Fadi Xu

Role of the cerebellar deep nuclei in respiratory modulation

The cerebellum contains three deep nuclei, i.e., the fastigial, interposed and lateral nucleus. Recent studies demonstrate that these nuclei play different roles in respiratory modulation. Activation of fastigial nuclear neurons predominantly increases ventilation via elevation of respiratory frequency and/or tidal volume. Ablation of the fastigial nucleus did not significantly alter eupneic breathing, but did markedly attenuate the respiratory response to medium and severe hypercapnia as well as hypoxia. The fastigial nucleus contains respiratory-modulated neurons and about 25% of these neurons do not show their respiratory-related phasic activity until exposed to hypercapnia. The fastigial nucleus also contains CO2/H+ chemosensitive sites that contributed to the respiratory response to hypercapnia. Therefore, it is concluded that fastigial nuclear facilitatory influence on chemoreflexes emerges during hypercapnia via recruiting intrinsic chemoreception and respiratory-modulated neurons. Full expression of the fastigial nucleus-mediated respiratory responses depends on the integrity of the medullary gigantocellular nucleus at least partially via monosynaptic projections. Additionally, the fastigial nucleus receives inhibitory inputs primarily from Purkinje cells located in the medial vermis and recent observations indicate that simulation of these Purkinje cells inhibits respiration. As compared to chemoreflexes, fastigial nuclear role in the respiratory mechanoreflexes is not significant. The studies related to the role of the interposed and lateral nucleus in eupneic breathing are limited and the results appear controversial. However, there is evidence to show that the interposed nucleus contains respiratory-modulated neurons and is involved in coughing motor control

Medullary respiratory neuronal activity modulated by stimulation of the fastigial nucleus of the cerebellum

The ability of the rostral fastigial nucleus (FNr) of the cerebellum to modulate medullary respiratory neuronal activity was examined in 17 anesthetized, paralyzed and ventilated cats. A bipolar stimulating electrode was positioned into the FNr and tungsten microelectrodes used to record units within the nucleus tractus solitarius (NTS), nucleus ambiguus (NA) and nucleus retroambigualis (NRA). Transient stimuli (< 150 microA, 5-200 Hz) were delivered during inspiration or expiration, and the effects noted on medullary neuronal activity and the phrenic neurogram. The results showed that FNr stimulation: (1) modulated inspiratory and expiratory neuronal (ramp-, early- and late-inspiratory and stage I and II expiratory) discharges recorded from the NTS, NA and NRA (n = 67, 14 and 28) when stimuli (> or = 20-50 Hz) were delivered during either the inspiratory or expiratory phases; (2) terminated the burst durations of inspiratory (77%) and expiratory (94%) neurons with stimulus-response latencies of 28.2 +/- 3.1 ms (inspiratory) and 29.4 +/- 3.6 ms (expiratory); (3) elicited changes in phrenic neurogram concomitant with the effects noted on medullary neuronal activities; (4) failed to change heart rate and arterial blood pressure; and (5) did not affect medullary neuronal and phrenic nerve activity following kainic acid injection into the FNr. We conclude that activation of the FNr (likely its cell bodies) can modulate the respiratory output via influences on medullary respiratory-related neurons. The primary cerebellar effect across all sub-types of respiratory neurons was early termination.

Activation of different vestibular subnuclei evokes differential respiratory and pressor responses in the rat

Activation of the vestibular system can either increase or decrease ventilation. The objectives of the present study were to clarify whether these different responses are the result of activating different vestibular subnuclei, by addressing three questions. Do neurones within the medial, lateral and spinal vestibular nuclei (VNM, VNL and VNS, respectively) function differently in respiratory modulation? Is the ventral medullary nucleus gigantocellularis (NGC) required to fully express the VN‐mediated respiratory responses? Is glutamate, by acting on N‐methyl‐d‐aspartic acid (NMDA) receptors in the vestibular subnuclei, capable of modulating respiration? In anaesthetized, tracheotomized and spontaneously breathing rats, electrical stimuli (< 10 s) applied in the VNL and VNS significantly elevated ventilation by 35 % and 30 % (P < 0.05), respectively. However, VNM stimulation produced statistically significant (P < 0.05) changes that differed depending upon the stimulation site: either ventilatory inhibition (by 40 % in 57 % of the trials) or excitation (by 55 % in 43 % of trials), and which were often accompanied by a pressor response. These electrical‐stimulation‐evoked cardiorespiratory responses were almost eliminated following microinjection of ibotenic acid into the stimulation sites (P < 0.05) or bilaterally into the NGC (P < 0.05). As compared to vehicle, microinjection of NMDA into the unilateral VNM, VNL and VNS significantly increased ventilation to 74 %, 58 % and 60 % (P < 0.05), respectively, with no effect on arterial blood pressure. These data suggest that neurones within the vestibular subnuclei play different roles in cardiorespiratory modulation, and that the integrity of the NGC is essential for the full expression of these VN‐mediated responses. The evoked respiratory excitatory responses are probably mediated by glutamate acting on NMDA receptors, whereas the neurotransmitters involved in VNM‐mediated respiratory inhibition and hypertension remain unknown.

Role of the Bötzinger complex in fastigial nucleus–mediated respiratory responses

We have reported that the phrenic neurogram (PN) is modulated by stimulation of the fastigial nucleus (FN) of the cerebellum. The present study was undertaken to search for brainstem site(s) involved in the FN efferent pathway to modulate phrenic nerve activities. Experiments were performed on 35 anesthetized, paralyzed, and ventilated cats, using the PN as the index of the respiratory motor output. Results showed that bilateral electrolytic lesions of the red nucleus (RN), the paramedian reticular nucleus (PRN), or the pontine respiratory group (PRG) had little effect on the ability of FN stimulation to modulate the respiratory output. However, the modulation was abolished by bilateral electrolytic lesions of the Bötzinger complex (BötC). Further studies showed that bilateral chemical inactivation of BötC neurons produced by topical microinjection of kainic acid or cobalt chloride failed to abolish the modulation. We concluded that fibers of passage, not synapses or cell bodies in the BötC, were involved in the modulatory effect of FN stimulation on the PN. The RN, PRN, and PRG appear not to be important in the neural circuitry responsible for the FN modulation of the phrenic activity. Anat Rec 254:542–548, 1999.

Hyperventilation evoked by activation of the vicinity of the caudal inferior olivary nucleus depends on the fastigial nucleus in anesthetized rats

Several studies have demonstrated that cerebellar deep nuclei, particularly the rostral fastigial nucleus (FNr), are involved in respiratory modulation. These nuclei receive inputs from the contralateral caudal inferior olivary nuclei of the medulla. The objectives of this study were to determine whether electrical and chemical activation of the vicinity of the caudal inferior olivary nuclei (vIOc) affected respiration and, if true, whether the FNr was involved in the vIOc stimulation-evoked ventilatory responses. Experiments were conducted in 30 anesthetized and spontaneously breathing rats. Our results showed that 1) electrical (25 or 100 microA at 10 or 20 Hz for 10 s) and chemical (1 or 100 mM, 25-50 nl N-methyl-D-aspartate) stimulation of the vIOc augmented ventilation predominantly via increasing tidal volume; 2) the responses to the electrical stimulation were almost eliminated by lesion of the contralateral FNr via microinjection of ibotenic acid; and 3) the respiratory responses to electrical stimulation in the vicinity of the rostral IO were 65-70% smaller compared with that evoked by vIOc stimulation. These findings strongly suggest that vIOc neurons play a significant role in modulation of respiratory activity, largely depending on their projections to the FNr.