Project 8I: Non-photic Entrainment of the Circadian Clock: Role of Methamphetamine

Charles Allen, Ph.D., Principal Investigator

Suprachiasmatic nucleus (SCN) neurons of mammals contain a molecular circadian clock that provides a mechanism to synchronize physiological processes with environmental conditions. Disruption of these circadian rhythms contributes to sleep, metabolic, cardiovascular and affective disorders.

To maintain proper temporal coupling between the circadian clock and the environment, neural systems have evolved to sense changing conditions and communicate that information to the clock. The most important of these environmental signals is light, and the retinohypothalamic tract (RHT), a glutamatergic pathway projecting from the retina to the SCN, is required for the maintenance of temporal coupling between environmental radiance and the circadian clock.

Nonphotic environmental cues can also entrain the circadian clock by pathways that include a serotoninergic projection from the raphe nuclei. Drugs of abuse, including methamphetamine, can disrupt the circadian clock and serve as non-photic entraining signals. Methamphetamine can also induce rhythmic behavior in the absence of a functioning circadian clock. However, the cellular mechanisms responsible for these effects of methamphetamine on the circadian system remain unknown. This lack of knowledge is an impediment to understanding the role that the circadian clock plays in methamphetamine abuse.

The goal of this proposal is to characterize the physiological mechanisms that mediate methamphetamine effects on the photic entrainment of the circadian clock. To this end, we will use electrophysiological and imaging techniques to examine how methamphetamine modulates glutamate release from RHT axon terminals.