Tactile information is actively acquired and processed in the brain through concerted interactions between movement and sensation. Somatosensory input is often the result of self-generated movement during the active touch of objects, and conversely, sensory information is used to refine motor control. There must therefore be important interactions between sensory and motor pathways, which we chose to investigate in the mouse whisker sensorimotor system. Voltage-sensitive dye was applied to the neocortex of mice to directly image the membrane potential dynamics of sensorimotor cortex with subcolumnar spatial resolution and millisecond temporal precision. Single brief whisker deflections evoked highly distributed depolarizing cortical sensory responses, which began in the primary somatosensory barrel cortex and subsequently excited the whisker motor cortex. The spread of sensory information to motor cortex was dynamically regulated by behavior and correlated with the generation of sensory-evoked whisker movement. Sensory processing in motor cortex may therefore contribute significantly to active tactile sensory perception.

Voltage-sensitive dye imaging resolves the spatiotemporal dynamics of supragranular subthreshold cortical activity with millisecond temporal resolution and subcolumnar spatial resolution. We used a flexible fiber optic image bundle to visualize voltage-sensitive dye dynamics in the barrel cortex of freely moving mice while simultaneously filming whisker-related behavior to generate two movies matched frame-by-frame with a temporal resolution of up to 2 ms. Sensory responses evoked by passive whisker stimulation lasted longer and spread further across the barrel cortex in awake mice compared to anesthetized mice. Passively evoked sensory responses were large during behaviorally quiet periods and small during active whisking. However, as an exploring mouse approached an object while whisking, large-amplitude, propagating cortical sensory activity was evoked by active whisker-touch. These experiments demonstrate that fiber optics can be used to image cortical sensory activity with high resolution in freely moving animals. The results demonstrate differential processing of sensory input depending upon behavior.

Hypersensitivity in response to sensory stimuli and neocortical hyperexcitability are prominent features of Fragile X Syndrome (FXS) and autism spectrum disorders, but little is known about the dendritic mechanisms underlying these phenomena. We found that the primary somatosensory neocortex (S1) was hyperexcited in response to tactile sensory stimulation in Fmr1(-/y) mice. This correlated with neuronal and dendritic hyperexcitability of S1 pyramidal neurons, which affect all major aspects of neuronal computation, from the integration of synaptic input to the generation of action potential output. Using dendritic electrophysiological recordings, calcium imaging, pharmacology, biochemistry and a computer model, we found that this defect was, at least in part, attributable to the reduction and dysfunction of dendritic h- and BKCa channels. We pharmacologically rescued several core hyperexcitability phenomena by targeting BKCa channels. Our results provide strong evidence pointing to the utility of BKCa channel openers for the treatment of the sensory hypersensitivity aspects of FXS.