The prefrontal cortex in primates receives signals from structures associated with sensory perception, cognition, emotion and action, and uses them flexibly for the task at hand or to ponder the past and plan the future. These functions are guided by attention that engages prefrontal and anterior cingulate cortices, and are disrupted in several neural diseases by unknown circuit mechanisms. The subgenual cingulate area 25 is a key node within the anterior cingulate, and has cellular and physiologic features consistent with its high activity at rest, a role in plastic processes, and complementary functions with dorsolateral task-related prefrontal areas. The goal of the proposed study is to investigate the largely unexplored circuitry of area 25 in a normal primate animal model. The working hypothesis is that specific cellular features of area 25 and interactions with excitatory and distinct types of inhibitory neurons in other prefrontal, temporal and thalamic structures underlie the plasticity of area 25 and engagement in networks for flexible behavior. Experiments are designed to test this hypothesis at high resolution in normal rhesus monkeys through study of: (1) glial and axon features in area 25 associated with excitability, synaptic function and axon remodeling; and the connections of area 25 with other cortices; (2) serial pathways through which dorsolateral prefrontal cortices may modulate activity in area 25 through the anterior cingulate area 32, by innervating excitatory and functionally distinct classes of inhibitory neurons; (3) key circuits that link the hippocampus with area 25, and link both structures with the inhibitory thalamic reticular nucleus, in a network associated with attention and the contextual significance of stimuli; (4) computational modeling to investigate how processing through area 25 and its local prefrontal and extended networks affects attention and appreciation of context. Hypotheses about pathway interactions are based on a theoretical framework that helps predict patterns of connections based on laminar structure. Multiple neural pathways will be labeled with neural tracers, combined with double- or triple-labeling of distinct classes of inhibitory neurons and receptors. Brain tissue will be processed for study at the light, confocal, and electron microscopic level to conduct quantitative analyses from the system of pathways to their synapses. Findings from these studies will provide the foundation to unravel in future studies the mechanisms underlying the preferential vulnerability of area 25 in neurologic and psychiatric diseases, such as frontotemporal dementia and major depression.
A region in the front part of the brain known as cingulate area 25 has flexible function that makes it possible for people to appreciate the context of events, and is active when one quietly thinks about the past or plans the future. Area 25 is disrupted in the neurological disease frontotemporal dementia, as well as in depression and autism, leading to loss of appreciation of the context of events affecting behavior and social interactions, but th causes are not understood. This project involves mapping the circuits of this region in a primate animal model, as well as specific cellular features that give A25 flexibility but may also render i vulnerable to disease, which is needed for development of therapies.
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