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The Journal of Neurophysiology Vol. 86 No. 1 July 2001, pp. 59-74
Copyright ©2001 by the American Physiological Society
1Cellular and Systems Neurobiology Section, Laboratory of Neural Control, National Institute for Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-4455; and 2School of Electrical and Computer Engineering, Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, Georgia 30332-0363
Del Negro, Christopher A.,
Sheree M. Johnson,
Robert J. Butera, and
Jeffrey C. Smith.
Models of Respiratory Rhythm Generation in the
Pre-Bötzinger Complex. III. Experimental Tests of Model
Predictions. J. Neurophysiol. 86: 59-74, 2001. We used
the testable predictions of mathematical models proposed by Butera et
al. to evaluate cellular, synaptic, and population-level components of
the hypothesis that respiratory rhythm in mammals is generated in vitro
in the pre-Bötzinger complex (pre-BötC) by a
heterogeneous population of pacemaker neurons coupled by fast
excitatory synapses. We prepared thin brain stem slices from neonatal
rats that capture the pre-BötC and maintain inspiratory-related motor activity in vitro. We recorded pacemaker neurons extracellularly and found: intrinsic bursting behavior that did not depend on Ca2+ currents and persisted after blocking
synaptic transmission; multistate behavior with transitions from
quiescence to bursting and tonic spiking states as cellular
excitability was increased via extracellular K+
concentration ([K+]o); a
monotonic increase in burst frequency and decrease in burst duration
with increasing [K+]o;
heterogeneity among different cells sampled; and an increase in
inspiratory burst duration and decrease in burst frequency by
excitatory synaptic coupling in the respiratory network. These data
affirm the basis for the network model, which is composed of
heterogeneous pacemaker cells having a voltage-dependent
burst-generating mechanism dominated by persistent
Na+ current
(INaP) and excitatory synaptic
coupling that synchronizes cell activity. We investigated
population-level activity in the pre-BötC using local
"macropatch" recordings and confirmed these model predictions:
pre-BötC activity preceded respiratory-related motor output by
100-400 ms, consistent with a heterogeneous pacemaker-cell population
generating inspiratory rhythm in the pre-BötC; pre-BötC population burst amplitude decreased monotonically with increasing [K+]o (while frequency
increased), which can be attributed to pacemaker cell properties; and
burst amplitude fluctuated from cycle to cycle after decreasing
bilateral synaptic coupling surgically as predicted from stability
analyses of the model. We conclude that the pacemaker cell and network
models explain features of inspiratory rhythm generation in vitro.
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