Spring Forward or Fall Back? Redox State as a Determinant in Glutamate Signaling Pathways Adjusting Our Brain Clock

The suprachiasmatic nucleus (SCN) of the hypothalamus is the master circadian clock in mammals. Nocturnal light, acting via neurotransmitter glutamate, synchronizes this clock to changes in the external environment by adjusting the phase of the SCN. The phase-resetting response depends on the temporal state of the clock: during the early night, light/glutamate delays clock phase, whereas during the late night, clock phase is advanced. Key signaling elements downstream of glutamate have been identified as ryanodine receptor (RyR) and soluble guanylate cyclase (sGC), in the early night and late night, respectively. However, the determinant of this signaling-pathway bifurcation remains unknown. I tested the hypothesis that cellular redox state functions as this determinant. I found that general redox state in the SCN exhibits circadian oscillation. Early night is more oxidized than late night, and daytime shows similar redox state as late night. Changing SCN redox state exogenously inverts the phase resetting response to glutamate. In the early night, changing the redox state with reducing reagents causes glutamate to advance the clock by activating sGC. Conversely, in the late night, oxidizing reagent causes glutamate to induce phase delay by activating RyR. These results demonstrate that cellular redox state is a dynamic variable over the circadian cycle that can profoundly modulate clock functions by altering targets of cell signaling. They indicate that cellular metabolic state may be a key determinant of the state of the circadian clock.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Neuroscience

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2015

Author dc:creator

• Yu, Yanxun

Contributors dc:contributor

• Gillette, Martha U.

• Biology, Neuroscience

Language dc:language

eng

Identifier

(MiAaPQ)AAI3290450

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/82518