Gregory J. Gerling, Lingtian Wan, Benjamin U. Hoffman, Yuxiang Wang, and Ellen A. Lumpkin
Despite past progress, the principles that govern the neural output for touch receptors have not been fully defined. We take an approach of combining computational models with experimental methods. Our work in collaboration of Dr. Ellen A. Lumpkin of Columbia University has sought to define rules in the end organ architecture of the Merkel cells and neurites that are innervated by slowly adapting type I afferents. We have built end organ models to show that the grouping of Merkel cells to heminodes strongly influence the sensitivity function of an afferent. Such computational single-unit models are built for neural afferents, comprising finite elements to capture skin mechanics, differential equations to represent sensory transduction, and integrate-and-fire models to mimic neural dynamics.
Slowly-adapting type I (SAI) cutaneous afferents help us discriminate fine spatial details. Their physiology and anatomy are distinguished by their slow adaptation in firing to held stimuli and innervation of Merkel cells, respectively. How mechanotransduction currents in Merkel cells and sensory neurons combine to give rise to neural spike firing is unknown. In considering wildtype animals, as well as Atoh1 conditional knockout animals that lack Merkel cells, this effort employs a computational modeling approach constrained by biological measurements.
For the developed generator function to recapitulate firing responses across genotype, a previously unsuspected current source is required that is ultra slowly adapting. Thus, the model makes specific predictions for future experimental studies.
Using computational approaches, constrained by biophysical measurements, we determine that matching the wildtype response requires extending the slowly inactivating (SI) time constant or adding an ultra slowly adapting (USI) decay. As is shown elsewhere in the paper, only the addition of an USI term is feasible in a Atoh1 knockout animal without Merkel cells. I.e., when the SI term is taken away, the remaining rapidly inactivating (RI) channels are far too fast to re-capitulate the Atoh1 knockout response.