Goal-directed behavior requires selection of signals from the external and internal emotional environments based on memory and prior experience for action. Processes that rely on emotions and memory engage the network of medial frontal area 25 and medial temporal lobe (MTL) cortices, which are affected in psychiatric diseases. The goal of the proposed studies is to investigate specific circuits of the medial frontal (subgenual area 25) and MTL regions in rhesus monkeys. Pathways will be studied in the context of the excitatory and inhibitory neuronal composition in both monkeys and humans, which critically affects function and disruption in brain diseases. Our overarching hypothesis is that the Structural Model, which predicts the patterns and strength of cortical connections studied in non-human primates, apply for study of the human brain and can be applied to understand the circuit basis of the involvement of subgenual area 25 and MTL in depression. The goal of the proposed studies is to use high resolution connections in monkeys to investigate the circuit mechanisms between medial prefrontal A25 and MTL areas through study of: (1) The synaptic targets of frontal area 25 to MTL area 28 in monkeys, and the excitatory-inhibitory neuronal composition of the respective areas in both monkeys and humans; (2) Laminar connections within MTL in monkeys and their relationship to the local architecture; (3) The normal excitatory and inhibitory neuronal and glial make-up of frontal area 25 in monkeys and humans, based on evidence that hyperactivity in area 25 perturbs function in depression; and (4) The density of axons below area 25 in human control brains, which give rise to bidirectional pathways that link it with nearby prefrontal and distant cortices. Hypotheses about pathway relationships are based on the theoretical and data based Structural Model, in the context of principles of excitatory and inhibitory control in primates. Pathways in rhesus monkeys will be labeled with distinct neural tracers, combined with multiple labeling for inhibitory neurons and receptors. Quantitative data will be obtained using correlated light, confocal and electron microscopy and analyzed using advanced statistical methods and synthesized through modeling. Findings will establish the still unknown circuit interactions of medial prefrontal areas and MTL, and their likely involvement in depression, which perturbs the excitation-inhibition balance and the processes of interoception, emotion and memory.