The sudden infant death syndrome (SIDS) remains the leading cause of postnatal infant mortality in the USA. Increasing evidence indicates that SIDS is due to a failure of autoresuscitation, which is a protective brainstem response to asphyxia or severe hypoxia. An essential mechanism for autoresuscitation is gasping, a respiratory motor pattern which is distinct from the normal respiration occurring in normoxia. However, despite considerable relevance, the question how gasping is generated by the nervous system remains largely unknown. Transections at the pontomedullary junction transforms the motor pattern for normal respiration into gasping (Lumsden, 1923), which suggested to some researchers that different forms of breathing are generated by separate """"""""centers"""""""" and that gasping is generated in the medulla. Using a slice preparation from the medulla of mice we demonstrated that the isolated respiratory network in the pre-Botzinger complex (PBC) generates not only one, but three forms of fictive respiratory activities with striking similarities to normal respiratory, sigh and gasping activity. Like in vivo, these three activities are generated in a stereotypic manner during the response to anoxia: An initial augmentation in the frequency of normal respiratory and sigh activities is followed by a depression and the generation of gasping. Our network characterization indicates that all three activities are generated by the reconfiguration of the same neuronal network located within the PBC. The proposed research aims at examining the cellular mechanisms that lead to the reconfiguration of the respiratory network. We specifically test the hypothesis that the transition from normal respiratory activity into gasping is associated with a change in the organization of the respiratory network: In normal respiratory activity pacemaker neurons are fully integrated in a network of inhibitory and excitatory non-pacemaker neurons. In gasping most nonpacemaker and calcium-dependent pacemaker neurons inactivate and only a small population of pacemaker neurons remains active that become essential for rhythm generation. We propose three Aims to examine this hypothesis:
Aim 1 compares the synaptic modulation of pacemaker and non-pacemaker neurons, Aim 2 investigates the differential modulation of ion channel properties in pacemaker and non-pacemaker neurons and Aim 3 proposes connectivity experiments to directly test the anoxia-induced changes in the network organization. By bridging different levels of integration the proposed research will lead to a better understanding of the neuronal mechanisms that underlie normal respiratory and gasping activities. Understanding how anoxia leads to the reconfiguration of neuronal network activity is of great general interest as every year numerous victims suffer brain damage from hypoxic insults. In the context of SIDS, our research may ultimately lead to a better understanding why certain infants fail to autoresuscitate.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL060120-06
Application #
6697278
Study Section
Special Emphasis Panel (ZRG1-IFCN-4 (02))
Program Officer
Twery, Michael
Project Start
1998-12-07
Project End
2007-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
6
Fiscal Year
2004
Total Cost
$228,750
Indirect Cost
Name
University of Chicago
Department
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Viemari, Jean-Charles; Garcia 3rd, Alfredo J; Doi, Atsushi et al. (2013) ?-Noradrenergic receptor activation specifically modulates the generation of sighs in vivo and in vitro. Front Neural Circuits 7:179
Carroll, Michael S; Viemari, Jean-Charles; Ramirez, Jan-Marino (2013) Patterns of inspiratory phase-dependent activity in the in vitro respiratory network. J Neurophysiol 109:285-95
Crone, Steven A; Viemari, Jean-Charles; Droho, Steven et al. (2012) Irregular Breathing in Mice following Genetic Ablation of V2a Neurons. J Neurosci 32:7895-906
Viemari, Jean-Charles; Garcia 3rd, Alfredo J; Doi, Atsushi et al. (2011) Activation of alpha-2 noradrenergic receptors is critical for the generation of fictive eupnea and fictive gasping inspiratory activities in mammals in vitro. Eur J Neurosci 33:2228-37
Hill, Andrew A; Garcia 3rd, Alfredo J; Zanella, Sebastien et al. (2011) Graded reductions in oxygenation evoke graded reconfiguration of the isolated respiratory network. J Neurophysiol 105:625-39
Ramirez, Jan-Marino (2011) The human pre-Bötzinger complex identified. Brain 134:8-10
Ramirez, Jan-Marino; Koch, Henner; Garcia 3rd, Alfredo J et al. (2011) The role of spiking and bursting pacemakers in the neuronal control of breathing. J Biol Phys 37:241-61
Koch, Henner; Garcia 3rd, Alfredo J; Ramirez, Jan-Marino (2011) Network reconfiguration and neuronal plasticity in rhythm-generating networks. Integr Comp Biol 51:856-68
Doi, Atsushi; Ramirez, Jan-Marino (2010) State-dependent interactions between excitatory neuromodulators in the neuronal control of breathing. J Neurosci 30:8251-62
Doi, Atsushi; Ramirez, Jan-Marino (2008) Neuromodulation and the orchestration of the respiratory rhythm. Respir Physiol Neurobiol 164:96-104

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