Machine learning elucidates electrophysiological properties predictive of multi- and single-firing human and mouse dorsal root ganglia neurons

Abstract

Human and mouse dorsal root ganglia (hDRG and mDRG) neurons are important tools in understanding the molecular and electrophysiological mechanisms that underlie nociception and drive pain behaviors. One of the simplest differences in firing phenotypes is that neurons are single-firing (exhibit only one action potential) or multi-firing (exhibit 2 or more action potentials). To determine if single- and multi-firing hDRG neurons exhibit differences in intrinsic properties, firing phenotypes, and AP waveform properties, and if these properties could be used to predict multi-firing, we measured 22 electrophysiological properties by whole-cell patch-clamp electrophysiology of 94 hDRG neurons from 6 male and 4 female donors. We then analyzed the data using several machine learning models to determine if these properties could be used to predict multi-firing. We used 1000 iterations of Monte Carlo Cross Validation to split the data into different train and test sets and tested the Logistic Regression, k-Nearest Neighbors, Random Forest, Support Vector Classifier, and XGBoost machine learning models. All models tested had a greater than 80% accuracy on average, with Support Vector Classifier and XGBoost performing the best. We found that several properties correlated with multi-firing hDRG neurons and together could be used to predict multi-firing neurons in hDRG including a long decay time, a low rheobase, and long first spike latency. We also found that the hDRG models were able to predict multi-firing with 90% accuracy in mDRG neurons. Understanding these properties could be beneficial in the elucidation of targets on peripheral sensory neurons related to pain.

Significance Statement This study will improve understanding of the electrophysiological mechanisms of DRG neurons. Our machine learning algorithms show few species differences between mouse and human DRG neuron electrophysiology under baseline conditions. These are important findings for the study of neuronal excitability in the context of pain therapeutic development.