Homeostatic regulation of blood gases and pH requires precise control of ventilation. The central nervous system (CNS) shapes and modulates the rhythmic activity pattern of the respiratory musculature for appropriate ventilation. The long term goal of this laboratory is to explain the genesis, control, development and adaptation of respiratory pattern in terms of the cellular, synaptic and network properties of identified neurons in the CNS. Determination of the mechanisms underlying breathing movements is basic to understanding human physiology and the pathophysiology of many diseases. Development of prophylaxis and treatment of such diseases as sudden infant death syndrome, apnea of prematurity, central alveolar hypoventilation, congenital central hypoventilation syndrome and other forms of respiratory failure critically depend on such knowledge. THIS PROPOSAL ADDRESSES SEVERAL ISSUES OF FUNDAMENTAL IMPORTANCE IN THE NEURAL CONTROL OF BREATHING: 1. A possible site for rhythmogenesis- We have found a region in the ventral medulla (pre- Botzinger Complex) that is critical for rhythmic breathing in neonatal rats; work from other laboratories supports this view. We will investigate this region in adult rat and cat by determining key properties of constituent neurons and the effect of perturbations of local neuronal activity on overall respiratory motor outflow. We will trace the connections of pre-BotC neurons to identify its interactions with other brainstem respiratory nuclei. 2. Production of phase transitions- The orderly transition between phases is a key component of the respiratory cycle, and basic to respiratory rhythm. We will use a novel experimental paradigm to study the underlying mechanisms by comparing neuronal behavior in cycles with normal phase transitions to cycles with severely perturbed phase transitions, i.e. apneusis. We will focus on 3 brainstem areas: i) the Kolliker-Fuse and parabrachial nuclei, referred to as the pontine respiratory group (PRG), ii) the retrotrapezoid nucleus, and; iii) the pre- Botzinger Complex. 3. Organization of the ventral respiratory group (VRG)- The VRG is the largest respiratory neuron population in the medulla. We will determine the network and pharmacological microorganization of the VRG to understand its role in the formation of the complex precisely coordinated spatiotemporal pattern of respiratory motor outflow. 4. Source/pharmacology of the inspiratory and expiratory drives to respiratory motoneurons- the medullary origins of likely amino acid mediated transmission of fast excitatory and inhibitory drive to spinal respiratory motoneurons and medullary premotoneurons will be determined. We will then perform double-labeling immunohistochemistry to determine whether non-amino acid neuromessengers are colocalized with glutamate, GABA ore glycine within these cells. In summary, this proposal is to study several fundamental aspects of the problem of CNS generation of respiratory rhythm and pattern and test specific hypotheses. Our multidisciplinary approach may provide further evidence that these hypotheses are reasonable or (better yet) disprove them. In the latter case, data relevant to the formation of new hypotheses will be obtained. We will also (further) delineate the connections among brainstem regions likely to be involved in respiratory control, and the neuromessengers used to transmit signals in each identified pathway. We believe that in all cases, significant new knowledge will be gained.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Method to Extend Research in Time (MERIT) Award (R37)
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University of California Los Angeles
Schools of Medicine
Los Angeles
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Tan, Wenbin; Janczewski, Wiktor A; Yang, Paul et al. (2008) Silencing preBotzinger complex somatostatin-expressing neurons induces persistent apnea in awake rat. Nat Neurosci 11:538-40
Mellen, Nicholas M; Roham, Maryam; Feldman, Jack L (2004) Afferent modulation of neonatal rat respiratory rhythm in vitro: cellular and synaptic mechanisms. J Physiol 556:859-74
Feldman, Jack L; Mitchell, Gordon S; Nattie, Eugene E (2003) Breathing: rhythmicity, plasticity, chemosensitivity. Annu Rev Neurosci 26:239-66
Mellen, Nicholas M; Milsom, William K; Feldman, Jack L (2002) Hypothermia and recovery from respiratory arrest in a neonatal rat in vitro brain stem preparation. Am J Physiol Regul Integr Comp Physiol 282:R484-91
Mellen, N M; Feldman, J L (2001) Phasic vagal sensory feedback transforms respiratory neuron activity in vitro. J Neurosci 21:7363-71
Mellen, N M; Feldman, J L (2000) Phasic lung inflation shortens inspiration and respiratory period in the lung-attached neonate rat brain stem spinal cord. J Neurophysiol 83:3165-8
Gray, P A; Rekling, J C; Bocchiaro, C M et al. (1999) Modulation of respiratory frequency by peptidergic input to rhythmogenic neurons in the preBotzinger complex. Science 286:1566-8
Rekling, J C; Feldman, J L (1998) PreBotzinger complex and pacemaker neurons: hypothesized site and kernel for respiratory rhythm generation. Annu Rev Physiol 60:385-405
Funk, G D; Johnson, S M; Smith, J C et al. (1997) Functional respiratory rhythm generating networks in neonatal mice lacking NMDAR1 gene. J Neurophysiol 78:1414-20
Dobbins, E G; Feldman, J L (1995) Differential innervation of protruder and retractor muscles of the tongue in rat. J Comp Neurol 357:376-94

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