Analysis Tools
mortality/aging
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• mice are born at normal Mendelian ratios but show a gradual reduction in survival from P1 to P3, with most mice dying within 3 days of birth
• surviving mice live to 12 months or longer without obvious physical problems
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cardiovascular system
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• heart rate is stable, rhythmic but slightly reduced at P1
• however, cardiac morphology is grossly normal
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respiratory system
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• whole-body plethysmography revealed severe respiratory arrhythmia with frequent apnea
• however, tidal volume is normal at P1, and mice exhibit a normal hypercapnic ventilatory response with a comparable increase in tidal volume relative to wild-type controls
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• pups exhibit aberrant respiration patterns at P1
• inspiratory time and expiratory time are prolonged under normoxic or hypercapnic conditions
• peak inspiratory flow (PIF) and peak expiratory flow (PEF) are both lower than those in wild-type mice under normoxia
• under hypercapnia, the PEF, but not the PIF, can be rescued to a level similar to that in hypercapnia-treated wild-type mice
• however, lung morphology is grossly normal with properly inflated alveoli
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• pups exhibit significantly reduced respiratory frequency at P1
• under hypercapnic conditions, respiratory frequency can be rescued to a level indistinguishable from that in wild-type littermates under normoxia but slightly less than that in hypercapnia-treated wild-type mice
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• pups exhibit significantly increased apneic episodes and duration at P1
• inhalation of nebulized tiotropium, an anticholinergic bronchodilator, results in partial rescue of the apneic phenotype
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• increased parasympathetic signaling leads to hyperactivated bronchoconstriction, as shown by elevated pulmonary acetylcholine levels and increased phosphorylated myosin light chain 2 signal (denoted by alpha-SMA staining) in bronchial smooth muscles at P1
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nervous system
| N |
• at P1, the pre-Botzinger complex and parafacial respiratory group (pFRG) appear morphologically normal, as shown by the distribution and expression of NK1R, a respiratory rhythm generator (RRG) marker
• in isolated brainstem-spinal cord preparations, the activities of C4 ventral roots are stable and rhythmic, with bursting frequencies similar to those in wild-type preparations
• no obvious alterations are detected in pontine and medullary (nor)adrenergic neurons or in diaphragm neuromuscular junctions
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• increased ChAT expression is restricted to central preganglionic parasympathetic neurons
• no alteration in ChAT expression is noted in airway postganglionic neurons near the dorsal trachea and medial bronchi
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• increased parasympathetic signaling leads to hyperactivated bronchoconstriction and abnormal respiration
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homeostasis/metabolism
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• pulmonary acetylcholine level is significantly increased at P1
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• choline acetyltransferase (ChAT) expression is increased by ~48% in the dorsal motor nucleus of vagus (DMNV)
• however, ChAT levels in the nucleus ambiguus (NA) and the facial motor nucleus (FMN) are not significantly altered
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growth/size/body
| N |
• body weight is normal at E18.5, P0 and P1
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