The Kölliker‐Fuse nucleus (KF) is a functionally distinct component of the parabrachial complex, located in the dorsolateral pons of mammals. The KF has a major role in respiration and upper airway control. A comprehensive understanding of the KF and its contributions to respiratory function and dysfunction requires an appreciation for its neurochemical characteristics. The goal of this review is to summarize the diverse neurochemical composition of the KF, focusing on the neurotransmitters, neuromodulators, and neuropeptides present. We also include a description of the receptors expressed on KF neurons and transporters involved in each system, as well as their putative roles in respiratory physiology. Finally, we provide a short section reviewing the literature regarding neurochemical changes in the KF in the context of respiratory dysfunction observed in SIDS and Rett syndrome. By over‐viewing the current literature on the neurochemical composition of the KF, this review will serve to aid a wide range of topics in the future research into the neural control of respiration in health and disease.

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Orexins are neuropeptides originating from the hypothalamus that serve broad physiological roles, including the regulation of autonomic function, sleep-wake states, arousal and breathing. Lack of orexins may lead to narcolepsy and sleep disordered breathing. Orexinergic hypothalamic neurons send fibers to Kӧlliker-Fuse (KF) neurons that directly project to the rostroventral respiratory group, and phrenic and hypoglossal motor neurons. These connections indicate a potential role of orexin-modulated KF neurons in functionally linking the control of wakefulness/arousal and respiration. In a reduced preparation of juvenile rats Orexin B microinjected into the KF led to a transient increase in respiratory rate and hypoglossal output, however Orexin B modulation of the KF in intact preparations has not been explored. Here, we performed microinjections of the Orexin B mouse peptide and the synthetic Orexin 2 receptor agonist, MDK 5220, in the KF of spontaneously breathing, isoflurane anesthetized wild type mice. Microinjection of Orexin-2 receptor agonists into the KF led to transient slowing of respiratory rate, which was more exaggerated in response to Orexin-B than MDK 5220 injections. Our data suggest that Orexin B signaling in the KF may contribute to arousal-mediated respiratory responses.

Impaired chemoreflex responses are a central feature of opioid-induced respiratory depression, however, the mechanism through which mu opioid receptor agonists lead to diminished chemoreflexes is not fully understood. One brainstem structure involved in opioid-induced impairment of chemoreflexes is the nucleus of the solitary tract (NTS), which contains a population of neurons that express mu opioid receptors. Here, we tested whether caudal NTS neurons activated during the chemoreflex challenge express mu opioid receptors and overlap with neurons activated by opioids. Using genetic labeling of mu opioid receptor-expressing neurons and cFos immunohistochemistry as a proxy for neuronal activation, we examined the distribution of activated NTS neurons following hypercapnia, hypoxia, and morphine administration. The main finding was that hypoxia and hypercapnia primarily activated NTS neurons that did not express mu opioid receptors. Furthermore, concurrent administration of morphine with hypercapnia induced cFos expression in non-overlapping populations of neurons. Together these results suggest an indirect effect of opioids within the NTS, which could be mediated through mu opioid receptors on afferents and/or inhibitory interneurons.

Rett syndrome (RTT) is an autism spectrum disorder caused by loss-of-function mutations in the methyl-CPG-binding protein 2 (Mecp2) gene. Frequent apneas and irregular breathing are prevalent in RTT, and also occur in rodent models of the disorder, including Mecp2(Bird) and Mecp2(R168X) mice. Sarizotan, a serotonin 5-HT1a and dopamine D2-like receptor agonist, reduces the incidence of apneas and irregular breathing in mouse models of RTT (Abdala et al., 2014). Targeting the 5HT1a receptor alone also improves respiration in RTT mice (Levitt et al., 2013). However, the contribution of D2 receptors in correcting these respiratory disturbances remains untested. PAOPA, a dopamine D2 receptor positive allosteric modulator, and quinpirole, a dopamine D2 receptor orthosteric agonist, were used in conjunction with whole-body plethysmography to evaluate whether activation of D2 receptors is sufficient to improve breathing disturbances in female heterozygous Mecp2(Bird/+) and Mecp2(R168X/+) mice. PAOPA did not significantly change apnea incidence or irregularity score in RTT mice. PAOPA also had no effect on the ventilatory response to hypercapnia (7% CO2). In contrast, quinpirole reduced apnea incidence and irregularity scores and improved the hypercapnic ventilatory response in Mecp2(R168X/+) and Mecp2(Bird/+) mice, while also reducing respiratory rate. These results suggest that D2 receptors do contribute to the positive effects of sarizotan in the correction of respiratory abnormalities in Rett syndrome. However, positive allosteric modulation of the D2 receptor alone is not sufficient to evoke these effects.