Ventilatory effects of glial dysfunction  in a rat brain stem chemoreceptor region

Erlichman, Joseph S.; Li, Aihua; Nattie, Eugene E.

doi:10.1152/jappl.1998.85.5.1599

Cited by 60 publications

(61 citation statements)

References 28 publications

(58 reference statements)

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“…The locations of all the cannulas in these animals fall within or closely adjacent to the RTN, which extends rostrocaudally from the rostral end of the facial nucleus to the rostral end of the nucleus ambiguus and mediolaterally between the pyramidal tract and the spinotrigeminal tract and is deep to the ventral surface 100 -300 m (49). These results indicate that the RTN is a CO 2 -chemosensitive area of the brain stem and are consistent with similar studies in adult rats (2,18,32,41). .…”

Section: Ventilatory Effects Of Unilateral Acidification Of Rtn With supporting

confidence: 92%

Ventilatory effects of gap junction blockade in the RTN in awake rats

Hewitt

Barrie²,

Graham³

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

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We tested the hypothesis that carbenoxolone, a pharmacological inhibitor of gap junctions, would reduce the ventilatory response to CO2 when focally perfused within the retrotrapezoid nucleus (RTN). We tested this hypothesis by measuring minute ventilation (VE), tidal volume (VT), and respiratory frequency (FR) responses to increasing concentrations of inspired CO2 (FICO 2 ϭ 0 -8%) in rats during wakefulness. We confirmed that the RTN was chemosensitive by perfusing the RTN unilaterally with either acetazolamide (AZ; 10 M) or hypercapnic artificial cerebrospinal fluid equilibrated with 50% CO2 (pH ϳ6.5). Focal perfusion of AZ or hypercapnic aCSF increased VE, VT, and FR during exposure to room air. Carbenoxolone (300 M) focally perfused into the RTN decreased VE and VT in animals Ͻ11 wk of age, but VE and VT were increased in animals Ͼ12 wk of age. Glyzyrrhizic acid, a congener of carbenoxolone, did not change VE, VT, or FR when focally perfused into the RTN. Carbenoxolone binds to the mineralocorticoid receptor, but spironolactone (10 M) did not block the disinhibition of VE or VT in older animals when combined with carbenoxolone. Thus the RTN is a CO2 chemosensory site in all ages tested, but the function of gap junctions in the chemosensory process varies substantially among animals of different ages: gap junctions amplify the ventilatory response to CO 2 in younger animals, but appear to inhibit the ventilatory response to CO 2 in older animals.

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Section: Ventilatory Effects Of Unilateral Acidification Of Rtn With supporting

confidence: 92%

Ventilatory effects of gap junction blockade in the RTN in awake rats

Hewitt

Barrie²,

Graham³

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

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“…The elevated inspired CO 2 reduced the pHe in the RTN by 0.07 Ϯ 0.1 pH units ( p Ͻ 0.05), but the pHe change was similar to that observed with the 4-CIN injection alone. These results suggest that both treatments result in a similar stimulus to the acid-sensitive cells in the RTN, an area that is known to increase ventilation when acidified in similar studies in adult rats (Akilesh et al, 1997;Erlichman et al, 1998;Li et al, 1999;Li and Nattie, 2002). Administration of 4-CIN may have decreased pHe outside the RTN (we did not make these measurements), but these regions do not contain a density of chemosensory neurons sufficient to stimulate ventilation (Akilesh et al, 1997;Li et al, 1999), or the density of astrocytes may be too low to generate sufficient lactate .…”

Section: Effects Of 4-cin On Phe In the Rtnmentioning

confidence: 56%

Inhibition of Monocarboxylate Transporter 2 in the Retrotrapezoid Nucleus in Rats: A Test of the Astrocyte–Neuron Lactate-Shuttle Hypothesis

