PROJECT SUMMARY / ABSTRACT Complex behaviors rely on the combination of sensory clues and internal factors like goals, expectations, memories, and attention. A breakdown of these interactions is thought to be at the core of many neuropsychiatric disorders. Sensory information is carried by feedforward inputs while internal factors are conveyed via feedback afferents. Robust evidence from humans, primates, and rodents indicates that sensory and feedback neuronal pathways converge in the posterior parietal cortex (PPC). Indeed, the PPC is thought to be fundamental to an array of cognitive processes including working memory and decision-making. These data suggest that PPC neurons play a key role in integrating sensory and cognitive information streams. Yet, we have a critical gap in our knowledge regarding the synaptic mechanisms integrating feedforward inputs with feedback signals in the PPC. This lack of insight limits our ability to understand how neuronal circuit interactions drive behavior and how impaired integration leads to neuropsychiatric disorders. In preliminary experiments, we used two-color optogenetics to independently control cortical afferent pathways. We discovered that PPC neurons receive direct, monosynaptic innervation from both feedforward and feedback sources. Furthermore, we found marked differences in how functionally distinct subclasses of layer 5 pyramidal neurons integrate inputs from discrete long-range afferents. Specifically, intratelencephalically projecting (IT) cells exhibited nonlinear response enhancement while subcortically projecting extratelencephalic (ET) neurons summed inputs linearly. These data motivate our central hypothesis that cell- type specific integration of feedforward and feedback synapses drives input / output transformations in the PPC. To test this hypothesis, we propose a complementary use of opto- and chemogenetic circuit manipulation, brain slice electrophysiology and computational modelling. First, we will determine the temporal rules governing the interaction of feedback and feedforward afferents in distinct layer 5 projection neurons (Aim 1). Then we will combine two-color optogenetics with circuit specific chemogenetic silencing (DREADDs) to determine how cell-type specific synaptic integration drives the functional output of the PPC network (Aim 2). Finally, we will take advantage of computational methods to determine what ionic conductances underlie the cell-type specificity of feedforward-feedback integration (Aim 3). Completion of this research will provide novel insights into the cellular mechanisms underpinning the interaction of sensory and feedback information streams. This knowledge will further our understanding of the principles that guide information processing in the neocortex and provide the foundation for future basic and translational research.