Forebrain projection neurons target functionally diverse respiratory control areas in the midbrain, pons, and medulla oblongata

Abstract

Eupnea is generated by neural circuits located in the ponto‐medullary brainstem, but can be modulated by higher brain inputs which contribute to volitional control of breathing and the expression of orofacial behaviors, such as vocalization, sniffing, coughing, and swallowing. Surprisingly, the anatomical organization of descending inputs that connect the forebrain with the brainstem respiratory network remains poorly defined. We hypothesized that descending forebrain projections target multiple distributed respiratory control nuclei across the neuroaxis. To test our hypothesis, we made discrete unilateral microinjections of the retrograde tracer cholera toxin subunit B in the midbrain periaqueductal gray (PAG), the pontine Kölliker‐Fuse nucleus (KFn), the medullary Bötzinger complex (BötC), pre‐BötC, or caudal midline raphé nuclei. We quantified the regional distribution of retrogradely labeled neurons in the forebrain 12–14 days postinjection. Overall, our data reveal that descending inputs from cortical areas predominantly target the PAG and KFn. Differential forebrain regions innervating the PAG (prefrontal, cingulate cortices, and lateral septum) and KFn (rhinal, piriform, and somatosensory cortices) imply that volitional motor commands for vocalization are specifically relayed via the PAG, while the KFn may receive commands to coordinate breathing with other orofacial behaviors (e.g., sniffing, swallowing). Additionally, we observed that the limbic or autonomic (interoceptive) systems are connected to broadly distributed downstream bulbar respiratory networks. Collectively, these data provide a neural substrate to explain how volitional, state‐dependent, and emotional modulation of breathing is regulated by the forebrain.

Galanin analogs prevent mortality from seizure-induced respiratory arrest in mice

“…It is possible that improper ICV injection and local diffusion rather than ventricular distribution may account for the effects observed. Further, IA injection not properly administered may have affected surrounding regions that also control respiration ( Homma and Masaoka, 2008 ; Evans, 2010 ; Trevizan-Bau et al, 2021 ). Because central injection parameters were not verified explicitly, it is possible that off-target effects arising from galanin analog administration may have contributed to the outcomes observed.…”

Effects of Insular Cortex on Post-Stroke Dysphagia: A Systematic Review and Meta Analysis

“…Brain imaging studies have provided evidence that dyspnea is associated with activation of the insular cortex [ 53 ]. Meanwhile, Trevizan-Baú et al adopted holera toxin subunit B (CT-B) for the retrograde tracing of the neural regulation of breathing and found that insular exists alongside a great number of neurons with CT-B labeled [ 54 ]. Van et al used the pseudorabies virus (PRV) inoculation into the thyroarytenoid muscle, which participates in the breathing–swallowing coordination, showing that the PRV transfer from the peripheral to the swCPG, rCPG, hypothalamus, insular, and motor cortex.…”

The pre-Bötzinger complex is necessary for the expression of post-inspiration

“…The recruitment of distributed post-inspiratory neurons during orofacial behaviors such as swallowing, vocalization or sniffing, which all require specific modulations of airway patency, is further supported by recent trans-synaptic tracing studies that identified a brainstem-wide pre-motor network that overlaps with key nodes of the primary respiratory pattern generation network, including the Kölliker-Fuse nucleus, BötC, pre-BötC and intermediate reticular nucleus (Kurnikova et al ., 2018; Takatoh et al ., 2021). Further, both the pre-BötC and the Kölliker-Fuse nucleus are specific targets of descending cortical projections (Yang et al ., 2020; Trevizan-Baú et al ., 2021) emphasizing that key nodes for the coordination of volitional orofacial behaviors with on-going breathing activities are likely to be anatomically distributed. Thus, the synaptic interplay of an extended and distributed brainstem circuit is required for the generation of cranial nerve motor patterns during eupnea as well as during the coordination of breathing with vital orofacial behaviors.…”