Raphé Neurons Stimulate Respiratory Circuit Activity by Multiple Mechanisms via Endogenously Released Serotonin and Substance P

Ptak, Krzysztof; Yamanishi, Tadashi; Aungst, Jason; Milescu, Lorin S.; Zhang, Ruli; Richerson, George B.; Smith, Jeffrey C.

doi:10.1523/jneurosci.5271-08.2009

Cited by 243 publications

(270 citation statements)

References 61 publications

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“…We restricted our observations to the ROb, as this midline medullary nucleus plays a major role in modulating the respiratory rhythm (35,36). In ROb, serotonergic (TpOH 1 ) neurons are distributed around the mid-sagittal plane in medullary coronal sections, as illustrated in Figure 1A.…”

Section: Morphological Effects Of Prenatal-perinatal Nicotine Upon Ramentioning

confidence: 99%

The Alteration of Neonatal Raphe Neurons by Prenatal–Perinatal Nicotine. Meaning for Sudden Infant Death Syndrome

Cerpa

Aylwin

Beltrán-Castillo

et al. 2015

Am J Respir Cell Mol Biol

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Nicotine may link maternal cigarette smoking with respiratory dysfunctions in sudden infant death syndrome (SIDS). Prenatal-perinatal nicotine exposure blunts ventilatory responses to hypercapnia and reduces central respiratory chemoreception in mouse neonates at Postnatal Days 0 (P0) to P3. This suggests that raphe neurons, which are altered in SIDS and contribute to central respiratory chemoreception, may be affected by nicotine. We therefore investigated whether prenatal-perinatal nicotine exposure affects the activity, electrical properties, and chemosensitivity of raphe obscurus (ROb) neurons in mouse neonates. Osmotic minipumps, implanted subcutaneously in 5-to 7-day-pregnant CF1 mice, delivered nicotine bitartrate (60 mg kg 21 d 21 ) or saline (control) for up to 28 days. In neonates, ventilation was recorded by head-out plethysmography, c-Fos (neuronal activity marker), or serotonin autoreceptors (5HT 1A R) were immunodetected using light microscopy, and patch-clamp recordings were made from raphe neurons in brainstem slices under normocarbia and hypercarbia. Prenatal-perinatal nicotine exposure decreased the hypercarbiainduced ventilatory responses at P1-P5, reduced both the number of c-Fos-positive ROb neurons during eucapnic normoxia at P1-P3 and their hypercapnia-induced recruitment at P3, increased 5HT 1A R immunolabeling of ROb neurons at P3-P5, and reduced the spontaneous firing frequency of ROb neurons at P3 without affecting their CO 2 sensitivity or their passive and active electrical properties. These findings reveal that prenatal-perinatal nicotine reduces the activity of neonatal ROb neurons, likely as a consequence of increased expression of 5HT 1A Rs. This hypoactivity may change the functional state of the respiratory neural network leading to breathing vulnerability and chemosensory failure as seen in SIDS.

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Section: Morphological Effects Of Prenatal-perinatal Nicotine Upon Ramentioning

confidence: 99%

The Alteration of Neonatal Raphe Neurons by Prenatal–Perinatal Nicotine. Meaning for Sudden Infant Death Syndrome

Cerpa

Aylwin

Beltrán-Castillo

et al. 2015

Am J Respir Cell Mol Biol

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“…However, another explanation could involve a loss of excitatory drive, wherein the ablation of rhythmic neurons that support CPG function via neuromodulation reduce preBötC excitability. Monoaminergic and peptidergic projections maintain excitability in the preBötC, and exogenous substance P (SP) stimulates the preBötC by acting on the core population of NK1R-expressing rhythmogenic interneurons (18). Monoaminergic and peptidergic neurons also receive feedback projections from the preBötC, which endows them with respiratory rhythmicity and makes them susceptible to loss of input due to the cumulative laser ablation protocol.…”

