Neuronal dendrites exist in an amazing variety of shapes. They consume most of the brain's energy and account for most of the neuronal surface area. The vast majority of synapses are located on dendrites. Over the last decade it has become clear that neuronal dendrites also contain a rich variety of Na+, Ca2+ and K+ channels that can support Na+ and Ca2+ action potentials. The """"""""back-propagating"""""""" Na+ action potential in particular has aroused considerable interest primarily because it could provide a natural mechanism for a feedback signal from the soma to distant synapses about the state of the soma. Back-propagating action potentials could therefore play an important role in facilitating Hebbian synaptic plasticity. Dendritic action potentials could in addition be involved in many physiological and pathological phenomena, including amplification of synaptic currents, learning and memory, ischemia, trauma, epilepsy, and neurodegenerative disorders. But despite many attractive proposals, the function of dendritic action potentials has remained unclear. Bridging the gap between dendritic physiology, brain function and behavior will require experimentation in vivo. For this purpose we recently developed the application of Two- Photon Laser Scanning Microscopy (TPLSM) to in vivo [Ca2+] imaging. TPLSM allows functional imaging at micrometer spatial resolution up to 600 mum deep into the brain. Using TPLSM together with intracellular somatic membrane potential measurements, working in the barrel cortex of the rat, we have previously shown that Na+ action potentials produce [Ca2+] transients in the proximal dendrites of neocortical pyramidal cells. In preliminary studies we developed techniques to measure the dendritic membrane potential in vivo, opening up the study of dendritic excitability in the intact neocortex at a level of detail that was previously reserved for experiments in cell culture and brain slices. As part of the Specific Aims of this proposal we will determine the: mechanisms of Na+ action potential back-propagation in layer 2/3 dendrites; mechanisms and function of excitability in the dendrites of layer 5 pyramidal cells; mechanisms of modulation of dendritic excitability by patterned activity, inhibition, and neuromodulatory systems. These studies will be helped by improvements to existing instrumentation for TPLSM-based physiology in vivo.
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