Midbrain serotonergic neurons are central pH chemoreceptors

Ruhr-Universität Bochum, Bochum, North Rhine-Westphalia, Germany
Nature Neuroscience (Impact Factor: 16.1). 12/2003; 6(11):1139-40. DOI: 10.1038/nn1130
Source: PubMed


Serotonergic neurons in the medulla are central respiratory chemoreceptors. Here we show that serotonergic neurons in the midbrain of rats are also highly chemosensitive to small changes in CO2/pH and are closely associated with large penetrating arteries. We propose that midbrain raphé neurons are sensors of blood CO2 that maintain pH homeostasis by inducing arousal, anxiety and changes in cerebrovascular tone in response to respiratory acidosis.

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    • "In rodents, serotonergic neurons located in raphe magnus are usually mildly activated by CO 2 in slices or in an arterially perfused preparation (<0.5 Hz, on average) (Brust et al., 2014; Iceman et al., 2013), whereas those in raphe obscurus are typically unresponsive (Figures 3E and 3G) (Depuy et al., 2011; Iceman et al., 2013) and parapyramidal serotonergic cells usually inhibited (Mulkey et al., 2004). A much higher proportion of serotonergic neurons from various raphe nuclei (73%–100%) are CO 2 -responsive when recorded in slices or in culture (Severson et al., 2003; Wang et al., 2001). Thus, CO 2 /H + -activated serotonergic neurons have been repeatedly identified within a variety of classically defined raphe neuron subgroups, albeit in highly variable proportion depending on the preparation. "
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    ABSTRACT: Recent advances have clarified how the brain detects CO2 to regulate breathing (central respiratory chemoreception). These mechanisms are reviewed and their significance is presented in the general context of CO2/pH homeostasis through breathing. At rest, respiratory chemoreflexes initiated at peripheral and central sites mediate rapid stabilization of arterial PCO2 and pH. Specific brainstem neurons (e.g., retrotrapezoid nucleus, RTN; serotonergic) are activated by PCO2 and stimulate breathing. RTN neurons detect CO2 via intrinsic proton receptors (TASK-2, GPR4), synaptic input from peripheral chemoreceptors and signals from astrocytes. Respiratory chemoreflexes are arousal state dependent whereas chemoreceptor stimulation produces arousal. When abnormal, these interactions lead to sleep-disordered breathing. During exercise, central command and reflexes from exercising muscles produce the breathing stimulation required to maintain arterial PCO2 and pH despite elevated metabolic activity. The neural circuits underlying central command and muscle afferent control of breathing remain elusive and represent a fertile area for future investigation. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 09/2015; 87(5):946-61. DOI:10.1016/j.neuron.2015.08.001 · 15.05 Impact Factor
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    • "This could be supported by the fact that, PA being capable to access to the brain could induce neurochemical effects on CNS function [8] including neurotransmitter synthesis and release. Of interest, PA is capable of altering dopamine, serotonin, GABA and glutamate systems in a manner similar to that observed in ASDs [40,13], partly via changing intracellular calcium release rate [41]. It could be easily observed that PA pre or post-treatment with Co Q (Table 1) or melatonin (Table 2) induced satisfactory amelioration of GABA levels, with Co Q being more potent compared to melatonin. "
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    ABSTRACT: Exposures to environmental toxins are now thought to contribute to the development of autism spectrum disorder. Propionic acid (PA) found as a metabolic product of gut bacteria has been reported to mimic/mediate the neurotoxic effects of autism. Results from animal studies may guide investigations on human populations toward identifying environmental contaminants that produce or drugs that protect from neurotoxicity. Forty-eight young male Western Albino rats were used in the present study. They were grouped into six equal groups 8 rats each. The first group received a neurotoxic dose of buffered PA (250 mg/Kg body weight/day for 3 consecutive days). The second group received only phosphate buffered saline (control group). The third and fourth groups were intoxicated with PA as described above followed by treatment with either coenzyme Q (4.5 mg/kg body weight) or melatonin (10 mg/kg body weight) for one week (therapeutically treated groups). The fifth and sixth groups were administered both compounds for one week prior to PA (protected groups). Heat shock protein70 (Hsp70), Gamma amino-butyric acid (GABA), serotonin, dopamine, oxytocin and interferon gamma-inducible protein 16 together with Comet DNA assay were measured in brain tissues of the six studied groups. The obtained data showed that PA caused multiple signs of brain toxicity revealed in depletion of GABA, serotonin, and dopamine, are which important neurotransmitters that reflect brain function, interferon gamma-inducible protein 16 and oxytocin. A high significant increase in tail length, tail DNA% damage and tail moment was reported indicating the genotoxic effect of PA. Administration of melatonin or coenzyme Q showed both protective and therapeutic effects on PA-treated rats demonstrated in a remarkable amelioration of most of the measured parameters. In conclusion, melatonin and coenzyme Q have potential protective and restorative effects against PA-induced brain injury, confirmed by improvement in biochemical markers and DNA double strand breaks.
    BMC Neuroscience 02/2014; 15(1):34. DOI:10.1186/1471-2202-15-34 · 2.67 Impact Factor
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    • "Some non-5-HT raphé cells have been implicated in the hypercapnic ventilatory response. Non-5-HT (likely GABAergic) cells in the raphé are inhibited by CO 2 in vitro and in situ (Wang et al., 1998; Wang and Richerson, 1999; Severson et al., 2003; Hodges et al., 2005; Iceman et al., 2012) and may play some role in the hypercapnic ventilatory response. Raphé neurokinin-1 receptor (NK1R) expressing cells do not synthesize 5-HT and toxic lesioning of these cells results in a blunted hypercapnic response in rats and goats in vivo (Nattie et al., 2004; Hodges et al., 2004; Commons, 2009). "
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    ABSTRACT: Serotonin/substance P synthesizing cells in the raphé nuclei of the brain are candidates for designation as central chemoreceptors that are stimulated by CO2/pH. We have previously demonstrated that these neurons are CO2-stimulated in situ. Evidence also suggests that CO2-inhibited raphé neurons recorded in vitro and in situ synthesize γ-aminobutyric acid (GABA). Unknown is whether there are other types of chemosensitive cells in the raphé. Here, we showed that a previously unrecognized pool of raphé neurons also exhibit chemosensitivity, and that they are not serotonergic. We used extracellular recording of individual raphé neurons in the unanesthetized juvenile rat in situ perfused decerebrate brainstem preparation to assess chemosensitivity of raphé neurons. Subsequent juxtacellular labeling of individually recorded cells, and immunohistochemistry for the serotonin synthesizing enzyme tryptophan hydroxylase (TPH) and for neurokinin-1 receptor (NK1R; the receptor for substance P) indicated a group of CO2-stimulated cells that are not serotonergic, but express NK1R and are closely apposed to surrounding serotonergic cells. CO2-stimulated serotonergic (5-HT) and non-5-HT cells constitute distinct groups that have different firing characteristics and hypercapnic sensitivities. Non-5-HT cells fire faster and are more robustly stimulated by CO2 than are 5-HT cells. Thus, we have characterized a previously unrecognized type of CO2-stimulated medullary raphé neuron that is not serotonergic, but may receive input from neighboring serotonin/substance P synthesizing chemosensitive neurons. The potential network properties of the three types of chemosensitive raphé neurons (the present non-5-HT cells, serotonergic cells, and CO2-inhibited cells) remain to be elucidated.
    Neuroscience 12/2013; · 3.36 Impact Factor
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