The influence of the developing circadian system on neuroimmune function and neuropsychiatric behaviors

PROJECT SUMMARY
Approximately 1 in 3 American adolescents have been diagnosed with an anxiety disorder; 3 in 20 with a mood
disorder, with 1 in 3 female adolescents experiencing at least one major depressive episode. The onset of
psychiatric disorders can occur in early life, potentially leading to a reduced quality of life due to a disruption in
emotional, psychological, and/or social development. Mental illness during youth may also result in long-term
consequences, including an increased risk of mental health challenges and diminished quality of life in adulthood.
Inflammation in the central nervous system (neuroinflammation) is thought to underlie anxiety and mood
disorders, yet there remain no broadly effective therapies. The neuroinflammatory pathology may be, in part,
caused by circadian dysregulation of the neuroimmune system. The circadian clock is critical for controlling
biological processes, generating time-of-day differences in gene expression, hormone release, and behaviors;
however, circadian rhythms dampen in psychiatric disorders. Although the percentage of individuals experiencing
psychiatric disorders concomitant with circadian disturbances remains unknown, circadian disruptions and sleep-
wake disturbances are used as diagnosable criteria for neuropsychiatric disorders. Therefore, circadian
dysregulation may be a potential biomarker and signal for early intervention in anxiety- and mood disorder-
related pathology. The immune system is tightly regulated by the circadian clock, and recent evidence
demonstrates circadian regulation of neuroimmune system components: microglia, meninges, and choroid
plexus. Microglia, the primary immune cell of the brain, are rhythmic cells that can trigger a release of
inflammatory molecules when activated, potentially triggering a suite of physiological and behavioral alterations.
The meninges and choroid plexus serve as immune surveillance sites and can also release inflammatory signals
that influence the activity of microglia. Together, these components may provide insights into the pathogenesis
and pathophysiology of mental disorders. However, the ontogeny of circadian rhythms in the neuroimmune
system has not been well-documented. Early developmental periods offer a potential window for intervention
and prevention of neuropsychiatric disorders. Thus, we hypothesize that circadian rhythms in the neuroimmune
system emerge early in life, and perturbations during development will alter neuroimmune function that leads to
behavioral changes. This proposal addresses the following specific aims: First, establish the development of
circadian rhythms in “clock” and inflammatory genes in critical neuroimmune tissues; second, reveal whether
early life environmental and genetic perturbations to the circadian system lead to long-term behavioral changes.
This contribution will be significant because our results will identify temporal windows of high and low
neuroimmune reactivity during development. We expect these results will uniquely combine expertise in
circadian biology, immunology, and behavioral neuroscience to identify a novel role for biological rhythms in
regulating neuroinflammatory pathology and mood-related behaviors via the neuroimmune system.

Grant Number: 5F31MH138131-02
NIH Institute/Center: NIH
Principal Investigator: Kiersten Bell