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1. Exploring the role of the Kölliker–Fuse nucleus in breathing variability by mathematical modelling

   https://doi.org/10.1113/JP285158  

   John, S. R. ; Barnett, W. H. ; Abdala, A. P. L. ; Zoccal, D. B. ; Rubin, J. E. ; Molkov, Y. I. ( December 2023 , The Journal of Physiology)

   The Kölliker–Fuse nucleus (KF), which is part of the parabrachial complex, participates in the generation of eupnoea under resting conditions and the control of active abdominal expiration when increased ventilation is required. Moreover, dysfunctions in KF neuronal activity are believed to play a role in the emergence of respiratory abnormalities seen in Rett syndrome (RTT), a progressive neurodevelopmental disorder associated with an irregular breathing pattern and frequent apnoeas. Relatively little is known, however, about the intrinsic dynamics of neurons within the KF and how their synaptic connections affect breathing pattern control and contribute to breathing irregularities. In this study, we use a reduced computational model to consider several dynamical regimes of KF activity paired with different input sources to determine which combinations are compatible with known experimental observations. We further build on these findings to identify possible interactions between the KF and other components of the respiratory neural circuitry. Specifically, we present two models that both simulate eupnoeic as well as RTT‐like breathing phenotypes. Using nullcline analysis, we identify the types of inhibitory inputs to the KF leading to RTT‐like respiratory patterns and suggest possible KF local circuit organizations. When the identified properties are present, the two models also exhibit quantal acceleration of late‐expiratory activity, a hallmark of active expiration featuring forced exhalation, with increasing inhibition to KF, as reported experimentally. Hence, these models instantiate plausible hypotheses about possible KF dynamics and forms of local network interactions, thus providing a general framework as well as specific predictions for future experimental testing.image

   The Kölliker–Fuse nucleus (KF), a part of the parabrachial complex, is involved in regulating normal breathing and controlling active abdominal expiration during increased ventilation.

   Dysfunction in KF neuronal activity is thought to contribute to respiratory abnormalities seen in Rett syndrome (RTT). This study utilizes computational modelling to explore different dynamical regimes of KF activity and their compatibility with experimental observations.

   By analysing different model configurations, the study identifies inhibitory inputs to the KF that lead to RTT‐like respiratory patterns and proposes potential KF local circuit organizations.

   Two models are presented that simulate both normal breathing and RTT‐like breathing patterns.

   These models provide testable hypotheses and specific predictions for future experimental investigations, offering a general framework for understanding KF dynamics and potential network interactions.

    

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2. Tonic extracellular glutamate and ischaemia: glutamate antiporter system x c − regulates anoxic depolarization in hippocampus

   https://doi.org/10.1113/JP283880  

   Heit, Bradley S. ; Chu, Alex ; Sane, Abhay ; Featherstone, David E. ; Park, Thomas J. ; Larson, John ( November 2022 , The Journal of Physiology)

   In stroke, the sudden deprivation of oxygen to neurons triggers a profuse release of glutamate that induces anoxic depolarization (AD) and leads to rapid cell death. Importantly, the latency of the glutamate‐driven AD event largely dictates subsequent tissue damage. Although the contribution of synaptic glutamate during ischaemia is well‐studied, the role of tonic (ambient) glutamate has received far less scrutiny. The majority of tonic, non‐synaptic glutamate in the brain is governed by the cystine/glutamate antiporter, system x_c⁻. Employing hippocampal slice electrophysiology, we showed that transgenic mice lacking a functional system x_c⁻display longer latencies to AD and altered depolarizing waves compared to wild‐type mice after total oxygen deprivation. Experiments which pharmacologically inhibited system x_c⁻, as well as those manipulating tonic glutamate levels and those antagonizing glutamate receptors, revealed that the antiporter's putative effect on ambient glutamate precipitates the ischaemic cascade. As such, the current study yields novel insight into the pathogenesis of acute stroke and may direct future therapeutic interventions.image

   Ischaemic stroke remains the leading cause of adult disability in the world, but efforts to reduce stroke severity have been plagued by failed translational attempts to mitigate glutamate excitotoxicity.

   Elucidating the ischaemic cascade, which within minutes leads to irreversible tissue damage induced by anoxic depolarization, must be a principal focus.

   Data presented here show that tonic, extrasynaptic glutamate supplied by system x_c⁻synergizes with ischaemia‐induced synaptic glutamate release to propagate AD and exacerbate depolarizing waves.

   Exploiting the role of system x_c⁻and its obligate release of ambient glutamate could, therefore, be a novel therapeutic direction to attenuate the deleterious effects of acute stroke.

    

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3. Computational framework for the generation of one‐dimensional vascular models accounting for uncertainty in networks extracted from medical images

   https://doi.org/10.1113/JP286193  

   Bartolo, Michelle_A ; Taylor‐LaPole, Alyssa_M ; Gandhi, Darsh ; Johnson, Alexandria ; Li, Yaqi ; Slack, Emma ; Stevens, Isaiah ; Turner, Zachary_G ; Weigand, Justin_D ; Puelz, Charles ; et al ( July 2024 , The Journal of Physiology)

