Interdependence of cellular and network properties in respiratory rhythm generation.

How breathing is generated by the preBötzinger complex (preBötC) remains divided between two ideological frameworks, and a persistent sodium current (I) lies at the heart of this debate. Although I is widely expressed, the pacemaker hypothesis considers it essential because it endows a small subset of neurons with intrinsic bursting or "pacemaker" activity. In contrast, burstlet theory considers I dispensable because rhythm emerges from "preinspiratory" spiking activity driven by feed-forward network interactions.

Inactivity-induced phrenic motor facilitation requires PKCζ activity within phrenic motor neurons.

Prolonged inhibition of respiratory neural activity elicits a long-lasting increase in phrenic nerve amplitude once respiratory neural activity is restored. Such long-lasting facilitation represents a form of respiratory motor plasticity known as inactivity-induced phrenic motor facilitation (iPMF). Although facilitation also occurs in inspiratory intercostal nerve activity after diminished respiratory neural activity (iIMF), it is of shorter duration.

Modeling Effects of Variable preBötzinger Complex Network Topology and Cellular Properties on Opioid-Induced Respiratory Depression and Recovery.

The preBötzinger complex (preBötC), located in the medulla, is the essential rhythm-generating neural network for breathing. The actions of opioids on this network impair its ability to generate robust, rhythmic output, contributing to life-threatening opioid-induced respiratory depression (OIRD). The occurrence of OIRD varies across individuals and internal and external states, increasing the risk of opioid use, yet the mechanisms of this variability are largely unknown.

Interdependence of cellular and network properties in respiratory rhythmogenesis.

How breathing is generated by the preBötzinger Complex (preBötC) remains divided between two ideological frameworks, and the persistent sodium current () lies at the heart of this debate. Although is widely expressed, the considers it essential because it endows a small subset of neurons with intrinsic bursting or "pacemaker" activity. In contrast, considers dispensable because rhythm emerges from "pre-inspiratory" spiking activity driven by feed-forward network interactions.

A comparative examination of morphine and fentanyl: unravelling the differential impacts on breathing and airway stability.

This study provides an in-depth analysis of the distinct consequences of the opioid drugs morphine and fentanyl during opioid-induced respiratory depression (OIRD). We explored the physiological implications of both drugs on ventilation and airway patency in anaesthetized mice. Our results revealed a similar reduction in respiratory frequency with equivalent scaled dosages of fentanyl and morphine, though the onset of suppression was more rapid with fentanyl.

Purinergic signaling mediates neuroglial interactions to modulate sighs.

Sighs prevent the collapse of alveoli in the lungs, initiate arousal under hypoxic conditions, and are an expression of sadness and relief. Sighs are periodically superimposed on normal breaths, known as eupnea. Implicated in the generation of these rhythmic behaviors is the preBötzinger complex (preBötC).

Peripheral macrophages drive CNS disease in the Ndufs4(-/-) model of Leigh syndrome.

Subacute necrotizing encephalopathy, or Leigh syndrome (LS), is the most common pediatric presentation of genetic mitochondrial disease. LS is a multi-system disorder with severe neurologic, metabolic, and musculoskeletal symptoms. The presence of progressive, symmetric, and necrotizing lesions in the brainstem are a defining feature of the disease, and the major cause of morbidity and mortality, but the mechanisms underlying their pathogenesis have been elusive.

Parabrachial tachykinin1-expressing neurons involved in state-dependent breathing control.

Breathing is regulated automatically by neural circuits in the medulla to maintain homeostasis, but breathing is also modified by behavior and emotion. Mice have rapid breathing patterns that are unique to the awake state and distinct from those driven by automatic reflexes. Activation of medullary neurons that control automatic breathing does not reproduce these rapid breathing patterns.

The sigh and related behaviors.

Breathing is a critical, complex, and highly integrated behavior. Normal rhythmic breathing, also referred to as eupnea, is interspersed with different breathing related behaviors. Sighing is one of such behaviors, essential for maintaining effective gas exchange by preventing the gradual collapse of alveoli in the lungs, known as atelectasis.

Inspiratory rhythm generation is stabilized by .

Cellular and network properties must be capable of generating rhythmic activity that is both flexible and stable. This is particularly important for breathing, a rhythmic behavior that dynamically adapts to environmental, behavioral, and metabolic changes from the first to the last breath. The pre-Bötzinger complex (preBötC), located within the ventral medulla, is responsible for producing rhythmic inspiration.

Leukocytes mediate disease pathogenesis in the Ndufs4(KO) mouse model of Leigh syndrome.

Symmetric, progressive, necrotizing lesions in the brainstem are a defining feature of Leigh syndrome (LS). A mechanistic understanding of the pathogenesis of these lesions has been elusive. Here, we report that leukocyte proliferation is causally involved in the pathogenesis of LS.

Dynamic Rhythmogenic Network States Drive Differential Opioid Responses in the Respiratory Network.

Death from opioid overdose is typically caused by opioid-induced respiratory depression (OIRD). A particularly dangerous characteristic of OIRD is its apparent unpredictability. The respiratory consequences of opioids can be surprisingly inconsistent, even within the same individual.

Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network.

