P312 Modeling Effects of Norepinephrine on Respiratory Neurons
Sreshta Venkatakrishnan*1, Andrew Kieran Tryba2, Alfredo J. Garcia, 3rd3, and Yangyang Wang1
1Department of Mathematics, Brandeis University, Waltham, MA, USA
2Department of Pediatrics, Section of Neurology, The University of Chicago, Chicago, IL, USA
3Institute for Integrative Physiology, The University of Chicago, Chicago, IL, USA
*Email: sreshtav@brandeis.edu
Introduction
The preBötzinger complex (pBC) within the mammalian brainstem,comprised ofintrinsically bursting and spiking neurons,generates the neural rhythm that drives the inspiratory phase of respiration. Norepinephrine (NE), a neuromodulator, differentially modulates synaptically isolated pBC neurons [1]. In cadmium (Cd)-insensitive N-bursting neurons, NE stimulates burst frequency without affecting burst duration. In Cd-sensitive C-bursting neurons, NE increases duration while minimally affecting frequency. NE also induces conditional bursts in tonic spiking neurons, while silent neurons remain inactivein the presenceof NE. In this work, we propose a novel mechanism to simulate the effects of NE in single pBC neurons.
Methods
The pBC neuron model we consider is a single-compartment dynamical system with Hodgkin-Huxley-style conductances, incorporating membrane potential and calcium dynamics, adapted from previous works [2,3,4]. Of particular interest to us amongst the ionic currents incorporated in this model are two candidate burst-generating currents: Cd-insensitive persistent sodium current (INaP) and Cd-sensitive calcium-activated nonspecific cationic current (ICAN). Building on previous efforts for modeling NE via modulating ICAN[2,3] and from experimental evidence in [5], we propose that NE application in the model also leads to an increase in the flux of [Ca2+] between the cytosol and the ER, modeled via inositol-triphosphate, IP3.
Results
The most important finding of this study is the identification of potential mechanisms underlying the NE-mediated induction of tonic spiking neurons to CAN-dependent bursting. Our model predicts that this conditional bursting requires an increase in both IP3and ICAN. This mechanism also induces an increase in N-burst frequency and C-burst duration, while N-burst duration remains unaltered. While modulatingICANincreases C-burst frequency in our model, the opposing effect brought bymodulating IP3effectivelycounters this increase and maintains frequency. Furthermore, we also identify discrete parameter regimes where silent neurons continue to remain inactive in NE. These results are consistent with [1].
Discussion
Conditional bursting has been previously described in rhythmic networks; however, the underlying mechanisms are often unknown. Our model predicts a new mechanism involving NE-signaling, elevating both IP3and ICANin a subset of pBC neurons. These predictions need to be experimentally tested by blocking either IP3or ICAN, and testing whether subsequent NE modulation can no longer recruit this subset of pBC neurons to burst. Moreover, while our model predictions for bursting neurons mostly agree with the experiments in [1], we also notice some discrepancies with respect to burst frequency and duration. Further investigation is required to analyze and understand these disparities.
Acknowledgements
This work has been supported byNIH R01DA057767:CRCNS: Evidence-based modeling of neuromodulatory action on network properties,granted to Yangyang Wang (PI)andAlfredo Garcia at UChicago.
References
[1]https://doi.org/10.1152/jn.01308.2005
[2]https://doi.org/10.1007/s10827-010-0274-z
[3]https://doi.org/10.1007/s10827-012-0425-5
[4]https://doi.org/10.1063/1.5138993
[5]https://doi.org/10.1152/ajpendo.1985.248.6.E633
