PROJECT SUMMARY Sensory representations are influenced by an animal’s external context, internal state, past experiences, expectations, and future goals. Prior information – including the history of recent stimuli, actions and rewards – plays an important role in guiding ongoing behavior, and can modulate the neural code even at the level of primary sensory cortex. The involvement of sensory cortex in mediating history- dependent shifts in behavior, and the contributions of specific cell types to these effects are not well understood. Using a novel whisker-based behavioral paradigm, I have demonstrated that mice can flexibly and selectively enhance sensory processing of recently rewarded whisker stimuli based on history cues. Here, I propose experiments to uncover the cell type-specific mechanisms in for history-based modulation in primary somatosensory cortex (S1), and test for their causal role in behavior. In Aim 1 (K99), I will use behavioral modeling approaches to systematically quantify history-based perceptual biases during goal-directed behavior in mice. I will examine modulation of pyramidal (PYR) cell activity in S1 of behaving mice while tracking trial-by-trial behavioral shifts in sensory detection performance guided by recent history. I will then empirically test the necessity of S1 in mediating history effects on behavior using reversible inactivation techniques. Two cortical interneuron classes, namely VIP cells and NDNF cells, are widely theorized to play a role in selective enhancement of sensory processing in cortex, since they receive a wide range of glutamatergic and neuromodulatory inputs and boost sensory responses in PYR cells through local disinhibition. Both these cell types are activated in different active behavioral states and learning contexts. In Aim 2 (K99/R00), I will test the role of VIP and NDNF interneurons in gating history-related signals using 2p imaging to monitor their neural activity, and through targeted activation or inactivation of these cell types using optogenetic techniques. VIP and NDNF interneurons are both recruited by acetylcholine, a neuromodulator that is necessary for stimulus-specific enhancement of sensory processing in primates, and behavioral state-based modulation of sensory cortex in rodents. In Aim 3 (R00), I will test the role of basal forebrain cholinergic projections in conveying history-related signals to S1. I will perform two-photon imaging of cholinergic terminals in S1 and use selective optogenetic activation to test whether the locus of prioritized processing on the whiskers can be artificially shifted in behaving mice. Together, the proposed studies will provide new insights into the local cortical circuits that facilitate prioritized processing of behaviorally relevant stimuli in sensory maps.

PROJECT NARRATIVE The ability to flexibly prioritize stimuli based on their ongoing behavioral relevance is critical for thriving in a complex environment. Behavioral flexibility is commonly affected in many neurodevelopmental conditions including attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorders, but the cell type-specific neural circuits underlying these processes are not well understood. The proposed project will use modern genetic tools in mice to mechanistically test the role of local interneurons and long-range cholinergic inputs in gating flexible modulation of sensory cortex and behavior in response to the history of stimuli, actions and rewards experienced in the recent past.