The analgesic utility of opioid-based drugs is limited by the life-threatening risk of respiratory depression. Opioid-induced respiratory depression (OIRD), mediated by the μ-opioid receptor (MOR), is characterized by a pronounced decrease in the frequency and regularity of the inspiratory rhythm, which originates from the medullary preBötzinger Complex (preBötC). To unravel the cellular- and network-level consequences of MOR activation in the preBötC, MOR-expressing neurons were optogenetically identified and manipulated in transgenic mice in vitro and in vivo.

Remodeling of the Homer-Shank interactome mediates homeostatic plasticity.

Neurons maintain stable levels of excitability using homeostatic synaptic scaling, which adjusts the strength of a neuron's postsynaptic inputs to compensate for extended changes in overall activity. Here, we investigated whether prolonged changes in activity affect network-level protein interactions at the synapse. We assessed a glutamatergic synapse protein interaction network (PIN) composed of 380 binary associations among 21 protein members in mouse neurons.

Unraveling the Mechanisms Underlying Irregularities in Inspiratory Rhythm Generation in a Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder anatomically characterized by a progressive loss of dopaminergic neurons in the substantia nigra compacta (SNpc). Much less known, yet clinically very important, are the detrimental effects on breathing associated with this disease. Consistent with the human pathophysiology, the 6-hydroxydopamine hydrochloride (6-OHDA) rodent model of PD shows reduced respiratory frequency (f) and NK1r-immunoreactivity in the pre-Bötzinger complex (preBötC) and PHOX2B neurons in the retrotrapezoid nucleus (RTN).

Neuronal mechanisms underlying opioid-induced respiratory depression: our current understanding.

Opioid-induced respiratory depression (OIRD) represents the primary cause of death associated with therapeutic and recreational opioid use. Within the United States, the rate of death from opioid abuse since the early 1990s has grown disproportionally, prompting the classification as a nationwide "epidemic." Since this time, we have begun to unravel many fundamental cellular and systems-level mechanisms associated with opioid-related death.

Peptides, Breathing, and Sudden Infant Death Syndrome.

Shi et al. recently identified a brainstem peptidergic circuit in mice that is activated at birth and stabilizes breathing during the transition from the intra-utero environment to air breathing. This network remains important for maintaining stable breathing and respiratory homeostasis throughout development, and deficiencies in this network may be linked to sudden infant death syndrome (SIDS).

Dissociable control of unconditioned responses and associative fear learning by parabrachial CGRP neurons.

Parabrachial CGRP neurons receive diverse threat-related signals and contribute to multiple phases of adaptive threat responses in mice, with their inactivation attenuating both unconditioned behavioral responses to somatic pain and fear-memory formation. Because CGRP neurons respond broadly to multi-modal threats, it remains unknown how these distinct adaptive processes are individually engaged. We show that while three partially separable subsets of CGRP neurons broadly collateralize to their respective downstream partners, individual projections accomplish distinct functions: hypothalamic and extended amygdalar projections elicit assorted unconditioned threat responses including autonomic arousal, anxiety, and freezing behavior, while thalamic and basal forebrain projections generate freezing behavior and, unexpectedly, contribute to associative fear learning.

Insights into the dynamic control of breathing revealed through cell-type-specific responses to substance P.

The rhythm generating network for breathing must continuously adjust to changing metabolic and behavioral demands. Here, we examined network-based mechanisms in the mouse preBötzinger complex using substance P, a potent excitatory modulator of breathing frequency and stability, as a tool to dissect network properties that underlie dynamic breathing. We find that substance P does not alter the balance of excitation and inhibition during breaths or the duration of the resulting refractory period.

Perinatal Breathing Patterns and Survival in Mice Born Prematurely and at Term.

Infants born prematurely, often associated with maternal infection, frequently exhibit breathing instabilities that require resuscitation. We hypothesized that breathing patterns during the first hour of life would be predictive of survival in an animal model of prematurity. Using plethysmography, we measured breathing patterns during the first hour after birth in mice born at term (Term 19.

A spatially dynamic network underlies the generation of inspiratory behaviors.

The ability of neuronal networks to reconfigure is a key property underlying behavioral flexibility. Networks with recurrent topology are particularly prone to reconfiguration through changes in synaptic and intrinsic properties. Here, we explore spatial reconfiguration in the reticular networks of the medulla that generate breathing.

The Dynamic Basis of Respiratory Rhythm Generation: One Breath at a Time.

Rhythmicity is a universal timing mechanism in the brain, and the rhythmogenic mechanisms are generally dynamic. This is illustrated for the neuronal control of breathing, a behavior that occurs as a one-, two-, or three-phase rhythm. Each breath is assembled stochastically, and increasing evidence suggests that each phase can be generated independently by a dedicated excitatory microcircuit.

The interdependence of excitation and inhibition for the control of dynamic breathing rhythms.

The preBötzinger Complex (preBötC), a medullary network critical for breathing, relies on excitatory interneurons to generate the inspiratory rhythm. Yet, half of preBötC neurons are inhibitory, and the role of inhibition in rhythmogenesis remains controversial. Using optogenetics and electrophysiology in vitro and in vivo, we demonstrate that the intrinsic excitability of excitatory neurons is reduced following large depolarizing inspiratory bursts.