Rhythms are ubiquitous in the brain. For humans and all mammals, neural rhythms drive patterns of movements for behaviors such as locomotion, feeding, and breathing. How does the brain generate these motor rhythms that are critical for the sustenance of homeostasis and life itself? We examine this question in the respiratory neural center, which is unique because the rhythm-generating cells and networks can be isolated in reduced preparations from neonatal mice that remain rhythmically active in vitro, and spontaneously produce inspiratory-related motor rhythms, which is advantageous from an experimental perspective. At the network level, we used confocal and two-photon laser-scanning microscopy to make unprecedented measurements of the population size generating respiratory rhythm: an essential core of approximately 180 inspiratory neurons makeup the rhythmogenic respiratory kernel. At the cellular level, we characterized a calcium-activated nonspecific cationic current (ICAN) in inspiratory neurons that underlies bursts of activity that are responsible for the inspiratory phase of the breathing cycle. Unlike many neurobiological systems that depend on voltage-dependent mechanisms and intrinsic bursting, i.e., "pacemaker" neurons, ICAN is evoked synaptically, via biochemical signaling pathways in the context of endogenous network function. Combining these new insights, we assembled a mathematical model of the network, which shows that respiratory rhythm is a form of biological "self organized" behavior. Neurons interact according to simple rules but none possesses a blueprint for the collective behavior that results. Studying a measurable behavior like breathing under controlled in vitro conditions enables us to elucidate general principles linking neurons and synapses to full-scale behaviors. This provides the necessary basis for treatment and prevention of breathing disorders and is generally important in understanding brain function.

SOME RECENT PUBLICATIONS

Pace RW, Mackay, DD, Feldman, JL, Del Negro, CA (2007) Role of Persistent Sodium Current in Mouse PreB?tzinger Complex Neurons and Respiratory Rhythm Generation. J Physiol, accepted pending revision.

Feldman JL, Del Negro CA (2006) Looking for inspiration: new perspectives on respiratory rhythm. Nat Rev Neurosci 7:232-241.

Del Negro CA, Morgado-Valle C, Hayes JA, Mackay DD, Pace RW, Crowder EA, Feldman JL (2005) Sodium and calcium dependent pacemaker neurons and respiratory rhythm generation. J Neurosci 25:446-453.

Del Negro CA, Morgado-Valle C, Feldman JL (2002) Respiratory rhythm: an emergent network property? Neuron 34:821-830.