Erlichman¹,

Hewitt²,

Damon³

et al. 2008

J. Neurosci.

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The astrocyte-neuronal lactate-shuttle hypothesis posits that lactate released from astrocytes into the extracellular space is metabolized by neurons. The lactate released should alter extracellular pH (pHe), and changes in pH in central chemosensory regions of the brainstem stimulate ventilation. Therefore, we assessed the impact of disrupting the lactate shuttle by administering 100 M ␣-cyano-4-hydroxycinnamate (4-CIN), a dose that blocks the neuronal monocarboxylate transporter (MCT) 2 but not the astrocytic MCTs (MCT1 and MCT4). Administration of 4-CIN focally in the retrotrapezoid nucleus (RTN), a medullary central chemosensory nucleus, increased ventilation and decreased pHe in intact animals. In medullary brain slices, 4-CIN reduced astrocytic intracellular pH (pHi) slightly but alkalinized neuronal pHi. Nonetheless, pHi fell significantly in both cell types when they were treated with exogenous lactate, although 100 M 4-CIN significantly reduced the magnitude of the acidosis in neurons but not astrocytes. Finally, 4-CIN treatment increased the uptake of a fluorescent 2-deoxy-D-glucose analog in neurons but did not alter the uptake rate of this 2-deoxy-D-glucose analog in astrocytes. These data confirm the existence of an astrocyte to neuron lactate shuttle in intact animals in the RTN, and lactate derived from astrocytes forms part of the central chemosensory stimulus for ventilation in this nucleus. When the lactate shuttle was disrupted by treatment with 4-CIN, neurons increased the uptake of glucose. Therefore, neurons seem to metabolize a combination of glucose and lactate (and other substances such as pyruvate) depending, in part, on the availability of each of these particular substrates.

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“…While these findings suggest that astrocytes do not directly modify neuronal activity in the pre-Bö tC, astrocytes may nonetheless be important for the maintenance of the respiratory rhythm generation in this complex. For instance, the astrocyte inhibitor methionine sulfoximine depresses breathing in vivo (Young et al, 2005), and glial inhibitors (fluorocitrate, fluoroacetate, and methionine sulfoximine) reduce respiratory-related activity in the preBö tC in vitro (Erlichman et al, 1998;Huxtable et al, 2010). We have not examined such inhibition of astrocytes in the present study.…”

Section: Resultsmentioning

confidence: 92%

Astrocytes release prostaglandin E2 to modify respiratory network activity

Forsberg

Ringstedt

Herlenius

2017

Preprint

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Previously (Forsberg et al., 2016), we revealed that prostaglandin E2 (PGE2), released during hypercapnic challenge, increases calcium oscillations in the chemosensitive parafacial respiratory group (pFRG/RTN). Here, we demonstrate that pFRG/RTN astrocytes are the PGE2 source. Two distinct astrocyte subtypes were found using transgenic mice expressing GFP and MrgA1 receptors in astrocytes. Although most astrocytes appeared dormant during time-lapse calcium imaging, a subgroup displayed persistent, rhythmic oscillating calcium activity. These active astrocytes formed a subnetwork within the respiratory network distinct from the neuronal network. Activation of exogenous MrgA1Rs expressed in astrocytes tripled astrocytic calcium oscillation frequency in both the preBö tzinger complex and pFRG/RTN. However, neurons in the preBö tC were unaffected, whereas neuronal calcium oscillatory frequency in pFRG/RTN doubled. Notably, astrocyte activation in pFRG/RTN triggered local PGE2 release and blunted the hypercapnic response. Thus, astrocytes play an active role in respiratory rhythm modulation, modifying respiratory-related behavior through PGE2 release in the pFRG/RTN.

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Ventilatory effects of glial dysfunction in a rat brain stem chemoreceptor region

Cited by 60 publications

References 28 publications

Ventilatory effects of gap junction blockade in the RTN in awake rats

Ventilatory effects of gap junction blockade in the RTN in awake rats

Inhibition of Monocarboxylate Transporter 2 in the Retrotrapezoid Nucleus in Rats: A Test of the Astrocyte–Neuron Lactate-Shuttle Hypothesis

Astrocytes release prostaglandin E2 to modify respiratory network activity

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