The normal breathing rhythm in mammals is hypothesized to be generated by neurokinin-1 receptor (NK1R)-expressing neurons in the preBötzinger complex (preBötC), a medullary region proposed to contain the kernel of the circuits generating respiration. If this hypothesis is correct, then complete destruction of preBötC NK1R neurons should severely perturb and perhaps even fatally arrest breathing. Here we show that specific and near complete bilateral (but not unilateral) destruction of preBötC NK1R neurons results in both an ataxic breathing pattern with markedly altered blood gases and pH, and pathological responses to challenges such as hyperoxia, hypoxia and anesthesia. Thus, these ~600 neurons seem necessary for the generation of normal breathing in rats.Breathing is an exceptionally reliable and continuous mammalian behavior that regulates blood gases and pH at rest and in response to diverse challenges such as exercise, sleep or altitude. The rhythm underlying breathing is postulated to depend critically on neurons in the preBötC1 , 2. Two recent developments allowed us to determine in awake adult rats whether this critical regulatory behavior would be affected by lesions in the preBötC. First, the extent of the preBötC can be anatomically defined by the sub-population of propriobulbar respiratory neurons within the ventrolateral respiratory column expressing NK1R3 -5 . Second, NK1R neurons can be specifically lesioned by substance P conjugated to saporin (SP-SAP) 6 , an effect that takes several days, allowing for complete recovery from surgery6. ResultsSP-SAP was effective in eliminating preBötC NK1R neurons in adult rats. Injections of 0.1-0.2 pmol of SP-SAP or 0.3 pmol each of unconjugated saporin and SP were made in the preBötC. Unilateral SP-SAP injection transiently produced sighs (large inspiratory efforts followed by prolonged expiration), consistent with the effects of injection of SP alone into the pre-BötC in vitro 7 and in vivo (P.A.G., D.R.M. and J.L.F., unpublished observations). All rats returned to normal behavior upon recovery from surgery. Two to eighteen days after injection, rats were perfused and their medullas were stained for NK1R immunoreactivity (n = 20 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript lesion extent was estimated by counting NK1R immunopositive neuronal soma in the rostral medulla inside a circle of 600-μm diameter approximating the preBötC (ventrolateral to the nucleus ambiguus) and in a rectangle (1600 × 1070 μm) outside this circle (Fig. 1, inset). Counts were estimated from four transverse sections beginning within 100 μm of the rostral border of the lateral reticular nucleus and spanning the preBötC 3,4 containing approximately 12-15% of the total preBötC volume. Uninjected controls (n = 4) had 35 ± 5.1 (mean ± s.e.m., per side) NK1R neurons within the preBötC (~600 preBötC NK1R neurons total, which we estimate represent less than 10% of all preBötC neurons) and 82 ± 9 NK1R neurons outside the preBötC. Most of the latter were i...

Current consensus holds that a single medullary network generates respiratory rhythm in mammals. Pre-Bötzinger Complex inspiratory (I) neurons, isolated in transverse slices, and preinspiratory (pre-I) neurons, found only in more intact en bloc preparations and in vivo, are each proposed as necessary for rhythm generation. Opioids slow I, but not pre-I, neuronal burst periods. In slices, opioids gradually lengthened respiratory periods, whereas in more intact preparations, periods jumped nondeterministically to integer multiples of the control period (quantal slowing). These findings suggest that opioid-induced quantal slowing results from transmission failure of rhythmic drive from pre-I neurons to preBötC I networks, depressed below threshold for spontaneous rhythmic activity. Thus, both I (in the slice), and pre-I neurons are sufficient for respiratory rhythmogenesis.

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