Section: Detecting Inspiratory Neurons In the Prebötc And Ventral Resmentioning

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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“…5-HT neurons in both loci are also juxtaposed to large cerebral blood vessels, making them ideally situated to accurately monitor changes in arterial PCO 2 (10,11). Medullary 5-HT neurons project to and stimulate respiratory neurons (12,13), and they have a large response to pH when they are isolated in vitro, with the firing rate increasing 3-fold on average when pH decreases from 7.4 to 7.2 (14). These and other observations have led to the proposal that medullary 5-HT neurons are central respiratory chemoreceptors that regulate respiratory motor output to maintain normal systemic CO 2 / pH (13,(15)(16)(17).…”

mentioning

confidence: 99%

Central serotonin neurons are required for arousal to CO ₂

Buchanan

Richerson

2010

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

233

213

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There is a long-standing controversy about the role of serotonin in sleep/wake control, with competing theories that it either promotes sleep or causes arousal. Here, we show that there is a marked increase in wakefulness when all serotonin neurons are genetically deleted in mice hemizygous for ePet1-Cre and homozygous for floxed Lmx1b (Lmx1b f/f/p ). However, this only occurs at cool ambient temperatures and can be explained by a thermoregulatory defect that leads to an increase in motor activity to generate heat. Because some serotonin neurons are stimulated by CO 2 , and serotonin activates thalamocortical networks, we hypothesized that serotonin neurons cause arousal in response to hypercapnia. We found that Lmx1b f/f/p mice completely lacked any arousal response to inhalation of 10% CO 2 (with 21% O 2 in balance N 2 ) but had normal arousal responses to hypoxia, sound, and air puff. We propose that serotonin neurons mediate the potentially life-saving arousal response to hypercapnia. Impairment of this response may contribute to sudden unexpected death in epilepsy, sudden infant death syndrome, and sleep apnea.S erotonin [5-hydroxytryptamine (5-HT)] has long been implicated in the regulation of sleep and wakefulness. However, its specific role remains unclear and controversial (1). 5-HT is considered by some as a sleep-promoting agent, because both pharmacological depletion of 5-HT and chemical lesions of 5-HT neurons lead to insomnia in cats (1-3). However, there are others who consider 5-HT to be a wakefulness promoter (4). Consistent with this, the firing rate of 5-HT neurons is fastest during waking (W), is slower during nonrapid eye movement sleep (NREM) and nearly ceases during rapid eye movement sleep (REM) (5, 6). 5-HT neurons in the dorsal raphé nucleus project to thalamic, cortical, and other structures involved in sleep/wake transitions (7), and 5-HT can convert the firing patterns of thalamic reticular and thalamocortical neurons in slices from a bursting pattern seen in NREM to a tonic single-spiking pattern seen in W (8). 5-HT (along with norepinephrine, histamine, and acetylcholine) is considered by some to be part of the ascending arousal system (AAS), which regulates transitions from sleep to wakefulness (4). However, there is no direct evidence that 5-HT neurons are required for normal arousal, and there is some evidence that they promote NREM (1, 3). Given the complexity of the 5-HT system, it has been difficult to define the roles, either direct or indirect, of 5-HT in different aspects of sleep regulation.In vitro studies have shown that a subset of 5-HT neurons in both the medullary and midbrain raphé increases firing rate in response to a rise in CO 2 or decrease in pH (9). When studied in unanesthetized behaving mammals, similar results have been obtained in vivo by multiple groups (9). 5-HT neurons in both loci are also juxtaposed to large cerebral blood vessels, making them ideally situated to accurately monitor changes in arterial PCO 2 (10, 11). Medullary 5-HT neurons project to ...

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Raphé Neurons Stimulate Respiratory Circuit Activity by Multiple Mechanisms via Endogenously Released Serotonin and Substance P

Cited by 243 publications

References 61 publications

The Alteration of Neonatal Raphe Neurons by Prenatal–Perinatal Nicotine. Meaning for Sudden Infant Death Syndrome

The Alteration of Neonatal Raphe Neurons by Prenatal–Perinatal Nicotine. Meaning for Sudden Infant Death Syndrome

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

Central serotonin neurons are required for arousal to CO ₂

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Raphé Neurons Stimulate Respiratory Circuit Activity by Multiple Mechanisms via Endogenously Released Serotonin and Substance P

Cited by 243 publications

References 61 publications

The Alteration of Neonatal Raphe Neurons by Prenatal–Perinatal Nicotine. Meaning for Sudden Infant Death Syndrome

The Alteration of Neonatal Raphe Neurons by Prenatal–Perinatal Nicotine. Meaning for Sudden Infant Death Syndrome

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

Central serotonin neurons are required for arousal to CO 2

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Central serotonin neurons are required for arousal to CO ₂