Linking molecular, electrical, and behavioral rhythms in the brain’s biological clock

Abstract

Understanding the relationship between gene networks, neurons, and circuits that determine behavior is a fundamental problem in neuroscience. The brain’s biological clock – the suprachiasmatic nucleus (SCN) – is an excellent model system in which to study this crucial problem. SCN neurons possess daily molecular transcriptional/translational feedback loops and exhibit rhythms in spontaneous action potential frequency. The synchronized output of the SCN neural network ultimately dictates circadian behavior and physiology. A key unsolved question in circadian neurobiology is how these rhythms interact to form a coherent pacemaker. To address this question, I combined electrophysiology, real-time imaging of gene expression, SCN-specific optogenetic manipulation of neuronal firing, and monitoring of locomotor activity to elucidate the links between the molecular and electrical rhythms that comprise the brain’s biological clock and their circadian behavioral output. I found that optogenetic induction or suppression of firing rate within SCN neurons is sufficient to reset the phase and alter the period of the molecular clockworks, that this resetting requires action potentials and network communication, and that in vivo optogenetic stimulation of the SCN entrains locomotor activity rhythms. Additionally, the expression of the clock gene Period1 is necessary for the coordination of molecular and electrical rhythms in SCN neurons. Thus, I conclude that there is a bidirectional relationship between circadian rhythms in gene expression and electrical activity in SCN neurons such that firing rate is both an output of and an input onto the molecular clock.