This application requests funds to replace several obsolete and deteriorating items of equipment currently forming part of the only electron-microscope facility available at McLean Hospital. This will enable a group of investigators to maintain or re- establish an orderly progression of their PHS-supported research programs. The central questions addressed by these programs can be summarized as follows: 1. Computer-assisted morphometric studies analyzing synaptic characteristics in the medial prefrontal cortex of normal rats as well as of rats treated either separately or sequentially with reserpine and/or ipromiazid. These two mutually antagonistic thymoleptic drugs are suspected of inducing synaptic alterations in certain brain regions. 2. An ultrastructural identification of the cell type(s) that synthesize ependymins, a class of glycoproteins recently discovered and isolated by one of the applicants (V.E. Shashoua) and shown to be crucially associated with learning, i.e., the acquisition of new patterns of learned behavior. 3. A cytobiological study of the role of proteolytic enzymes in intracellular processes governing protein degradation, post- translational modification, and the release of biologically active macromolecules and peptides from precursors. 4. An electron-microscopic verification of transynaptic continuities between individual neuronal components of demonstrated or suspected circuits linking the corpus striatum to certain regions of the basal forebrain known or suspected to be involved in normal and disordered mental function. 5. An expansion of the function of the NIMH and NINCDS-funded Brain Tissue Resource Center to include the distribution of tissue prepared for E.M. and to examine cellular morphology at the ultrastructural level in diseased and aged human brain. 6. An investigation of structural abnormalities within neurons of the arcuate region of the hypothalamus in male androgen-deprived rats. 7. An immunocytochemical analysis at the ultrastructual level of amyloid protein in the Alzheimer's disease brain. 8. A study to morphologically correlate changes in phospholipid metabolism resulting from the action of cationic amphiphilic drugs (CADs) such as chlorpromazine, desmethylimipramine and propanolol.
