Post-Critical Period Transcriptional and Physiological Adaptations of Primary Sensory Cortex after Sensory Loss

Single cell transcriptomics supports both cell-specific characterization and the identification of responses to changes in neural activity. Unilateral whisker denervation in adult male and female mice activates post-critical period synaptic plasticity, but the transcriptional responses of neuronal subtypes remain unknown. Single nucleus RNA sequencing and multiplex fluorescence in situ hybridization identified previously unexplored plasticity mechanisms in layer 4 (L4) excitatory neurons in intact sensory cortex. We detected differentially expressed genes related to glutamate receptor signaling and synaptogenesis in thalamocortical (TC) recipient L4 sensory cortex neurons after whisker denervation. L4 excitatory neurons increase expression of glutamate receptors indicative of stabilized and potentiated TC synapses along the intact pathway. Immunohistochemistry and electrophysiology determined that intracortical connections to L4 neurons were specifically increased. Transcriptionally unique subtypes of L4 neurons responded uniformly to whisker denervation, likely responding to the global upregulation of activity in the intact sensory cortex after unilateral whisker denervation. These adaptations likely underlie the increased cortical activity responding to intact sensory inputs that are observed in rodents and humans after unilateral denervation injury.