Dual Mechanisms for Heterogeneous Responses of Inspiratory Neurons to Noradrenergic Modulation

Abstract

Respiration is an essential involuntary function necessary for survival. This poses a challenge for the control of breathing. The preBotzinger complex (preBotC) is a heterogeneous neuronal network responsible for driving the inspiratory rhythm. While neuromodulators such as norepinephrine (NE) allow it to be both robust and flexible for all living beings to interact with their environment, the basis for how neuromodulation impacts neuron-specific properties remains poorly understood. In this work, we examine how NE influences different preBotC neuronal subtypes by modeling its effects through modulating two key parameters: calcium-activated nonspecific cationic current gating conductance (gCAN) and inositol-triphosphate (IP3), guided by experimental studies. Our computational model captures the experimentally observed differential effects of NE on distinct preBotC bursting patterns. We show that this dual mechanism is critical for inducing conditional bursting and identify specific parameter regimes where silent neurons remain inactive in the presence of NE. Furthermore, using methods of dynamical systems theory, we uncover the mechanisms by which NE differentially modulates burst frequency and duration in NaP-dependent and CAN-dependent bursting neurons. These results align well with previously reported experimental findings and provide a deeper understanding of cell-specific neuromodulatory responses within the respiratory network. MSC codes37N25, 34C23, 34C60, 34E13, 34E15, 92C20