In the rodent whisker-related sensorimotor system, sensory and motor processing are tightly related both behaviorally and anatomically. Sensory and motor areas are extensive interconnected throughout different stages in the brain. During active whisking, neural responses in whisker-related primary motor cortex (wM1) are elevated, yet sensory-evoked responses in primary somatosensory barrel cortex (S1) are attenuated. Axons of S1-projecting M1 neurons branch off in infragranular layers of S1 and project to superficial layers where the axons ramify profusely. In sensory cortex, superficial layers are central to the processing of sensory information. Upon arrival to thalamo-recipient layer 4, sensory information is transferred to superficial layers, where it is integrated with information from other columns and other cortical areas. We recently found that 5HT3a (5-hydroxytryptamine 3a) receptor-expressing interneurons (5HT3aR INs) are the major population of GABAergic neurons in superficial layers, representing about 60% of the total interneuron population, and exceeding nearly two fold the proportion of fast-spiking (FS) parvalbumin (PV) expressing neurons, traditionally viewed as the dominant inhibitory system in neocortex. We recently showed that all 5HT3aR neurons are potently modulated by serotonin (5HT) and acetylcholine (ACh) acting on ionotropic 5HT3a and nicotinic receptors, respectively (Lee et al., in pres). Thus, 5HT3aR INs are uniquely poised to influence cortical sensory processes through their ability to convey fast effects of convergent neuromodulatory afferents during specific brain states and behavioral contexts. Based on location and prevalence of 5HT3aR INs together with extensive innervations of M1 inputs in superficial layers of S1, I hypothesize that inputs from wM1 directly activate 5HT3aR INs, thus providing feedforward inhibition in sensroimotor integration of the wM1-to-S1 circuitry. I wil investigate M1 inputs to 5HT3aR neurons in S1 superficial layers and the modulation of those inputs by subcortical neuromodulatory inputs using in vitro and in vivo electrophysiology combined with optogenetic methods. These studies will contribute to understanding circuit mechanisms of sensorimotor computation, and serve as a prototype of interareal communication in neocortex. ! PUBLIC HEALTH RELEVANCE: Neuromodulator systems such as serotonin and acetylcholine provide a mechanism by which small groups of neurons in subcortical nuclei can broadly influence activity in cortical networks. Conversely, disruption of such modulation of cortical circuits may impair various physiological processes, including cognitive function, and can potentially lead to diverse neurological and psychiatric disorders, including schizophrenia and mood disorders. The profound influence of these ascending neuromodulatory systems on cortex likely stems from their preferential targeting of cortical GABAergic inhibitory interneurons. We recently found that 5HT3a (5- hydroxytryptamine 3a) receptor-expressing interneurons (5HT3aR INs) are the major population of GABAergic neurons in superficial layers, representing about 60% of the total interneuron population. Our study showed that all 5HT3aR neurons are potently modulated by serotonin (5HT) and acetylcholine (ACh) acting on ionotropic 5HT3a and nicotinic receptors, respectively. In sensory cortex, superficial layers are central to integrate sensory processing with information from other columns and other cortical areas. Thus, 5HT3aR INs are uniquely poised to influence cortical sensory processes through their ability to convey fast effects of convergent neuromodulatory afferents during specific brain states and behavioral contexts. This project will elucidate the role of a 5HT3aR interneurons in interareal communication of cortex and will provide one of the circuit mechanisms by which neuromodulators can exert control over ongoing cortical activity.