My laboratory studies two major questions in circadian neurobiology using the model system Drosophila.
First, we ask how circadian timing information is organized in neuronal circuits to regulate daily behavior. In Drosophila, a small (150) complement of neuronal pacemakers in the fly brain have special dedication to circadian timekeeping and control daily rhythmic locomotor behavior. Using novel imaging methods in collaboration with Tim Holy (Neuroscience, WUMS) to measure calcium levels brain-wide in vivo over 24 hr, we found that different circadian pacemaker groups are sequentially active at precise times of day. These represent different temporal outputs of the circadian pacemaker circuit, presumably controlling different physiological functions, (e.g., sensory, motor, integrative functions). Thus the circadian timing circuit of the fly brain produces multiple timing cues across the 24 hr cycle: we aim to define the respective downstream circuits controlled by these different circadian output elements and to define the endpoints they gate.
The sequential activation pattern is unexpected because these dynamic calcium oscillations depend on the circadian molecular clock within each pacemaker which runs synchronously across the network. Thus the second area we study is the cellular and molecular basis for decoding synchronous circadian timing system into staggered neuronal activation patterns. Predominantly, the transformation results from a series of suppressive signals within the network, representing numerous cell interactions mediated by neuropeptides. Morning appears to be the cardinal phase for neuronal activation, and all pacemaker groups except the canonical “Morning Pacemakers” are delayed by many hours via neuropeptide-mediated suppression of their calcium levels. The novel, long-lasting and pervasive nature of these suppressive signals prompt us to study the signaling details by which neuropeptides (like PDF) regulate calcium levels. We have shown that activation of the receptor for PDF (a GPCR) generates cAMP via certain adenylate cyclases, and that receptivity to PDF is itself daily rhythmic, with a peak at dawn (which is when behaviorally-functional signaling takes place). Further the rhythm of sensitivity is gated by the small GTPase Ral A. Ultimately we would like to understand how this GPCR signals to control the phases of daily calcium peaks in different pacemaker neurons.