Reduced computational modelling of Kölliker‐Fuse contributions to breathing patterns in Rett syndrome

Abstract

Key pointsr Reduced computational models are used to test effects of loss of inhibition to the Kölliker-Fuse nucleus (KFn).r Three reduced computational models that simulate eupnoeic and vagotomized respiratory rhythms are considered.r All models exhibit the emergence of respiratory perturbations associated with Rett syndrome as inhibition to the KFn is diminished.r Simulations suggest that application of 5-HT 1A agonists can mitigate the respiratory pathology. r The three models can be distinguished and tested based on their predictions about connections and dynamics within the respiratory circuit and about effects of perturbations on certain respiratory neuron populations.Abstract Rett syndrome (RTT) is a developmental disorder that can lead to respiratory disturbances featuring prolonged apnoeas of variable durations. Determining the mechanisms underlying these effects at the level of respiratory neural circuits would have significant implications for treatment efforts and would also enhance our understanding of respiratory rhythm generation and control. While experimental studies have suggested possible factors contributing to the respiratory patterns of RTT, we take a novel computational approach to the investigation of RTT, which allows for direct manipulation of selected system parameters and testing of specific hypotheses. Specifically, we present three reduced computational models, developed using an established framework, all of which successfully simulate respiratory outputs across eupnoeic and vagotomized conditions. All three models show that loss of inhibition to the Kölliker-Fuse nucleus reproduces the key respiratory alterations associated with RTT and, as suggested experimentally, that effects of 5-HT 1A agonists on the respiratory neural circuit suffice Sam Wittman graduated from the University of Pittsburgh in 2017 with BS degrees in mathematical biology and neuroscience. As an undergraduate, he performed modelling research on the neural basis of Rett syndrome under Dr Jonathan Rubin, and he worked in the vestibular electrophysiology lab of Dr Bill Yates and Dr Andrew McCall. He is currently pursuing a MS in S. Wittman and others J Physiol 597.10to alleviate this respiratory pathology. Each of the models makes distinct predictions regarding the neuronal populations and interactions underlying these effects, suggesting natural directions for future experimental testing.

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

“…The models presented in this work are adapted from previous models for respiratory neurons and circuits (Rubin et al, 2009(Rubin et al, , 2011Wittman et al, 2019). To form these models, we incorporated the KF component into a pre-existing model presented by Rubin et al (2011).…”

“…We analyse the extent to which each of these inhibition types, within each model, yields outputs consistent with respiratory perturbations seen in Rett syndrome (RTT), and we also study the emergence of late-E activity (active expiration). Previous work by Wittman et al (2019) introduced a simplified representation of pulmonary stretch receptor feedback related to I phase output. As part of the analysis of the silent model done in the current paper, we study the primary effect of this pathway by considering what happens if we introduce an additional excitatory connection from post-I to KF-s (shown as a black dashed arrow in Fig.…”

“…There is a long tradition of using mathematical modelling and computational techniques to build theoretical models of the rCPG, develop intuition about how it functions, and test hypotheses on respiratory rhythm and pattern generation (Lindsey et al, 2012;Molkov et al, 2017;Phillips & Rubin, 2022). In the past, we developed models integrating a medullary CPG circuit with a pontine component using an established reduced, activity-based mathematical framework (Barnett et al, 2018;Flor et al, 2020;Molkov et al, 2017;Rubin et al, 2009Rubin et al, , 2011Wittman et al, 2019). Previous models differed in their assumptions about pontine interactions and intrinsic dynamics, which need to be better characterized experimentally.…”

“…Understanding the mechanisms underlying the control of KF activity is essential to identify its role in breathing pattern formation in eupnoea (Smith et al, 2007) and to determine how changes in these mechanisms affect the expiratory motor pattern (Barnett et al, 2018;Koolen, 2021) and contribute to inducing stereotyped breathing patterns such as those observed in Rett syndrome (Abdala et al, 2016). The latter was previously modelled by Wittman et al (2019) who showed that certain assumptions about the intrinsic properties of the KF neurons and patterns of connections between KF and other respiratory structures can explain the emergence of irregular breathing when inhibition in KF is compromised. However, the validity of some of the assumptions made in that work is unknown and they await experimental testing, and the authors did not compare model behaviour with experimental findings about manipulations that change the efficacy of inputs to KF neurons.…”

“…The details of these predictions, however, depend on the assumptions made about intrinsic properties and activity patterns of KF neurons, synaptic interactions in the circuit, and conditions leading to aberrant KF activity and subsequent perturbations of breathing. To reproduce specific experimental observations, model networks that include the KF have required the presence of specific synaptic pathways, such as from inhibitory neurons in the Bötzinger complex (BötC) (Wittman et al., 2019) and nucleus tractus solitarii (NTS) pump cells (Molkov et al., 2013). Models have also suggested that KF neurons may have certain intrinsic properties modulating their activity such as endogenous bursting (Wittman et al., 2019).…”