Visual experience during an early critical period is essential for the normal maturation of visual cortex, such that altered vision at this stage can have deleterious consequences, including amblyopia. Previous studies established that synaptic connections in the visual could be modified through a process that depends on both neural activity (Hebbian synaptic plasticity) and long-range neuromodulatory inputs that convey information on the behavioral state of the animals. The goal of this project is to elucidate the cellular mechanisms by which two prominent neuromodulators, norepinephrine and serotonin, control the induction Hebbian synaptic plasticity in the visual cortex. Specifically we will examine the hypothesis that norepinephrine and serotonin can act retroactively as reward-like signals to reinforce recently activated synapses. This proposal builds upon our recent finding that in cortical slices certain patterns of synaptic activity produce “eligibility traces” for synaptic modification. These eligibility traces are transient and silent tags that can be converted into long-term potentiation if 2-adrenergic receptors (AR) are promptly activated, or into long-term depression if 5HT2C serotonergic receptors are activated. This retroactive action of the monoamines on Hebbian plasticity is a novel mechanism of neuromodulator that contrast and complement the more traditional view of neuromodulators as enabling factor that prime of promote subsequent plasticity. We plan to study the role of the induction/conversion of eligibility traces in visual cortical plasticity in vivo and to assess its impact in visual cortical responses. The findings resulting from the proposed can have translational consequences. In particular, the possibility of inducing rapid and targeted cortical modifications with the aid of neuromodulators can be relevant for restoring visual cortical functions in adults. Besides the obvious relevance of neural plasticity to the development of visual capabilities, it is likely that similar processes may form the basis for some forms of learning and memory in the adult brain.