Evidence is substantial that neurons within the lateral pons play a fundamental role in the neurogenesis, control and modulation of breathing. From the day of birth, perturbation of its neuronal activity significantly alters breathing. The fundamental goal of this proposal is the systematic analysis of the lateral pons, an important but poorly understood region involved in respiratory control. Our preliminary data indicate that a moderately dense corridor of lateral pontine neurons extending ventrally from the parabrachial complex, monosynaptically projects to respiratory neurons within the ventrolateral medulla, i.e., the ventral respiratory group (VRG), generally accepted as a crucial region in the generation of respiratory rhythm and pattern. The specific VRG neurons receiving this input are unclear, as is the nature of the pontine neurons giving rise to this connection. The discharge pattern (tonic or phasic respiratory) of pontine neurons targeting the VRG is not known, nor is the excitatory or inhibitory nature of their transmitters providing synaptic inputs to VRG neurons. Although the contiguous nature of the VRG projecting pontine regions suggests they form a respiratory related macrostructure, distinct anatomical connections for its different segments suggests as many as 5 discrete functional groups. A combination of techniques will be used to address the following Specific Aims. 1) Where are the lateral pontine neurons responsible for controlling inspiratory and expiratory durations and do they exhibit phasic respiratory discharge patterns? 2) Which anatomically defined classes of VRG neurons receive monosynaptic inputs from pontine neurons in each identified region, and what fast amino acid transmitters do they use? 3) Are activity patterns and monosynaptic connections of individual pontine neurons onto specific VRG neurons consistent with their selective role in respiratory rhythm and pattern control as predicted by computational models? Chemical stimulation and inhibition will identify discrete pontine neuron clusters that change the activity of identified VRG neurons and respiratory rhythm. Light and electron micrographic (EM) analysis of anterogradely labeled pontine axons will be combined with retrograde labeling and the presence of neurochemical markers (e.g., neurokinin-1 receptors) to distinguish propriobulbar and bulbospinal VRG neuron subgroups and cranial motoneurons. Cross-correlation analysis and spike-triggered averaging will be used to assess functional associations between respiratory cells of the lateral pons and electrophysiologically defined VRG neurons. ? ? ? ? ? ?
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