Selective modification of ascending spinal outputs in acute and neuropathic pain states.

Pain hypersensitivity arises from the plasticity of peripheral and spinal somatosensory neurons, which modifies nociceptive input to the brain and alters pain perception. We utilized chronic calcium imaging of spinal dorsal horn neurons to determine how the representation of somatosensory stimuli in the anterolateral tract, the principal pathway transmitting nociceptive signals to the brain, changes between distinct pain states. In healthy conditions, we identify stable, narrowly tuned outputs selective for cooling or warming, and a neuronal ensemble activated by intense/noxious thermal and mechanical stimuli. Induction of an acute peripheral sensitization with capsaicin selectively and transiently retunes nociceptive output neurons to encode low-intensity stimuli. In contrast, peripheral nerve injury-induced neuropathic pain results in a persistent suppression of innocuous spinal outputs coupled with activation of a normally silent population of high-threshold neurons. These results demonstrate the differential modulation of specific spinal outputs to the brain during nociceptive and neuropathic pain states.

Silent synapses dictate cocaine memory destabilization and reconsolidation.

Cocaine-associated memories are persistent, but, on retrieval, become temporarily destabilized and vulnerable to disruptions, followed by reconsolidation. To explore the synaptic underpinnings for these memory dynamics, we studied AMPA receptor (AMPAR)-silent excitatory synapses, which are generated in the nucleus accumbens by cocaine self-administration, and subsequently mature after prolonged withdrawal by recruiting AMPARs, echoing acquisition and consolidation of cocaine memories. We show that, on memory retrieval after prolonged withdrawal, the matured silent synapses become AMPAR-silent again, followed by re-maturation ~6 h later, defining the onset and termination of a destabilization window of cocaine memories. These synaptic dynamics are timed by Rac1, with decreased and increased Rac1 activities opening and closing, respectively, the silent synapse-mediated destabilization window. Preventing silent synapse re-maturation within the destabilization window decreases cue-induced cocaine seeking. Thus, cocaine-generated silent synapses constitute a discrete synaptic ensemble dictating the dynamics of cocaine-associated memories and can be targeted for memory disruption.