Project Abstract The many classes of neurons in the mammalian brain use many different neurotransmitters to communicate. Nevertheless, it has generally been assumed that each neuron uses one principal neurotransmitter. This notion has dominated the analysis of the contributions of synaptic transmission to circuit function and behavior. However, we and others have found that many neurons in the mammalian brain actually release several neurotransmitters at the same time, often targeting each neurotransmitter to a specific and different postsynaptic cell class. We propose that the co-released neurotransmitters act in concert to have consistent and mutually reinforcing effects on their enclosing circuit. Here we propose to study the integration and coordination of peptidergic, GABAergic, and cholinergic signaling and reveal how these diverse signaling molecules act together to dictate the activity and plasticity state of cerebral cortex. The pathways that we have uncovered are potentially powerful means of regulating cortical function and may, in the future, be exploited to restore cognitive function in neurodegenerative disorders.