Warren H. Meck, Ph.D. - US grants

The ability to remember and use information accurately is very important, and impairments of visuospatial memory profoundly disrupt and individual's life. These observations motivate research to understand the brain mechanisms involved in normal memory processing, and the types of lifespan developmental changes that produce memory dysfunctions and amnesia. At the same time it is of critical importance to understand the early developmental stages that brain and behavior processes go through in terms of defining memory function in later life. previous work in rats, monkeys, and humans has demonstrated that modification of frontal and temporal lobe structures, particularly the hippocampus and frontal cortex, produce behavioural changes that have some of the basic characteristics of an amnesic syndrome. The purpose of the present proposal is to investigate further our recent findings that indicate the potential for organization changes in these same structures that subserve visuospatial memory by exposing the developing nervous system to choline supplementation. Such perinatal choline supplementation has produced relatively permanent changes in the spatial ability of rats treated during specified periods (embryonic days 12-17 and postnatal days 15-30). The behavioral changes have been interpreted as reflecting an increase in memory capacity and precision. One of the major goals is to determine if there are any negative consequences of these treatments that might be revealed by the recruitment of normal aging processes. In this regard, we will investigate the three possibilities that perinatal choline supplementation either has a) a positive effect on the accuracy of visuospatial memory as a function of aging, b) a neutral effect on visuopatial memory as a function of aging. These behavioral data will stimulate additional studies of the anatomical and neurochemical basis of these effects.

(Adapted from applicant's abstract): The neural circuits that link the bas ganglia with the cerebral cortex are critically involved in the generation and control of temporal sequences of responses that are guided by an internal timing system that includes pacemaker, memory, and decision states. The input of the basal ganglia (that is the caudate and putamen) receive substantial projections from diverse regions of the cerebral cortex including motor, sensory, prefrontal, and limbic cortical areas. The outp nuclei of the basal ganglia (that is, the globus palladiums and the substantial Nigeria pars reticulate send their axons to the thalamus and, by this route, project back upon the cortex. Thus, a major aspect of basal ganglia circuitry is its participation in multiple open and closed loops wi the cerebral cortex. Our understanding of the organization of basal ganglia loops with the cerebral cortex has evolved considerably over the last 20 years. It is now believed that both cognitive and motor impairments result from damage to the basal ganglia, either studied with animal models or in the naturally occurring conditions of Parkinson's disease, Huntington's disease, and various types of focal lesions that occu as a result of stroke or accident. Attempts to separate the cognitive and motor components these various conditions has been hindered because it has been difficult to develop tests that were selectively sensitive to the types of dysfunctions presented by these subcortical dementias. Behavioral paradigms designed to study interval-timing mechanisms in and analogous fashion with both animals and humans have now been developed. Scalar Timing Theory is a mathematical model that describes formal properties of the analysis has successfully accounted for an extremely high percentage of the variance in behavior of both rats and humans. It has also led to the validation of a set of experimental procedures that can be used to separate the different psychological processes involved in interval timing. A battery of peak-interval timing procedures have been developed to evaluate basic temporal integration processes, temporal memory, and divided attention when auditory and visual stimuli are presented sequentially or simultaneously. By combining these behavioral procedures with the micro injection of series of selective gultamiergic receptor agonists or with placement of axon sparing lesions into specific nuclei of the basal ganglia an attempt will be made to map the neural circuitry involved in interval timing is represented by the ganglia thalamocortical loops.

DBI-9732149 Abstract The Undergraduate Neurosciences Program at Duke University will give undergraduates the opportunity to become involved in neuroscience research at a major research university. Research and training experiences will be organized around the theme of "Mechanisms of Behavior." The emphasis on integrative systems and behavioral neuroscience that unifies faculty research interests within this interdisciplinary field at Duke serves as the common theme for the individual projects available to student participants in the program. The focus of the 10-week summer program for each student will be a research mentorship with a participating faculty member. Two weekly seminar series - "Research in the Neurosciences" and "Science Basics"- will be included in the summer schedule. "Research in the Neurosciences" will focus on ongoing faculty research so that students in the program gain exposure to the field of neuroscience research beyond their mentor's specific interests. "Science Basics" will address practical matters pertaining to science careers. The summer program will begin with a two-day familiarization retreat and will close with a research forum during which students will make formal presentations of their research projects. Applications to participate in "Mechanisms in Behavior" will be accepted from sophomore undergraduates. The Program is especially interested in receiving applications from women and minorities as well as undergraduates at liberal-arts colleges.

