Functional tuning and network dynamics of touch-sensitive dorsal horn neurons in normal and disease states

Abstract

Tactile signal integration begins in the spinal cord dorsal horn (DH) where axons of primary sensory neurons that innervate the skin and convey discrete streams of sensory information, including innocuous and noxious touch, synapse onto diverse populations of DH interneurons and small populations of projection neurons. How tactile features are represented and transformed at this subcortical processing region and its influence on tactile representations in the brain are poorly understood. Using in vivo electrophysiological recordings and genetic manipulations, we observed that neurons in the mouse DH receive convergent inputs from both low- and high-threshold mechanoreceptor subtypes and exhibit one of six functionally distinct response profiles to mechanical stimulation of the skin. Disruption of DH inhibitory circuit motifs revealed an interconnected DH network that enables heterogeneous tuning of postsynaptic dorsal column output neurons and dictates tactile responses of neurons in primary somatosensory cortex. These findings indicate that mechanoreceptor subtype convergence and signal transformations within the DH shape how touch is represented in the brain. We next asked how tactile encoding and representations in the DH may change following nerve injury and ensuing mechanical allodynia, in which normally innocuous tactile stimuli are perceived as painful. Using the spared nerve injury (SNI) model of neuropathic pain and in vivo electrophysiological recordings, we investigated whether mechanically-evoked responses and population dynamics of DH interneurons change in the allodynic state. Surprisingly, despite dramatic behavioral over-reactivity to mechanical stimuli in SNI mice, an overall increase in sensitivity or reactivity of DH interneurons was not observed. However, we did observe decreases in correlated activity in SNI mice, including the synchrony of evoked firing. These alterations in DH temporal activity patterns are recapitulated by silencing DH PV+ interneurons, inhibitory interneurons previously implicated in neuropathic pain, as are the pain-like behaviors observed in allodynic mice. These findings suggest that decorrelated network activity in the DH, driven by alterations in PV+ interneurons, may be a general feature of the neuropathic pain state. Together, this work reveals remarkable functional diversity of DH interneurons and their critical roles in DH network dynamics, activity patterns of DH outputs, and tactile representation in the brain.