The neocortex is organized into neural circuits that perform distinct computations, from sensory processing and motor control to memory, learning and language. Neuromodulatory systems projecting to the neocortex exert a powerful influence on cortical computations through neurotransmitters such as acetylcholine, monoamines and neuropeptides. The prefrontal cortex (PFC), a cortical region required for working memory, attention and goal-directed behavior, receives dense projections from multiple neuromodulatory systems that dramatically impact its function. Pioneering work has shown that pharmacological manipulation of these systems can potently modulate attention and cognitive function and that impaired neuromodulation can lead to psychiatric disease. Yet, much of the view of high level cortical function is focused on models that either ignore neuromodulation altogether or treat it as a reward or arousal signal.We propose to elucidate the dynamics and mechanisms of prefrontal neuromodulatory tuning, from the level of synapses and cells to circuits and animal behavior. To achieve this goal, we will map the circuit-level impact of synaptic neuromodulatory inputs on the prefrontal cortex circuit dynamics, develop and apply two novel optogenetic approaches for light-based synaptic silencing and optical recording of cortical neuromodulatory activity in vivo, and establish the causal roles of PFC neuromodulation in attention and working memory. These experiments will enable us for the first time to delineate the specific contribution of distinct neuromodulatory systems to prefrontal function, integrating comprehensive cell- and circuit-level analysis with unique opto-physiological readouts in behaving animals. The project will yield an integrative view of prefrontal neuromodulation, revealing its impact on cortical function and dissecting its roles in cognitive function.