The ability to attend to and use information accurately is very important and impairments of attention is indexed by conditioned stimulus processing profoundly disrupt an individual's life. These observations motivate research to understand the brain mechanisms involved in normal attentional processing, and the types of lifespan developmental changes that produce dysfunctions of conditioned stimulus processing and the ability to increment and decrement attention to auditory and visual cues. At the same time it is of critical importance to understand the early developmental stages that brain and behavior processes go through in terms of defining cognitive function in later life. Previous work in rats, monkeys, and humans has demonstrated that modification of frontal and temporal lobe structures, particularly the hippocampus and frontal cortex, produce behavioral changes that have some of the basic characteristics of an amnesic syndrome with associated dysfunctions in executive processes. The purpose of the present proposal is to extend our recent findings that indicate the potential for organization changes in brain structure that subserve conditioned stimulus processing by exposing the developing neurons system to different quantities of choline or folate; two nutrients shown to be critical to brain development. Previous research has shown that perinatal choline or folate supplementation leads to relatively permanent changes in the spatial ability of rats treated during specified periods (embryonic days 12-17 and postnatal days 15-30). The behavioral changes have been interpreted as reflecting an increase in memory capacity and precision. One of the major goals of our proposed research is to determine the role that attentional mechanisms play in behavioral facilitation and to determine if there are any negative consequences of these treatments that might be revealed by the recruitment of normal aging processes. In this regard, we will investigate the three possibilities that perinatal choline/folate supplementation/deficiency either have a) a positive effect on conditioned stimulus processing as a function of aging, b) a neutral effect on conditioned stimulus processing as a function of aging, or c) a negative effect on conditioned stimulus processing as a function of aging. These behavioral data will stimulate additional studies of the anatomical and neurochemical basis of the effects of aging on attention and memory.

Duke University's Summer REU Program in "Mechanisms of Behavior" provides an emphasis on integrative, systems, and behavioral neuroscience. The focus on the study of animal learning and behavior unifies faculty research interests within this interdisciplinary field and serves as the common theme for the individual projects available to student participants in the program. The program is designed to provide opportunities for highly qualified individuals; including women, minority, and disabled undergraduate students who would like to expand their laboratory skills. Each summer, undergraduate students will participate in a 10-week research program that includes a one-on-one mentorship with a participating faculty member. In addition, 3 weekly seminar series including "Research in the Neurosciences", "Science Basics", and "Science Ethics and Practice" will serve to integrate the individual laboratory experiences. The primary goal of the program is to provide opportunities for undergraduates to receive training in the cutting-edge methodologies of behavioral neuroscience and genomics. Mentors for the program are prominent researchers in their fields and have substantial experience in supervising and training undergraduates. The students will work on research projects that are within their grasp, and which present real opportunities for new discoveries that will be of value to the neuroscience community.

Dr. Warren H. Meck will be the point-of-contact for student recruitment (Department of Psychological and Brain Sciences, 103 Research Drive, Box 91050, Duke University, Durham, NC 27708. Phone: 919-660-5765; E-mail: meck@psych.duke.edu). Further information regarding the program can be found at: http://www.duke.edu/neurosci/research/mob.html.

Separate lines of evidence have shown that age-related impairments in memory are correlated with the prenatal availability of choline and changes in rapid eye movement (REM) sleep. For example, prenatal choline supplementation leads to adult modifications in cholinergic metabolism that are associated with enhancements in cognition and reduced age-related decline in memory. In addition, evidence that deficits in both REM sleep and memory are ameliorated in adult animals by cholinergic agonists suggests that organizational changes in cholinergic metabolism may be able to alter the structure and continuity of sleep in adulthood and directly influence cognitive processes. In order to investigate the relationship between sleep and the prenatal availability of choline, baseline levels of REM and slow-wave sleep (SWS) will be measured as a function of prenatal choline deficiency, sufficiency, and supplementation in adult rats. The overall goals of the project are to conduct a series of studies that will determine if adult animals with variations in choline metabolism caused by the prenatal availability of choline have selective alterations in the quantity or quality of sleep that are evident early in adulthood and are sustained or enhanced with aging. The proposed studies will also examine whether changes in sleep patterns (e.g., ratio of SWS to REM sleep) are associated with age-related changes in behavior and whether different types of behavioral tasks (e.g., hippocampal or non-hippocampal dependent) are differentially sensitive to alterations in sleep patterns as a function of age and early choline availability. Ensemble recording techniques will be used in order to access the efficacy of hippocampal-neocortical reactivation mechanisms that may be involved in the consolidation of memory processes as a function of the prenatal availability of choline in 4 mo, 14 mo, and 24+ mo old rats. A final series of experiments is designed to develop a murine model of cholinergic metabolism as a function of apolipoprotein e-deficiency, prenatal choline availability, gene dosage, and age. All of these studies are designed to evaluate the relationships between sleep control mechanisms and the memory enhancing effects of prenatal choline supplementation in young, mature, and aged animals.

The Duke University REU Site will provide a research program for undergraduates during the summers of 2009-2012. Ten students will be selected each year to participate in an intensive 10-week research program in "Mechanisms of Behavior". The program provides an emphasis on integrative, systems, and behavioral neuroscience. The focus on the study of animal learning and behavior unifies faculty research interests within this interdisciplinary field and serves as the common theme for the individual projects available to student participants in the program. The program is designed to provide opportunities for highly qualified individuals, including women, minority, and disabled undergraduate students who would like to expand their laboratory skills. Each summer, undergraduate students will participate in the research program that includes a one-on-one mentorship with a participating faculty member. In addition, three weekly seminar series including "Research in the Neurosciences", "Science Basics", and "Science Ethics and Practice" will serve to integrate the individual laboratory experience. The primary goal of the program is to provide opportunities for undergraduates to receive training in the cutting-edge methodologies of behavioral neuroscience and genomics. Mentors for the program are prominent researchers in their fields and have substantial experience in supervising and training undergraduates. The students will work on research projects that are within their grasp, and which present real opportunities for new discoveries that will be of value to the neuroscience community. Additional information can be found at http://unp.aas.duke.edu/research/mob.php, or by containing the Program Director, Dr. Warren H. Meck at 919-660-5765 or meck@psych.duke.edu.