Determinants of sparse activity in neocortex

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ABSTRACT Synaptic plasticity in neocortical neurons is intimately tied to learning and memory. Decades of research in acute brain slices have characterized the patterns of spike timing required to evoke synaptic change in minute detail, but it remains unknown whether these conditions occur and are sufficient to drive synaptic plasticity in the living brain. Indeed, in vivo recordings indicate that neocortical neurons live in an environment of profound inhibition that lowers overall firing rates and prevents plasticity. How then do cortical neurons escape this inhibition to encounter appropriate conditions for plasticity during learning? New evidence suggests that parvalbumin (PV) GABAergic neurons may play a dominant role in regulating cortical activity and controlling network rewiring, particularly at the early stages of learning. Using a multiwhisker stimulus coupled to a water reward, we have developed a paradigm for sensory association learning that drives rapid changes in excitatory synaptic strength in mouse barrel cortex. Importantly, our new data indicate that PV output to neocortical pyramidal neurons is markedly suppressed at the earliest stages of sensory training. Our experiments will integrate in vivo and acute brain slice recordings to test the hypothesis that PV neurons are a dominant regulator of sensory- evoked activity in mouse barrel cortex. We propose that reward-related acetylcholine release indirectly suppresses PV neural firing to depress PV output and increase sensory-evoked activity during learning. Our experiments will identify mechanisms for cortical disinhibition that facilitate experience-dependent synaptic plasticity in sensory cortex.