The study of human eye movements provides an extremely useful approach to the examination of a variety of cognitive functions. It is obvious that the latency and goal saccadic eye movements are related to attention. What is not so obvious is that other aspects of cognition such as short-term memory, preparatory set, and inhibition of context inappropriate responses can also be assessed using eye movement techniques. Short-term memory, preparatory set, and inhibition of context inappropriate responses constitute core functions of the prefrontal cortex, the brain region most involved in the control of higher order cognitive processes. We have used a number of different tasks to elicit saccades, including Go/No Go tasks and delayed response tasks. These tasks allow us to independently assess core functions of the prefrontal cortex by measuring the accuracy and latency of memory guided saccades, as well as the frequency of context inappropriate saccades that should be inhibited. Using these tasks we have demonstrated that schizophrenics are impaired in all three core aspects of prefrontal cortex function while children with Attention Deficit Hyperactivity Disorder (ADHD) are impaired in only their ability to inhibit context inappropriate saccades. During the past year we have demonstrated that, similar to children with ADHD, alcoholics are impaired in their ability to inhibit context inappropriate saccades. The smooth pursuit eye movements of alcoholics are completely normal. We are in the process of extending our eye movement recording equipment so that we will be able to measure vertical as well as horizontal eye movements. This addition will allow us to develop new tasks examining modulation and control of visual attention. Z01AA00003 The objectives of this project are to: (1) investigate the interaction of alcohol with proteins and lipids in biological membranes; (2) study structure and dynamics of membranes composed of lipids with polyunsaturated fatty acids such as docosahexaenoic acid (DHA) 22:6n-3; and (3) study lipid-protein interactions related to alcoholism and lipid polyunsaturation. (1) The interface location of ethanol lowers interfacial energy of bilayers, increasing the area per lipid molecule. This provides more space for movement of the lipid hydrocarbon chains which become progressively more disordered with increasing ethanol concentration. Ethanol-induced chain disordering is smaller in polyunsaturated bilayers, most likely because polyunsaturated hydrocarbon chains already occupy a larger area per molecule and are therefore less sensitive to ethanol-induced disordering. The ethanol molecules at the lipid-water interface block pathways for water diffusion through lipid bilayers as seen in decreased rates of water permeation. (2) Dehydration of membranes under polyethylene glycol (PEG)-controlled osmotic stress is equivalent to applying a lateral tension which compresses membranes. We have measured with 2-H NMR the changes in lipid chain order resulting from stepwise osmotic dehydration and, on the same samples, with X-ray diffraction the reduction of lamellar repeat spacing. The combination of NMR and X-ray methods allows exact determination of lipid area and lateral compressibility coefficients. Mixed-chain 18:0-22:6 PC has lower lateral compressibility coefficients than monounsaturated 18:0-18:1 PC. In the polyunsaturated mixed-chain 18:0-22:6 PC, the saturated 18:0 chain appears to be far less compressible than the polyunsaturated 22:6 chain. (3) The peptide fragment 828 848 with the sequence RVIEVVQGACRAIRHIPRRIR from the carboxy terminal region of the envelope glycoprotein gp41 of HIV-1 deeply incorporates into negatively charged dimyristoyl- phosphatidylglycerol (DMPG) bilayers as an amphipathic alpha helix. Measurements on peptide with specifically deuterated isoleucine amino acids demonstrate that three of the four isoleucine residues are deeply imbedded in the hydrocarbon core of the membrane. The positively charged carboxy terminus of the peptide is located at the bilayer surface and shows a higher degree of flexibility.
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