Modulation of Respiratory Frequency by Peptidergic Input to Rhythmogenic Neurons in the PreBötzinger Complex

Gray, Paul A.; Rekling, Jens C.; Bocchiaro, Christopher M.; Feldman, Jack L.

doi:10.1126/science.286.5444.1566

Cited by 576 publications

(699 citation statements)

References 30 publications

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“…As an additional metric to assess the postlesion state of the CPG, we exploited previous evidence that SP excites NK1R-expressing preBötC neurons to boost respiratory activity (24). Lesioned preBötC-surface slices exhibited irregular SP-evoked rhythms that were unsustainable (Fig.…”

Section: Discussionmentioning

confidence: 99%

Cumulative lesioning of respiratory interneurons disrupts and precludes motor rhythms in vitro

Hayes

Wang²,

Negro³

2012

Proc. Natl. Acad. Sci. U.S.A.

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How brain functions degenerate in the face of progressive cell loss is an important issue that pertains to neurodegenerative diseases and basic properties of neural networks. We developed an automated system that uses two-photon microscopy to detect rhythmic neurons from calcium activity, and then individually laser ablates the targets while monitoring network function in real time. We applied this system to the mammalian respiratory oscillator located in the pre-Bötzinger Complex (preBötC) of the ventral medulla, which spontaneously generates breathing-related motor activity in vitro. Here, we show that cumulatively deleting preBötC neurons progressively decreases respiratory frequency and the amplitude of motor output. On average, the deletion of 120 ± 45 neurons stopped spontaneous respiratory rhythm, and our data suggest ≈82% of the rhythm-generating neurons remain unlesioned. Cumulative ablations in other medullary respiratory regions did not affect frequency but diminished the amplitude of motor output to a lesser degree. These results suggest that the preBötC can sustain insults that destroy no more than ≈18% of its constituent interneurons, which may have implications for the onset of respiratory pathologies in disease states.central pattern generator | calcium imaging | brainstem C entral pattern generator (CPG) networks produce coordinated motor patterns that underlie behaviors such as breathing, locomotion, and chewing (1, 2). A key issue is not just which cell types generate these patterns of activity, but how many? This question pertains to whether and how cumulative cell loss will impair and, possibly preclude, network function.Breathing consists of inspiratory and expiratory phases. The preBötzinger Complex (preBötC) of the medulla putatively contains the inspiratory CPG (3, 4). Over several days in vivo, saporinmediated destruction of preBötC neurons that express neurokinin-1 receptors (NK1Rs) causes sleep-disordered breathing and fatal respiratory pathology (5, 6). Similarly, acute cell-silencing of a subset of the same NK1R-expressing population of preBötC neurons stops spontaneous breathing in awake adult rats (7). These studies helped to determine the cellular composition of the preBötC and confirmed that it was essential for breathing in an otherwise intact animal, but could not measure the resiliency of the preBötC when faced with silencing or deleting its core piecewise.We examined this issue by using slice preparations that capture the preBötC and spontaneously generate fictive breathing-related activity in vitro. We developed a computer-automated system that detects rhythmically active interneurons via two-photon calcium imaging, stores their physical locations in memory, and then laser ablates the targets sequentially, while electrophysiologically monitoring the motor output of the circuit. We applied this system to the preBötC to test the hypothesis that piecewise destruction of the CPG core would cause graded loss of motor activity up to rhythm cessation. We surmised that this effect ...

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Section: Discussionmentioning

confidence: 99%

Cumulative lesioning of respiratory interneurons disrupts and precludes motor rhythms in vitro

Hayes

Wang²,

Negro³

2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Our current view of respiratory rhythm generation in mammals is that there are two distinct, normally coupled, rhythm generators. The primary site, the preBötC, is ventral to the nucleus ambiguus, midway between the facial nucleus and the obex, caudal to the Bötzinger Complex and rostral to the ventral respiratory group (VRG) in the rostroventrolateral medulla [32,33] . The preBötC is postulated to generate inspiratory rhythmic activity that dominates breathing in mammals at rest [34,35] .…”

Section: Cholinergic Innervation and Nachrs In Brainstem And Spinal Cmentioning

confidence: 99%

“…In this review, we focus on the role of nAChRs in the preBötC, an essential site for respiratory rhythm generation [32][33][34] , and in brainstem and spinal cord respiratory motor nuclei in regulation of respiration.…”

