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Integration of autonomic and metabolic regulation, including hepatic function, is a critical role played by the brain's hypothalamic region. Specifically, the paraventricular nucleus of the hypothalamus (PVN) regulates autonomic functions related to metabolism, such as hepatic glucose production. Although insulin can act directly on hepatic tissue to inhibit hepatic glucose production, recent evidence implicates central actions of insulin within PVN also regulates glucose metabolism. However, specific central circuits responsible for insulin signaling with relation to hepatic regulation are poorly understood. As a heterogenous nucleus essential to controlling parasympathetic motor output with notable expression of insulin receptors, PVN is an appealing target for insulin-dependent modulation of parasympathetic activity. Here, we tested the hypothesis that insulin activates hepatic-related PVN (PVN hepatic ) neurons through a parasympathetic pathway. Using transsynaptic retrograde tracing, labeling within PVN was first identified 24 h after its expression in DMV and 72 h after hepatic injection. Critically, nearly all labeling in medial PVN was abolished after a left vagotomy, indicating that PVN hepatic neurons in this region are part of a central circuit innervating parasympathetic motor neurons. Insulin also significantly increased firing frequency of PVN hepatic neurons in this subregion. Mechanistically, rapamycin pretreatment inhibited insulin-dependent activation of PVN hepatic neurons. Therefore, central insulin signaling can activate a subset of PVN hepatic neurons which are part of a unique parasympathetic network in control of hepatic function. Taken together, PVN hepatic neurons related to parasympathetic output regulation could serve as a key central network in insulin's ability to control hepatic functions.

Background: Neural circuits produce reliable activity patterns despite disturbances in the environment. For this to occur, neurons elicit synaptic plasticity during perturbations. However, recent work suggests that plasticity not only regulates circuit activity during disturbances, but these modifications may also linger to stabilize circuits during future perturbations. The implementation of such a regulation scheme for real-life environmental challenges of animals remains unclear. Amphibians provide insight into this problem in a rather extreme way, as circuits that generate breathing are inactive for several months during underwater hibernation and use compensatory plasticity to promote ventilation upon emergence., Results: Using ex vivo brainstem preparations and electrophysiology, we find that hibernation in American bullfrogs reduces GABA A receptor (GABA A R) inhibition in respiratory rhythm generating circuits and motor neurons, consistent with a compensatory response to chronic inactivity. Although GABA A Rs are normally critical for breathing, baseline network output at warm temperatures was not affected. However, when assessed across a range of temperatures, hibernators with reduced GABA A R signaling had greater activity at cooler temperatures, enhancing respiratory motor output under conditions that otherwise strongly depress breathing., Conclusions: Hibernation reduces GABA A R signaling to promote robust respiratory output only at cooler temperatures. Although frogs do not ventilate lungs during underwater hibernation, we suggest this would be beneficial for stabilizing breathing when the animal passes through a large temperature range during emergence in the spring. More broadly, these results demonstrate that compensatory synaptic plasticity can increase the operating range of circuits in harsh environments, thereby promoting adaptive behavior in conditions that suppress activity., (© 2024. The Author(s).)

Background: Neural circuits produce reliable activity patterns despite disturbances in the environment. For this to occur, neurons elicit synaptic plasticity during perturbations. However, recent work suggests that plasticity not only regulates circuit activity during disturbances, but these modifications may also linger to stabilize circuits during future perturbations. The implementation of such a regulation scheme for real-life environmental challenges of animals remains unclear. Amphibians provide insight into this problem in a rather extreme way, as circuits that generate breathing are inactive for several months during underwater hibernation and use compensatory plasticity to promote ventilation upon emergence., Results: Using ex vivo brainstem preparations and electrophysiology, we find that hibernation in American bullfrogs reduces GABA A receptor (GABA A R) inhibition in respiratory rhythm generating circuits and motor neurons, consistent with a compensatory response to chronic inactivity. Although GABA A Rs are normally critical for breathing, baseline network output at warm temperatures was not affected. However, when assessed across a range of temperatures, hibernators with reduced GABA A R signaling had greater activity at cooler temperatures, enhancing respiratory motor output under conditions that otherwise strongly depress breathing., Conclusions: Hibernation reduces GABA A R signaling to promote robust respiratory output only at cooler temperatures. Although animals do not ventilate lungs during hibernation, we suggest this would be beneficial for stabilizing breathing when the animal passes through a large temperature range during emergence in the spring. More broadly, these results demonstrate that compensatory synaptic plasticity can increase the operating range of circuits in harsh environments, thereby promoting adaptive behavior in conditions that suppress activity., Competing Interests: Competing interests: Santin is a Guest Editor of the Special Issue “Synaptic plasticity, learning, and memory” at BMC Biology. The authors have no other competing interests to declare.

