PROJECT SUMMARY Learning and memory involve multiple brain areas. However, the hippocampus (CA1) and ventral tegmental area (VTA) are the brain regions primarily involved in novelty detection and context discrimination. Abnormal connection between these brain regions leads to deficits in novelty behavior. For decades, the function of the VTA-CA1 circuit in learning, and the dysregulation of midbrain neurotransmitter systems in diseases like schizophrenia, depression, and addictions have been attributed (primarily) to the dopamine neurons. Because of this traditional focus on the midbrain dopaminergic systems, the glutamate pathway has been overlooked and is less understood in normal brain function and neuropsychiatric disorders. In a recent study, we showed that the VTA glutamate terminals are anatomically dominant in the CA1 while VTA dopamine terminals were limited to the basal dendrite layer. Functional tracing of the VTA-CA1 pathway shows that selective activation of VTA glutamate and dopamine neurons has distinguishable effects on CA1 local circuits. Photostimulation of VTA glutamate – but not the dopamine – neurons increased burst firing of CA1 pyramidal cells. Likewise, stimulation of the VTA glutamate pathway increased putative pyramidal cells (PYR) excitation of interneurons (INT) in CA1 ensembles. In freely behaving mice, novelty detection tasks that activate the VTA-CA1 circuit increased CA1 PYR/INT connectivity while its inhibition altered novelty-linked behavior. Based on preliminary results, the proposed research will elucidate the functional significance of the VTA glut→CA1 tract in the hippocampal encoding of novelty-dependent behavior including context discrimination and habituation. The results of the proposed research will increase our understanding of VTA excitatory modulation of cognitive processes and control of adaptive behavior.