Mark Rosenzweig - US grants

The overall aim of our project is to test and extend hypotheses about the neurochemical processes that must occur between input of information and its eventual recall; these extend from short-term processes through the latter aspects of consolidation of long-term memory. To assure generality of testing, we plan to use and compare both an avian (chick) and mammalian (mouse and rat) models, to employ positive as well as aversive training, and active as well as passive tests. By attempting to test the generality of promising current formulations, we expect to measure how far along the field is towards a satisfactory neurochemical account of memory. To achieve this overall purpose we plan to carry out the following specific steps: 1. Test the replicability of reports on several stages of memory formation in the chick--short-term memory (STM), intermediate-term memory (ITM), and long-term memory (LTM). We will also attempt to reproduce in the chick some of our main findings on protein synthesis and LTM in the mouse. 2. Attempt to extend to the mouse and rat the research on STM and ITM in the chick. As part of this work, investigate the sequential dependence (or lack thereof) among stages of memory formation. 3. Employ a little-used agent to test the latter stages of protein synthesis in memory. 4. Parallel the behavioral studies by investigating the neurochemical actions and the localization/diffusion of the agents employed. Investigating the various phases of memory formation should increase the chances of making findings that can be applied to improving human memory, since each stage is probably subject to impairments and each can probably be enhanced. The findings will be relevant to psychology, neuroscience, mental retardation, aging and rehabilitation from injury and disease of the brain.

The main aims are (1) to develop and test a chick learning system for behavioral-pharmacological-neurochemical studies of effects an mechanisms of opioids, and (2) to use this system to elucidat actions of opioids in the CNS in relation to learning and memory in order to increase understanding of the mechanisms of drug abuse. Chicks 1-3 days posthatch have many advantages for such research, but to date few studies have reported effects of opioids on learning and memory in th chick. Finding more precisely how opioids affect learning and memory would be valuable in itself and also as a model for the development of dependence on opiates. Specific lines of research to be undertaken in parallel are the following: 1. Analyze major anatomical regions of chick brain for several main opioids and for opioid receptors; i.e., use high performance liquid chromatography to analyze major metabolic products of the 3 parent opioid molecules, and use radioligands that are highly selective for the 3 major types of opioid receptors. The results will help to guide and interpret behavioral-pharmacological experiments using opioid agents with chicks (2 below). 2. Test opioids of the 3 main classes for amnestic effectiveness at certain brain sites, and investigate which stage(s) of memory formation are affected by amnestic opioids of the 3 main classes. Choice of opioid agents will be determined in part by those known to be effective in mammals and in part by our mapping of opioids and opioid receptors (1 above). 3. Investigate the neurochemical actions and time courses for some opioids found to be effective amnestic agents. As a major focus, test the dependence of LTM formation on protein synthesis by using an in vitro approach: test whether opioid amnestic agents reduce significantly the synthesis of proteins that are induced by one-trial training in the chick. We hypothesize that the brain measurements will closely parallel the behavioral end points, i.e., the opioid agents, given under appropriate conditions to produce amnesia, will significantly reduce the normal training- induced increase in synthesis of proteins. Also, determine the half-life of major opioids in chick brain; compare these with time- effect curves of these opioids on memory to see how they are related and to better understand the mechanisms involved. This project is based on a combination of mehods and expertise of the PIs with one-trial discrimination learning in the chick, opioids and opioid systems in behavioral experiments, and neurochemical techniques to study mechanisms of memory formation and of opioid effects.

The main aims of this project are (1) to further develop and test a chick learning system for behavioral-pharmacological-neurochemical studies of effects and mechanisms of opioids, and (2) to use this system to elucidate actions of opioids in the CNS in relation to learning and memory in order to increase understanding of the mechanisms of drug abuse and of effects of opioid drugs on cognition and behavior. Specific lines of research to be undertaken with the chick system include the following: (1) test agonists and antagonists selective for the three main classes of opioid receptor for memory-enhancing and amnestic effectiveness when injected either at certain brain sites or peripherally, and investigate which stage(s) of memory formation (short-, intermediate-, or long-term memory) are affected by these agents; (2) determine whether the metabolites of opioids influence learning and memory in the chick; (3) test effects of opioid agonists and antagonists in modulating the role of the cholinergic system on learning and memory in the chick to better understand how opioids affect memory with other neurotransmitter systems; and (4) extend the analyses of opioid degrading enzyme activity of chick brain to smaller functionally distinct areas, using high performance liquid chromatography with electrochemical detection (HPLC-ECD) and measure the concentrations of opioids in the same brain areas using radioimmunoassays (RIA) to compare the resulting map to that of opioid degrading enzyme activity. This project is based on a combination of methods and expertise of the PI's with one-trial learning in neonate chicks, opioids and opioid systems in behavioral experiments, and neurochemical techniques to study mechanisms of memory formation and of opioid effects.