout the day. Approximately 30% of the analyzed transcripts displayed rhythmic expression. Daily oscillations were also confirmed for key circadian clock genes – Per2 and Nr1d1.
Rhythmic transcripts were associated with various biological processes, including growth and development, neuronal signaling, apoptosis, and immune function. Activity peaks for these genes occurred at different times of day.
The most important finding was that transcripts associated with immune processes reached maximal activity at the onset of the dark phase. During this period, expression of genes involved in the innate antiviral response and cytokine signaling increased.
Thus, with the onset of darkness, the olfactory bulb enters a state of heightened readiness for antiviral defense.
Time of Day Alters the Antiviral Response of the Olfactory Bulb
The researchers examined how the time of day affects the olfactory bulb’s response to intranasal poly(I:C) – a synthetic analog of viral RNA.
When poly(I:C) was administered to mice at the beginning of the dark phase, expression of genes associated with IFN-I signaling and antiviral defense increased within 3–12 hours. In contrast, when exposure occurred at the beginning of the light phase, the activity of immune-related genes transiently decreased.
After 24 hours, the differences between the mouse groups had nearly disappeared – antiviral mechanisms were activated in both cases.
Thus, at the onset of the dark phase, the olfactory bulb’s immune system responds more rapidly to viral stimuli.
Microglia Are Sensitive to Circadian Rhythms
The researchers analyzed which cells in the olfactory bulb contributed most strongly to daily fluctuations in immune activity. The largest proportion of rhythmically expressed genes – 37% – was associated with microglia.
In addition, the scientists identified rhythmic gene expression in the microglial sensome – the receptor system through which microglia detect damage and inflammatory signals.
These findings indicate that microglial functions and responses in the olfactory bulb vary with time of day.
