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Articles in PresS, published online ahead of print November 16, 2001
J Appl Physiol, 10.1152/jap.00609.2001
Submitted on June 14, 2001
Accepted on November 9, 2001
1 Environmental Health Sciences, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
2 Physiology and Biophysics, Howard University College of Medicine, Washington, DC, USA
3 Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
* To whom correspondence should be addressed. E-mail: drclarke{at}welchlink.welch.jhu.edu.
Genetic determinants confer variation between inbred mouse strains with respect to the magnitude and pattern of ventilation associated with acute hypercapnic challenge. Specifically, inheritance patterns derived from low responsive C3H/HeJ (C3) and high responsive C57BL/6J (B6) mouse strains suggest that differential hypercapnic ventilatory sensitivity (HCVS) is controlled by as few as two independent genes. In addition, the present study tests whether or not differential neuronal activity in respiratory control regions of the brain is positively associated with strain variation in HCVS between C3 and B6 mice. Using whole-body plethysmography, the magnitude and pattern of ventilation were assessed in C3 and B6 strains at baseline (room air) and during 30 min of inspired normoxic hypercapnia (FICO2 = 0.15, FIO2 = 0.21 in N2). Subsequently, in situ hybridization histochemistry was performed to determine changes in c-fos gene expression in the commissural subnucleus of the nucleus tractus solitarius (nTS). During hypercapnic exposure, breathing frequency (f) and tidal volume (VT) were significantly (P < 0.01) different between strains; C3 mice consistently demonstrated a slow, deep breathing pattern relative to a rapid, shallow phenotype of B6 mice. CO2-induced increase in c-fos gene expression (i.e. number of silver grains per neuron) was significantly (P < 0.01) greater in nTS regions of B6 compared to C3 mice. During room air exposure, c-fos gene expression was not different between mouse strains. In this genetic model of differential HCVS, the results suggest that a genomic basis for varied hypercapnic chemoreception or transduction confers greater afferent neuronal activity within the caudal nTS for high responsive B6 mice compared to low responsive C3 mice as measured by c-fos gene expression.
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