Carotid chemoreceptors tune breathing via multipath routing: reticular chain and loop operations supported by parallel spike train correlations

Abstract

We tested the hypothesis that carotid chemoreceptors tune breathing through parallel circuit paths that target distinct elements of an inspiratory neuron chain in the ventral respiratory column (VRC). Microelectrode arrays were used to monitor neuronal spike trains simultaneously in the VRC, peri-nucleus tractus solitarius (p-NTS)-medial medulla, the dorsal parafacial region of the lateral tegmental field (FTL-pF), and medullary raphe nuclei together with phrenic nerve activity during selective stimulation of carotid chemoreceptors or transient hypoxia in 19 decerebrate, neuromuscularly blocked, and artificially ventilated cats. Of 994 neurons tested, 56% had a significant change in firing rate. A total of 33,422 cell pairs were evaluated for signs of functional interaction; 63% of chemoresponsive neurons were elements of at least one pair with correlational signatures indicative of paucisynaptic relationships. We detected evidence for postinspiratory neuron inhibition of rostral VRC I-Driver (pre-Bötzinger) neurons, an interaction predicted to modulate breathing frequency, and for reciprocal excitation between chemoresponsive p-NTS neurons and more downstream VRC inspiratory neurons for control of breathing depth. Chemoresponsive pericolumnar tonic expiratory neurons, proposed to amplify inspiratory drive by disinhibition, were correlationally linked to afferent and efferent "chains" of chemoresponsive neurons extending to all monitored regions. The chains included coordinated clusters of chemoresponsive FTL-pF neurons with functional links to widespread medullary sites involved in the control of breathing. The results support long-standing concepts on brain stem network architecture and a circuit model for peripheral chemoreceptor modulation of breathing with multiple circuit loops and chains tuned by tegmental field neurons with quasi-periodic discharge patterns. NEW & NOTEWORTHY We tested the long-standing hypothesis that carotid chemoreceptors tune the frequency and depth of breathing through parallel circuit operations targeting the ventral respiratory column. Responses to stimulation of the chemoreceptors and identified functional connectivity support differential tuning of inspiratory neuron burst duration and firing rate and a model of brain stem network architecture incorporating tonic expiratory "hub" neurons regulated by convergent neuronal chains and loops through rostral lateral tegmental field neurons with quasi-periodic discharge patterns.

A spatially dynamic network underlies the generation of inspiratory behaviors

“…Recruitment of the rostral column during gasping may also provide an explanation for how, in some cases, gasping can be generated after the preBötC is lesioned and eupnea is abolished (50), a finding that is difficult to reconcile with the hypothesis that the preBötC compartment is the exclusive site for gasping (83). In contrast to our in vivo finding, we found a relatively blunted gasping response in vitro (48), which suggests that descending input from the pons, excitatory drive from the carotid body, or neuromodulatory inputs (66, 84) play an important role in generating gasping in vivo.…”

“…During a transient 5-min episode of anoxia, burst amplitudes during fictive gasping were reduced at both the preBötC center (−26 ± 6%) and 540 ± 64 µm rostral of the preBötC (−15 ± 8%; P > 0.05). Frequency depression during fictive gasping (−24 ± 7%) was also modest compared with gasping in vivo, likely related to, for example, a lack of chemosensory drive from carotid bodies and/or excitatory neuromodulatory inputs that contribute to the hypoxic response in vivo (66–68).…”

Carotid Bodies and the Integrated Cardiorespiratory Response to Hypoxia

“…11B in Ref. 177). This model is consistent with the observation that some chemoresponsive NTS neurons have an evoked or enhanced inspiratory-modulated firing pattern during carotid body stimulation (194).…”

“…Neurons in the NTS and adjacent medial medulla have heterogeneous phenotypes and diverse responses to carotid body stimulation (2,4,36,116,120,157,194,265). These "chemoresponsive" neurons operate through multiple circuit pathways to regulate the depth and frequency of breathing and, concurrently, cardiac output and vascular tone (FIGURE 1) (91,177).…”

“…Carotid chemoreceptor stimulation can shorten the inspiratory burst duration of some I-Driver neurons, which otherwise exhibit little or no change in their firing rate, whereas their targets, including bulbospinal premotor neurons, exhibit larger rate increases, enhancing inspiratory drive. These observations led to a model with parallel circuit mechanisms for tuning tidal volume and breathing frequency (173,177).…”