Despite widespread interest in the neural control of respiration, cellular and molecular mechanisms that mediate afferent transmission from peripheral chemoreceptors to brainstem respiratory neurons remain poorly understood. Recent studies, however, implicate specific classes of neuroactive substances as mediators and modulators of the hypoxic ventilatory response at multiple levels of the neuraxis (the carotid body, petrosal ganglion and medulla). In the periphery, for example, tachykinin peptidergic and dopaminergic elements in the carotid body and petrosal ganglion appear to be critical for shaping chemosensory discharge. Centrally, chemosensory afferents project to regions that contain not only tachykinins and dopamine, but also other molecules known to modulate respiratory output, including opiate peptides and somatostatin. However, the physiologic significance of transmitter heterogeneity in the petrosal ganglion and medulla, and the morphologic and physiologic mechanisms by which most of these neurochemical systems interact are unknown. To approach this issue, the proposed research aims to define anatomic, physiologic and biochemical substrates that underlie synaptic interactions between chemoreceptor afferent neurons in the petrosal ganglion and their peripheral and central targets. Studies in the carotid body, for example, will focus on the role of dopaminergic and tachykinin peptidergic elements in modulating chemosensory function, using immunocytochemical, ultrastructural and neurophysiologic methods. In the petrosal ganglion, biochemical methods will define the role of hypoxia and other stimuli in regulating dopaminergic traits in carotid body afferents. In the nucleus tractus salitarius (nTS), light and electron microscopic methods will be used to identify and characterize synaptic terminals and postsynaptic targets of carotid body afferent neurons. Quantitative receptor autoradiography will be used to correlate the subnuclear distribution of specific receptor subtypes with the distribution of carotid body afferents. These findings will be correlated with physiologic and microiontophoretic studies on the role of tachykinin peptides, dopamine and other neuroactive agents in regulating chemoafferent inputs to Nts. Finally, neuroanatomic and immunocytochemical techniques will characterize transmitter properties expressed by a newly discovered subpopulation of carotid body afferents that project directly to the region of the caudal ventrolateral medulla. These studies are part of a broader long-range effort aimed at understanding neurochemical mechanisms of respiratory control.
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