AGED-RELATED CHANGES IN CORTICAL CIRCUITS IN HUMANS

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This application is in response to the program announcement PA-92-07 for research grants on Neural Systems and Mental, Neurological and Aging Disorders. The goal of the proposed research is to determine how functional circuits develop in the human visual cortex and how these circuits change with advancing age. These questions will be approached by tracing connections in the aldehyde fixed, postmortem human brain with the fluorescent dye, DiI. This is a technology which we have first introduced for studying circuits in the human brain (Burkhalter and Bernardo, 1989). The study will be focused on connections in the visual cortex, not because understanding vision or visual disorders are the main interest here, but because this is the only system in the CNS whose functional architecture is understood well enough that meaningful structure/function relationships can be derived, and small alterations in the normal connectivity pattern can be detected. If successful, it is anticipated that the study will provide information on a number of important issues. It will show that l) microcircuits in the human brain can be studied by an experimental method, 2) neuronal circuits develop in a preprogrammed sequence which determines the maturation of specific functions, 3) cortical connections change throughout life, and 4) connectivity changes are restricted to systems that develop late in life and whose development may be strongly influenced by experience. The proposal is based on preliminary studies in the human primary visual cortex (VI) which revealed three principal findings: 1) local connections within cortical columns develop prenatally, 2) horizontal connections between columns develop postnatally in a manner that circuits related to the motion processing pathway develop before circuits the are more closely associated with form and color analysis, and 3) the laminar organization of feedback projections to striate cortex is selectively altered in aged brains. The experiments proposed in this application are focused on horizontal connections within V1, the second visual area V2 and feedback projections between V2 and V1. Specifically, we will determine: 1) how local connections form within V2, 2) whether feedback connections emerge before forward projections, 3) whether feedback projections are altered in aged brains and, 4) whether local connections within V1 change over the span of life. These connections have in common that they allow the intracortical comparison of distant points of the visual field. This property is essential for the segmentation of a figure from its surround. Psychophysical tests indicate that visual tasks that require integration over large portions of the visual field do not develop until 1 year of age and deteriorate with advanced age. Thus, it is possible that these changes are due to alterations of long-range connections within V1, V2 or modified feedback input from V2 to V1. Similar connections may be important in other cortical areas where they may underlie sensory-motor integration or provide for integration across functionally different systems.