Section: Introductionmentioning

confidence: 99%

Central cholinergic regulation of respiration: nicotinic receptors

Shao

Feldman

2009

Acta Pharmacol Sin

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Nicotinic acetylcholine receptors (nAChRs) are expressed in brainstem and spinal cord regions involved in the control of breathing. These receptors mediate central cholinergic regulation of respiration and effects of the exogenous ligand nicotine on respiratory pattern. Activation of α4* nAChRs in the preBötzinger Complex (preBötC), an essential site for normal respiratory rhythm generation in mammals, modulates excitatory glutamatergic neurotransmission and depolarizes preBötC inspiratory neurons, leading to increases in respiratory frequency. nAChRs are also present in motor nuclei innervating respiratory muscles. Activation of post-and/or extra-synaptic α4* nAChRs on hypoglossal (XII) motoneurons depolarizes these neurons, potentiating tonic and respiratory-related rhythmic activity. As perinatal nicotine exposure may contribute to the pathogenesis of sudden infant death syndrome (SIDS), we discuss the effects of perinatal nicotine exposure on development of the cholinergic and other neurotransmitter systems involved in control of breathing. Advances in understanding of the mechanisms underlying central cholinergic/nicotinic modulation of respiration provide a pharmacological basis for exploiting nAChRs as therapeutic targets for neurological disorders related to neural control of breathing such as sleep apnea and SIDS.

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“…Several studies have attempted to define the boundaries of the preBötzC. Studies in adult rats found a distinct increase in NK1R-positive neurons ventral to NA (6,7,34,35). Subsequently, data from other studies suggested that a high density of somatostatin immunoreactive neurons ventral to NA accurately defined the boundaries of the preBötzC (34).…”

Section: Discussionmentioning

confidence: 99%

Focal acidosis in the pre-Bötzinger complex area of awake goats induces a mild tachypnea

Krause¹,

Forster²,

Davis³

et al. 2009

Journal of Applied Physiology

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Krause KL, Forster HV, Davis SE, Kiner T, Bonis JM, Pan LG, Qian B. Focal acidosis in the pre-Bötzinger complex area of awake goats induces a mild tachypnea. J Appl Physiol 106: 241-250, 2009. First published November 13, 2008 doi:10.1152/japplphysiol.90547.2008There are widespread chemosensitive areas in the brain with varying effects on breathing. In the awake goat, microdialyzing (MD) 50% CO2 at multiple sites within the medullary raphe increases pulmonary ventilation (V I), blood pressure, heart rate, and metabolic rate (V O2) (11), while MD in the rostral and caudal cerebellar fastigial nucleus has a stimulating and depressant effect, respectively, on these variables (17). In the anesthetized cat, the pre-Bötzinger complex (preBötzC), a hypothesized respiratory rhythm generator, increases phrenic nerve activity after an acetazolamide-induced acidosis (31, 32). To gain insight into the effects of focal acidosis (FA) within the preBötzC during physiological conditions, we tested the hypothesis that FA in the preBötzC during wakefulness would stimulate breathing, by increasing respiratory frequency (f). Microtubules were bilaterally implanted into the preBötzC of 10 goats. Unilateral MD of mock cerebral spinal fluid equilibrated with 6.4% CO2 did not affect V I, tidal volume (VT), or f. Unilateral MD of 25 and 50% CO2 significantly increased V I and f by 10% (P Ͻ 0.05, n ϭ 10, 17 trials), but VT was unaffected. Bilateral MD of 6.4, 25, or 50% CO2 did not significantly affect V I, VT, or f (P Ͼ 0.05, n ϭ 6, 6 trials). MD of 80% CO2 caused a 180% increase in f and severe disruptions in airflow (n ϭ 2). MD of any level of CO2 did not result in any significant changes in mean arterial blood pressure, heart rate, or V O2. Thus the data suggest that the preBötzC area is chemosensitive, but the responses to FA at this site are unique compared with other chemosensitive sites.breathing; chemosensitivity CENTRAL RESPIRATORY CO 2 /H ϩ chemoreception has been traditionally attributed to sites at or near the ventrolateral medullary surface (16,24,27). However, studies over the last 15-20 yr indicate that the ventrolateral medullary surface is not the sole CO 2 /H ϩ -sensitive area (1-3, 5, 15, 17, 21, 24, 31, 32). Electrophysiological recordings of in vitro preparations have shown that neurons in the retrotrapezoid nucleus, nucleus of the solitary tract, the medullary raphe nucleus (MRN), locus coeruleus, and the pre-Bötzinger complex (preBötzC) increase discharge frequency when the pH in the bathing solution is reduced (3,5,8,14,22,24). Studies in anesthetized preparations that either created a focal acidosis (FA) or assessed the effects of lesions on the hypercapnic ventilatory response also support the concept of widespread chemosensitivity in the medulla, pons, and cerebellum (11,18,32,33,35,36,37).While the in vivo data, under physiological conditions, suggest that chemoreceptors at multiple sites influence breathing, the observed ventilatory effects are not uniform, and the hyperpnea is small, with FA at a single si...

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Modulation of Respiratory Frequency by Peptidergic Input to Rhythmogenic Neurons in the PreBötzinger Complex

Cited by 576 publications

References 30 publications

Cumulative lesioning of respiratory interneurons disrupts and precludes motor rhythms in vitro

Cumulative lesioning of respiratory interneurons disrupts and precludes motor rhythms in vitro

Central cholinergic regulation of respiration: nicotinic receptors

Focal acidosis in the pre-Bötzinger complex area of awake goats induces a mild tachypnea

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