Breathing is generated by a rhythmic neural circuit in the brainstem, which contains conserved elements across vertebrate groups. In adult frogs, the 'lung area' located in the reticularis parvocellularis is thought to represent the core rhythm generator for breathing. Although this region is necessary for breathing-related motor output, whether it functions as an endogenous oscillator when isolated from other brainstem centers is not clear. Therefore, we generated thick brainstem sections that encompass the lung area to determine whether it can generate breathing-related motor output in a highly reduced preparation. Brainstem sections did not produce activity. However, subsaturating block of glycine receptors reliably led to the emergence of rhythmic motor output that was further enhanced by blockade of GABAA receptors. Output occurred in singlets and multi-burst episodes resembling the intact network. However, burst frequency was slower and individual bursts had longer durations than those produced by the intact preparation. In addition, burst frequency was reduced by noradrenaline and μ-opioids, and increased by serotonin, as observed in the intact network and in vivo. These results suggest that the lung area can be activated to produce rhythmic respiratory-related motor output in a reduced brainstem section and provide new insights into respiratory rhythm generation in adult amphibians. First, clustering breaths into episodes can occur within the rhythm-generating network without long-range input from structures such as the pons. Second, local inhibition near, or within, the rhythmogenic center may need to be overridden to express the respiratory rhythm., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Respiratory depression is the proximal cause of death in opioid overdose, yet the mechanisms underlying this potentially fatal outcome are not well understood. The goal of this review is to provide a comprehensive understanding of the pharmacological mechanisms of opioid-induced respiratory depression, which could lead to improved therapeutic options to counter opioid overdose, as well as other detrimental effects of opioids on breathing. The development of tolerance in the respiratory system is also discussed, as are differences in the degree of respiratory depression caused by various opioid agonists. Finally, potential future therapeutic agents aimed at reversing or avoiding opioid-induced respiratory depression through non-opioid receptor targets are in development and could provide certain advantages over naloxone. By providing an overview of mechanisms and effects of opioids in the respiratory network, this review will benefit future research on countering opioid-induced respiratory depression. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc., (© 2021 The British Pharmacological Society.)

Neurons tightly regulate firing rate and a failure to do so leads to multiple neurological disorders. Therefore, a fundamental question in neuroscience is how neurons produce reliable activity patterns for decades to generate behavior. Neurons have built-in feedback mechanisms that allow them to monitor their output and rapidly stabilize firing rate. Most work emphasizes the role of a dominant feedback system within a neuronal population for the control of moment-to-moment firing. In contrast, we find that respiratory motoneurons use 2 activity-dependent controllers in unique combinations across cells, dynamic activation of an Na+ pump subtype, and rapid potentiation of Kv7 channels. Both systems constrain firing rate by reducing excitability for up to a minute after a burst of action potentials but are recruited by different cellular signals associated with activity, increased intracellular Na+ (the Na+ pump), and membrane depolarization (Kv7 channels). Individual neurons do not simply contain equal amounts of each system. Rather, neurons under strong control of the Na+ pump are weakly regulated by Kv7 enhancement and vice versa along a continuum. Thus, each motoneuron maintains its characteristic firing rate through a unique combination of the Na+ pump and Kv7 channels, which are dynamically regulated by distinct feedback signals. These results reveal a new organizing strategy for stable circuit output involving multiple fast activity sensors scaled inversely across a neuronal population., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Pellizzari et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Opioids suppress breathing through actions in the brainstem, including respiratory-related areas of the dorsolateral pons, which contain multiple phenotypes of respiratory patterned neurons. The discharge identity of dorsolateral pontine neurons that are impacted by opioids is unknown. To address this, single neuronal units were recorded in the dorsolateral pons of arterially perfused in situ rat preparations that were perfused with an apneic concentration of the opioid agonist fentanyl, followed by the opioid antagonist naloxone (NLX). Dorsolateral pontine neurons were categorized based on respiratory-associated discharge patterns, which were differentially affected by fentanyl. Inspiratory neurons and a subset of inspiratory/expiratory phase-spanning neurons were either silenced or had reduced firing frequency during fentanyl-induced apnea, which was reversed upon administration of naloxone. In contrast, the majority of expiratory neurons continued to fire tonically during fentanyl-induced apnea, albeit with reduced firing frequency. In addition, pontine late-inspiratory and postinspiratory neuronal activity were absent from apneustic-like breaths during the transition to fentanyl-induced apnea and the naloxone-mediated transition to recovery. Thus, opioid-induced deficits in respiratory patterning may occur due to reduced activity of pontine inspiratory neurons, whereas apnea occurs with loss of all phasic pontine activity and sustained tonic expiratory neuron activity. NEW & NOTEWORTHY Opioids can suppress breathing via actions throughout the brainstem, including the dorsolateral pons. The respiratory phenotype of dorsolateral pontine neurons inhibited by opioids is unknown. Here, we describe the effect of the highly potent opioid fentanyl on the firing activity of these dorsolateral pontine neurons. Inspiratory neurons were largely silenced by fentanyl, whereas expiratory neurons were not. We provide a framework whereby this differential sensitivity to fentanyl can contribute to respiratory pattern deficits and apnea.