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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    • "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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    • "Rodents display perturbed ventilation when 5-HT function is altered genetically (Li and Nattie 2008; Hodges et al. 2008, 2009, 2011; Buchanan and Richerson 2010; Cummings et al. 2011b; Penatti et al. 2011a; Barrett et al. 2012) or disrupted by targeted pharmacalogical lesion (Nattie et al. 2004; Dias et al. 2007; Cummings et al. 2011a), by selective silencing (Ray et al. 2011), or by dietary tryptophan restriction (Penatti et al. 2011b). Intrinsically CO -stimulated 5-HT neurons occur in the brainstem raphé nuclei in vitro, and 5-HT neurons occur in highly vascular regions connected to major homeostatic integration and respiratory control centers (Wang et al. 2001; Severson et al. 2003; Ptak et al. 2009). Hypercapnia induces immediate early gene (e.g., c-Fos) expression in raphé 5-HT neurons (Larnicol et al. 1994; Haxhiu et al. 2001; Johnson et al. 2005; Pete et al. 2002) and 5-HT release in respiratory motor nuclei in vivo (Harper et al. 2005). "
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    ABSTRACT: Brainstem central chemoreceptors are critical to the hypercapnic ventilatory response, but their location and identity are poorly understood. When studied in vitro, serotonin synthesizing (5-HT) neurons within the rat medullary raphe are intrinsically stimulated by CO2/acidosis. The contributions of these neurons to central chemosensitivity in vivo, however, are controversial. Lacking is documentation of CO2-sensitive 5-HT neurons in intact experimental preparations and understanding of their spatial and proportional distribution. Here we test the hypothesis that 5-HT neurons in the rat medullary raphe are sensitive to arterial hypercapnia. We use extracellular recording and hypercapnic challenge of spontaneously active medullary raphe neurons in the unanesthetized in situ perfused decerebrate brainstem preparation to assess chemosensitivity of individual cells. Juxtacellular labeling of a subset of recorded neurons and subsequent immunohistochemistry for the 5-HT synthesizing enzyme tryptophan hydroxylase identify or exclude this neurotransmitter phenotype in electrophysiologically characterized chemosensitive and insensitive cells. We show that the medullary raphe houses a heterogeneous population, including chemosensitive and insensitive 5-HT neurons. Of 124 recorded cells, 16 cells were juxtacellularly filled, visualized, and immunohistochemically identified as 5-HT-synthesizing, based on TPH immunoreactivity (TPH-ir). 44% of 5-HT cells were CO2-stimulated (increased firing rate with hypercapnia), while 56% were unstimulated. Our results demonstrate that medullary raphe neurons are heterogeneous and clearly include a subset of 5-HT neurons that are excited by arterial hypercapnia. Together with data identifying intrinsically CO2-sensitive 5-HT neurons in vitro, these results support a role for such cells as central chemoreceptors in the intact system.
    Journal of Neurophysiology 09/2013; 110(11). DOI:10.1152/jn.00288.2013 · 2.89 Impact Factor
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