Mutual coupling of neurons in the circadian master clock: What we can learn from fruit flies.

Circadian master clocks in the brain consist of multiple neurons that are organized into populations with different morphology, physiology, and neuromessenger content and presumably different functions. In most animals, these master clocks are distributed bilaterally, located in close proximity to the visual system, and synchronized by the eyes with the light-dark cycles of the environment. In mammals and cockroaches, each of the two master clocks consists of a core region that receives information from the eyes and a shell region from which most of the output projections originate, whereas in flies and several other insects, the master clocks are distributed in lateral and dorsal brain regions. In all cases, morning and evening clock neurons seem to exist, and the communication between them and other populations of clock neurons, as well as the connection across the two brain hemispheres, is a prerequisite for normal rhythmic function. Phenomena such as rhythm splitting, and internal desynchronization are caused by the "decoupling" of the master clocks in the two brain hemispheres or by the decoupling of certain clock neurons within the master clock of one brain hemisphere. Since the master clocks in flies contain relatively few neurons that are well characterized at the individual level, the fly is particularly well suited to study the communication between individual clock neurons. Here, we review the organization of the bilateral master clocks in the fly brain, with a focus on synaptic and paracrine connections between the multiple clock neurons, in comparison with other insects and mammals.