This proposal is to study the neurobiological mechanisms underlying the transmission of respiratory drive to the diaphragm. Respiratory rhythm is generated in the brainstem, with the drive transmitted to spinal motoneurons via bulbospinal neurons, which have three target populations in spinal cord: I - Phrenic, intercostal and abdominal motoneurons; II - Propriospinal neurons in the upper cervical spinal cord; III - Segmental interneurons in the cervical and thoracic spinal cord. The relative importance of projections to each of these targets sites in determining the discharge of a given motoneuron is yet to be determined. We will focus on the monosynaptic projection to phrenic motoneurons. Our analysis will exploit the facile localization of bulbospinal respiratory neurons in the brainstem and of phrenic motoneurons in the spinal cord and their clear separation (greater than 20 mm in cat, greater than 10 mm in adult rat and greater than 2 mm in neonatal rat). The following questions will be addressed: 1 - What are the microanatomical, morphological and immunohistochemical characteristics of the descending monosynaptic projection to phrenic motoneurons? With neuroanatomical and immunohistochemical techniques, we propose to a) determine the neuromessengers localized within identified bulbospinal synaptic terminals; b) determine the neuromessengers localized in synapses of other inputs. 2 - What neuromessengers are released at the presynaptic terminals of descending bulbospinal neurons? We have preliminary evidence that an excitatory amino acid or related small peptide may be involved. What are the mechanisms of their pre- and post-synaptic action? These questions will be addressed in physiological and pharmacological studies in vivo and in vitro. This proposal represents a coordinated multidisciplinary approach, with descriptive studies providing the basis for specific experimental tests of factors influencing the behavior of phrenic motoneurons. Understanding the transmission of respiratory drive to motoneurons is of considerable importance in defining the mechanisms responsible for respiratory homeostasis and for pathologies where ventilatory failure results from the inability to generate the appropriate motor output. Moreover, we will be able to characterize in detail the relationship between a population of motoneurons and the premotoneurons providing their rhythmic drive. We will benefit greatly in this analysis by the physical separation of these populations and the ability to readily isolate each one from the other. Thus, we should be able to provide information relevant to the control of other important rhythmic motor acts such as locomotion mastication and nystagmus.
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