Serotonergic neurons in the nucleus raphe obscurus contribute to interaction between central and peripheral ventilatory responses to hypercapnia

Abstract

Serotonergic (5-HT) neurons in the nucleus raphe obscurus (ROb) are involved in the respiratory control network. However, it is not known whether ROb 5-HT neurons play a role in the functional interdependence between central and peripheral chemoreceptors. Therefore, we investigated the role of ROb 5-HT neurons in the ventilatory responses to CO₂ and their putative involvement in the central-peripheral CO₂ chemoreceptor interaction in unanaesthetised rats. We used a chemical lesion specific for 5-HT neurons (anti-SERT-SAP) of the ROb in animals with the carotid body (CB) intact or removed (CBR). Pulmonary ventilation (V (E)), body temperature and the arterial blood gases were measured before, during and after a hypercapnic challenge (7% CO₂). The lesion of ROb 5-HT neurons alone (CB intact) or the lesion of 5-HT neurons of ROb+CBR did not affect baseline V (E) during normocapnic condition. Killing ROb 5-HT neurons (CB intact) significantly decreased the ventilatory response to hypercapnia (p < 0.05). The reduction in CO₂ sensitivity was approximately 15%. When ROb 5-HT neurons lesion was combined with CBR (anti-SERT-SAP+CBR), the V (E) response to hypercapnia was further decreased (-31.2%) compared to the control group. The attenuation of CO₂ sensitivity was approximately 30%, and it was more pronounced than the sum of the individual effects of central (ROb lesion; -12.3%) or peripheral (CBR; -5.5%) treatments. Our data indicate that ROb 5-HT neurons play an important role in the CO₂ drive to breathing and may act as an important element in the central-peripheral chemoreception interaction to CO₂ responsiveness.

Raphe serotonergic neurons modulate genioglossus corticomotor activity in intermittent hypoxic rats

“…Nattie et al have also observed that the exposure of medullary raphe neuron cultures to anti-SERT-SAP leads to the killing of serotonergic neurons without any effects on the other neurons in vitro [18]. In our study, the method was a repeat from the previous statement [18,32,33]. Furthermore, immunohistochemistry was applied to verify the specific lesions of the 5-HT neurons.…”

“…Furthermore, immunohistochemistry was applied to verify the specific lesions of the 5-HT neurons. Using a similar approach, Da Silva GS et al reported that the 5-HT neurons were reduced by 37%-38% and focal killing (12.3 to 12.8 mm posterior to the bregma) was about 44%-68% after specific lesions by anti-SERT-SAP [32,33]. Dias et al reported that the reduction of 5-HT neurons was approximately 35%, and 5-HT neurons in the raphe magnus had a 50% reduction via injection of the anti-SER-SAP [20].…”

Hypercapnia attenuates inspiratory amplitude and expiratory time responsiveness to hypoxia in vagotomized and vagal-intact rats

“…Central and peripheral chemoreceptor influences on breathing are traditionally modeled as additive for simplicity although many extant data in human subjects and animal models suggest the possibility of not only additive (Clement et al, 1992, 1995; Heeringa et al, 1979; Mohan and Duffin, 1997; StCroix et al, 1996; Swanson and Bellville, 1974; van Beek et al, 1983) but also hyperadditive (Adams et al, 1978; Cunningham et al, 1986; da Silva et al, 2011; Honda et al, 1981; Loeschcke et al, 1963; Robbins, 1988; Roberts et al, 1995; Tenney and Brooks, 1966; Teppema et al, 2010) or even hypoadditive interaction (Adams and Severns, 1982; Berger et al, 1978; Cragg and Drysdale, 1983; Eldridge et al, 1981; Gesell et al, 1940; Giese et al, 1978; Ou et al, 1976; Smith et al, 1984). A major confound on this issue is that hypercapnia and hypoxia are often used as physiological stimuli to activate the central and peripheral (carotid) chemoreflex loops, respectively, whereas hypercapnia may stimulate both and hence its effect is nonspecific.…”

CO2 rebreathing: an undergraduate laboratory to study the chemical control of breathing

“…The relative contributions of the peripheral and central chemoreceptors to the ventilatory response to CO 2 under different experimental conditions [e.g., altered PO 2 , or blood gas alteration at only one (central or peripheral) chemosensory site] are complex and not fully understood (3,35,36,56,58). However, interactions between central and peripheral chemoreceptors may be of greater importance than heretofore believed in controlling the ventilatory response to CO 2 (3,15), as central responses to CO 2 are modulated by afferent input from the carotid body during wakefulness, with notable interspecific differences [as evidenced by a hyperadditive effect in dogs with intact carotid bodies versus unilateral denervation (3), a hypoadditive effect in anesthetized rats (11), and an additive effect in conscious humans (12)]. Furthermore, hypoxia during rebreathing lowers the central chemoreflex threshold and increases sensitivity in lowlanders compared with results obtained during hyperoxic rebreathing (55).…”