ALzheimer's disease (AD) is characterized by a number of neuropathological alterations in the architecture of the cerebral cortex. The anatomical distribution of some of these changes and their correlation with the severity of dementia have led to the hypothesis that the dementia of AD is due to a progressive disruption in the flow of information processing among higher-order cortical association regions. These corticocortical connections are furnished primarily by pyramidal neurons located in layers 2, 3, and 3. However, pyramidal cells also give rise to extensive axon collaterals which form a majority of cortical synapses, and which appear to be the primary propagators of intracortical excitatory activity. In higher-order association regions of monkey cortex, these axon collaterals form a unique lattice-like structure composed of a series of discontinuous, repeating stripes with a specific orientation in layers 1- 3. Disruption of these intracortical connections in AD would impair the recruitment of networks of neurons within a region that appear to be essential to the generation of specific patterns of output from that region. This disruption of intracortical information flow would in turn lead to a failure to activate specific neuronal populations distributed across other cortical regions, producing cognitive impairment. In this project, we will use the macaque monkey as a model of the human brain in order to develop specific hypotheses regarding the integrity of the lattice structure of intracortical connectivity in AD. Combinations of anterograde and retrograde tracers, intracellular injections, and electron microscopy will be used to fully characterize the organization of the lattice structure, to determine the morphology and extrinsic projection site of the neurons that furnish the intrinsic lattice, and to define the synaptic targets of lattice connections. Parallel studies will then be conducted in postmortem monkey and control human brain in order to determine the extent to which the monkey accurately predicts the organization of intracortical connections in human brain. The results of these studies will be used to generate specific hypotheses regarding the integrity of the lattice circuitry in AD, which will then be tested in postmortem studies of AD brains. Understanding the unique arrangement of intracortical connections in higher-order association regions of the primate brain, and the integrity of this circuitry in AD, may provide critical insights into the manner in which the pathology of AD produces the cognitive dysfunction characteristic of this disorder.
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