Liu, Qiuli, and Margaret T. T. Wong-Riley. Postnatal expression of neurotransmitters, receptors, and cytochrome oxidase in the rat pre-Bötzinger complex. J Appl Physiol 92: 923-934, 2002; 10.1152/japplphysiol.00977.2001.-The preBötzinger complex (PBC) is postulated as the center of respiratory rhythmogenesis. Previously, we found a reduction or plateau of cytochrome oxidase (CO) activity in the PBC and other respiratory nuclei at postnatal days 3-4, despite a general increase of CO with age, suggesting a period of synaptic readjustment. The present study examined the expression of CO and a number of neurochemicals in the PBC at closer time intervals. At postnatal days 3-4 and, more prominently, at postnatal day 12, expression of CO, glutamate, and N-methyl-D-aspartate receptor subunit 1 was reduced, whereas expression of GABA, GABAB receptor, glycine receptor, and ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor subunit 2 was increased. These findings are consistent with our hypothesis that decreased CO activity is associated with an increase in inhibitory drive (mediated by GABA and glycine, their receptors, and possibly blockage of Ca 2ϩ entry by glutamate receptor subunit 2) and a decrease in excitatory drive (mediated by glutamate and its receptors). Our findings point to two critical periods during postnatal development of the rat when their respiratory system may be more vulnerable to respiratory insults.N-methyl-D-aspartate receptor subunit 1; glutamate receptor subunit 2; GABAB receptor; neurokinin-1 receptor; glutamate THE MECHANISM OF RESPIRATORY rhythmogenesis is not fully understood, but cumulative evidence suggests that the pre-Bötzinger complex (PBC) may be the center or kernel of respiratory rhythm generation (12,37,38,42). The PBC is located at the rostroventrolateral medulla, ventral to the nucleus ambiguus (NA), and can be anatomically defined by the distribution of immunoreactive neurokinin-1 receptors (NK1R) (15). Removal of only the PBC in the brain stem eliminated respiratory rhythm generation in neonatal rats (42). All six basic types of respiratory neurons were identified in the PBC (9, 42), and neurons with voltagedependent pacemaker-like properties were also found there (6,7,17,22,47). It has been implied that the PBC functions as a central hypoxia chemosensor for respiration (44,45). The application of agonists and antagonists of some neurotransmitters and neuromodulators to the PBC can induce apparent changes in respiratory rhythm and pattern (8,21,34,41,43). However, very little is known about postnatal development of neurochemicals in the PBC when the system may be more vulnerable to respiratory distress.Cytochrome oxidase (CO) is the terminal enzyme of the mitochondrial respiratory chain and is considered to be a reliable marker of neurons' metabolic capacity and levels of functional activity (51). Previously, we found that the PBC and other respiratory nuclei in the rat exhibited a general increase in CO activity with postnatal development. However, there was a distin...

Previously, we found heightened expression of inhibitory neurochemicals and depressed expression of excitatory neurochemicals with a sudden drop in metabolic activity around postnatal day (P) 12 in rat brainstem respiratory nuclei, suggesting that this period is a critical window during which respiratory control or regulation may be distinctly different. To test this hypothesis, the hypoxic ventilatory responses (HVR) to 10% oxygen were tested in rats every day from P0 to P21. Our data indicate that (1) during normoxia (N), breathing frequency (f ) increased with age, peaking at P13, followed by a gradual decline, whereas both tidal volume (V T ) and minute ventilation (V E ) significantly increased in the second postnatal week, followed by a progressive increase in V T and a relative plateau inV E ; (2) during 5 min of hypoxia (H), V E exhibited a biphasic response from P3 onward. Significantly, the ratio ofV E(H) toV E(N) was generally > 1 during development, except for P13-16, when it was < 1 after the first 1-2 min, with the lowest value at P13; (3) the H : N ratio for f , V T andV E during the first 30 s and the last minute of hypoxia all showed a distinct dip at P13, after which the V T andV E values rose again, while the f values declined through P21; and (4) the H : N ratios for f , V T andV E averaged over 5 min of hypoxia all exhibited a sudden fall at P13. The f ratio remained low thereafter, while those for V T andV E increased again with age until P21. Thus, hypoxic ventilatory response is influenced by both f and V T before P13, but predominantly by V T after P13. The striking changes in normoxic ventilation as well as HVR at or around P13, together with our previous neurochemical and metabolic data, strongly suggests that the end of the second postnatal week is a critical period of development for brainstem respiratory nuclei in the rat.

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