   One‐dimensional (1D) cardiovascular models offer a non‐invasive method to answer medical questions, including predictions of wave‐reflection, shear stress, functional flow reserve, vascular resistance and compliance. This model type can predict patient‐specific outcomes by solving 1D fluid dynamics equations in geometric networks extracted from medical images. However, the inherent uncertainty inin vivoimaging introduces variability in network size and vessel dimensions, affecting haemodynamic predictions. Understanding the influence of variation in image‐derived properties is essential to assess the fidelity of model predictions. Numerous programs exist to render three‐dimensional surfaces and construct vessel centrelines. Still, there is no exact way to generate vascular trees from the centrelines while accounting for uncertainty in data. This study introduces an innovative framework employing statistical change point analysis to generate labelled trees that encode vessel dimensions and their associated uncertainty from medical images. To test this framework, we explore the impact of uncertainty in 1D haemodynamic predictions in a systemic and pulmonary arterial network. Simulations explore haemodynamic variations resulting from changes in vessel dimensions and segmentation; the latter is achieved by analysing multiple segmentations of the same images. Results demonstrate the importance of accurately defining vessel radii and lengths when generating high‐fidelity patient‐specific haemodynamics models.image

   This study introduces novel algorithms for generating labelled directed trees from medical images, focusing on accurate junction node placement and radius extraction using change points to provide haemodynamic predictions with uncertainty within expected measurement error.

   Geometric features, such as vessel dimension (length and radius) and network size, significantly impact pressure and flow predictions in both pulmonary and aortic arterial networks.

   Standardizing networks to a consistent number of vessels is crucial for meaningful comparisons and decreases haemodynamic uncertainty.

   Change points are valuable to understanding structural transitions in vascular data, providing an automated and efficient way to detect shifts in vessel characteristics and ensure reliable extraction of representative vessel radii.

    

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4. Inspiratory and sigh breathing rhythms depend on distinct cellular signalling mechanisms in the preBötzinger complex

   https://doi.org/10.1113/JP285582  

   Borrus, Daniel S. ; Stettler, Marco K. ; Grover, Cameron J. ; Kalajian, Eva J. ; Gu, Jeffrey ; Conradi Smith, Gregory D. ; Del Negro, Christopher A. ( February 2024 , The Journal of Physiology)

   Breathing behaviour involves the generation of normal breaths (eupnoea) on a timescale of seconds and sigh breaths on the order of minutes. Both rhythms emerge in tandem from a single brainstem site, but whether and how a single cell population can generate two disparate rhythms remains unclear. We posit that recurrent synaptic excitation in concert with synaptic depression and cellular refractoriness gives rise to the eupnoea rhythm, whereas an intracellular calcium oscillation that is slower by orders of magnitude gives rise to the sigh rhythm. A mathematical model capturing these dynamics simultaneously generates eupnoea and sigh rhythms with disparate frequencies, which can be separately regulated by physiological parameters. We experimentally validated key model predictions regarding intracellular calcium signalling. All vertebrate brains feature a network oscillator that drives the breathing pump for regular respiration. However, in air‐breathing mammals with compliant lungs susceptible to collapse, the breathing rhythmogenic network may have refashioned ubiquitous intracellular signalling systems to produce a second slower rhythm (for sighs) that prevents atelectasis without impeding eupnoea.image

   A simplified activity‐based model of the preBötC generates inspiratory and sigh rhythms from a single neuron population.

   Inspiration is attributable to a canonical excitatory network oscillator mechanism.

   Sigh emerges from intracellular calcium signalling.

   The model predicts that perturbations of calcium uptake and release across the endoplasmic reticulum counterintuitively accelerate and decelerate sigh rhythmicity, respectively, which was experimentally validated.

   Vertebrate evolution may have adapted existing intracellular signalling mechanisms to produce slow oscillations needed to optimize pulmonary function in mammals.

    

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5. Mitochondrial phosphagen kinases support the volatile power demands of motor nerve terminals

   https://doi.org/10.1113/JP284872  

   Justs, Karlis A. ; Sempertegui, Sergio ; Riboul, Danielle V. ; Oliva, Carlos D. ; Durbin, Ryan J. ; Crill, Sarah ; Stawarski, Michal ; Su, Chenchen ; Renden, Robert B. ; Fily, Yaouen ; et al ( November 2023 , The Journal of Physiology)

   Motor neurons are the longest neurons in the body, with axon terminals separated from the soma by as much as a meter. These terminals are largely autonomous with regard to their bioenergetic metabolism and must burn energy at a high rate to sustain muscle contraction. Here, through computer simulation and drawing on previously published empirical data, we determined that motor neuron terminals inDrosophila larvae experience highly volatile power demands. It might not be surprising then, that we discovered the mitochondria in the motor neuron terminals of bothDrosophila and mice to be heavily decorated with phosphagen kinases ‐ a key element in an energy storage and buffering system well‐characterized in fast‐twitch muscle fibres. Knockdown of arginine kinase 1 (ArgK1) inDrosophilalarval motor neurons led to several bioenergetic deficits, including mitochondrial matrix acidification and a faster decline in the cytosol ATP to ADP ratio during axon burst firing.image

   Neurons commonly fire in bursts imposing highly volatile demands on the bioenergetic machinery that generates ATP.

   Using a computational approach, we built profiles of presynaptic power demand at the level of single action potentials, as well as the transition from rest to sustained activity.

   Phosphagen systems are known to buffer ATP levels in muscles and we demonstrate that phosphagen kinases, which support such phosphagen systems, also localize to mitochondria in motor nerve terminals of fruit flies and mice.

   By knocking down phosphagen kinases in fruit fly motor nerve terminals, and using fluorescent reporters of the ATP:ADP ratio, lactate, pH and Ca²⁺, we demonstrate a role for phosphagen kinases in stabilizing presynaptic ATP levels.

   These data indicate that the maintenance of phosphagen systems in motor neurons, and not just muscle, could be a beneficial initiative in sustaining musculoskeletal health and performance.

    

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