The rotation of the Earth provides one of the most salient environmental signals: the circadian (daily) alternation of night and day. Nearly all terrestrial organisms, from single-celled to multi-cellular species, possess internal biological clocks allowing for synchronization of internal processes with the environment. In mammals (including humans), a master circadian clock in the brain synchronizes other clocks throughout the brain and body, maintaining temporal organization in the whole organism. The importance of these clocks becomes apparent during times of temporal disruption, with the degradation of circadian rhythms associated with numerous negative health effects. However, to fully understand how "broken" clocks cause negative effects, understanding how they promote optimal function under normal circumstances is necessary. The goal of this research is to understand how circadian clocks promote normal functioning of brain circuits important in complex behaviors like decision making, attention, and cognitive flexibility. A mouse model is used to investigate how normal or disrupted circadian rhythms regulate the size, shape, and function of neurons in the brain, and how these changes affect cognition. Advanced techniques in the measurement of brain chemistry, imaging, 3-dimensional reconstruction of neurons, and pharmacology is used to help understand how circadian clocks maintain normal function, and how disrupted clocks lead to negative outcomes. An integral component of this award engages rural and urban undergraduate students in outreach involving the Mobius Science Center and Children's Museum in Spokane, helping increase awareness of how biological clocks affect physiological function, from the simplest organisms, to our own brain.
Significant inroads have been made in understanding the cellular and molecular function of the suprachiasmatic nucleus (SCN) circadian clock. However, the fundamental role of circadian rhythms in brain areas underlying complex behaviors, such as the prefrontal cortex (PFC), remains illusive. Using environmental circadian disruption as a tool, this research determines how circadian rhythms modulate normal PFC function at the behavioral, physiological, structural, and biochemical levels. This research builds upon our findings that circadian disruption impairs cognitive flexibility and causes atrophy of PFC neurons. The overarching hypothesis of this project is that circadian rhythms promote normal PFC function primarily through modulation of glutamatergic signaling, since glutamate is crucial for optimal PFC function. Circadian disruption effects on the PFC is determined by examining PFC mediated behaviors, and through the use of implantable biosensors to determine effects on extra-cellular PFC glutamate in real time. To establish a causal role for glutamate, pharmacological manipulation of PFC AMPA and NMDA signaling is undertaken. Confocal microscopy and 3-D reconstruction of PFC neurons is used to investigate circadian changes in neural morphology and dendritic spines, primary sites of excitatory signaling. Biochemical studies determine how normal and abnormal circadian rhythms drive membrane trafficking of glutamate receptors, providing another substrate on which circadian rhythms may act to modulate PFC function. The third and final experimental aim is to determine whether changes in a rhythmic hormone (corticosterone) mediates these effects, which would provide a mechanism by which normal and disrupted timing cues are relayed to extra-SCN brain regions.
