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Michael Nitabach Assistant Professor of Cellular & Molecular Physiology J.D. 1998 New York University Ph.D. 1995 Columbia University B.A. 1988 University of Pennsylvania

"Genes, Clocks, and Neurons: Molecular Genetics and Systems Physiology of Animal Behavior"

Our laboratory applies cellular, molecular, and genetic approaches to the question of how neuronal physiological properties determine the information processing characteristics of neural networks. As a model system for exploring this fundamental question of neurobiology, we study the neural circuit that controls daily circadian rhythms of rest and activity in the fruit fly, Drosophila melanogaster. Each of the clock neurons in this circuit has the capacity to oscillate autonomously with a circadian rhythm even in the absence of environmental cues of the passage of time. Under normal circumstances, however, these autonomous oscillators coordinate via intercellular communication of phase information throughout the circuit.

Figure Legend: Immunodetection of epitope-tagged calcium buffer protein genetically targeted to Drosophila clock neurons.

We address two main questions about neural control of circadian rhythms: (1) What are the physiological mechanisms underlying autonomous cellular oscillation of clock neurons?
(2) What are the physiological mechanisms that mediate intercellular communication of clock phase?

We take a hybrid approach to these questions. We manipulate the physiological properties of clock neurons in directed ways by genetically targeted cell-specific expression of engineered proteins in transgenic flies. These engineered proteins include ion channel subunits, intracellular ionic buffers, signaling enzymes, and membrane-tethered peptide neurotoxins that target specific ion channel subtypes. Subsequently, we measure the effects of these manipulations on circadian behavioral rhythms in intact flies, as well as on various physiological parameters of the clock neurons using cell biological, neurophysiological, and calcium imaging techniques.

Using this hybrid approach, we have most recently been exploring the hypothesis that a plasma membrane-delimited feedback loop involving calcium entry through voltage-gated calcium channels and consequent cytoplasmic calcium signals is an essential element of the mechanism for cellular circadian oscillation.

Selected recent publications:

Nitabach, M. N., Blau, J., and Holmes, T. C. (2002). Electrical silencing of Drosophila pacemaker neurons stops the free-running circadian clock. Cell 109, 485-495.

Nitabach, M. N., Holmes, T. C., and Blau, J. (2005). Membranes, ions, and clocks: testing the njus-sulzman-hastings model of the circadian oscillator. Methods Enzymol 393, 682-693.

Michael.Nitabach@yale.edu