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 pathology in brain diseases in humans. Subgenual area 25 and MTL areas are affected in depression, which often manifests early in chronic traumatic encephalopathy (CTE). Medial frontal and temporal areas show distinct types of pathology in CTE by unknown circuit mechanisms. The goal of the proposed studies is to use high resolution connections in monkeys to investigate the circuit mechanisms of the distinct pathology in medial frontal and MTL areas in CTE 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, to compare with laminar-specific tau pathology in CTE; (3) The normal excitatory and inhibitory neuronal and glial make-up of frontal area 25 in monkeys and humans to compare with CTE, based on evidence that hyperactivity in area 25 perturbs normal function in depression; and (4) The density and integrity of axons below area 25 in human control and CTE brains, which give rise to bidirectional pathways that link 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. High-resolution data from monkeys will be compared with CTE cortex to identify distinct pathology in MTL and medial frontal regions. Quantitative data will be obtained using correlated light, confocal and electron microscopy, analyzed using advanced statistical methods and synthesized through modeling. Findings will establish the still unknown circuit basis for distinct pathology in MTL and medial frontal areas in CTE, which perturbs the excitation-inhibition balance in depression and the processes of interoception, emotion and memory.