William T. Greenough - US grants

As an approach to the neural substrates of memory, this project examines characteristics and functional roles of structural changes that occur in nerve cells in the forelimb region of rat motor-sensory cortex when they learn to reach into a chamber for food. Prolonged training increases dexterity and, when the innately nonpreferred forepaw is exclusively trained, paw preference for reaching is reversed. Dendritic fields of nerve cells in a motor-sensory cortex region that appears from lesion, electrical stimulation, unit recording and metabolic activity studies to be critically involved in this behavior increase in size with training. This suggests that new synapses are formed as a consequence of learning and by implication that synapse formation may be a basis for long term memory. To further test this hypothesis, we propose to: 1) delineate the pattern of changes across nerve cell types as a partial description of a "memory circuit", 2) determine the temporal sequence of the dendritic field changes for comparison with nerve cell recording studies of behavioral acquisition, 3) determine whether the structural changes persist beyond the training period, as the memory does, 4) ascertain whether training causes above background levels of formation of synapses in the motor-sensory cortex, and 5) determine where and when in the brain synthetic and energy-producing metabolic processes occur during acquisition and stable performance of the task. Results of these studies will provide evidence as to the involvement of synaptogenesis in the memory process and indicate whether learning (training) brings about active synapse formation.

The goal is to understand how experiential information becomes integrated into the functional organization of the mammalian brain. One likely mechanism involves alteration of synaptic patterns. In adults, this may occur through active formation of synapses in response to experience, whereas in early development, selective retention of part of a population of constitutively overproduced synapses may be involved. Housing of animals under conditions of differential environmental complexity, either at weaning or in adulthood, changes the number and the structure of forebrain synapses. This procedure will be used to test the hypothesis that active synaptogenesis underlies information storage. Preliminary anatomical data suggest stable experience effects in occipital cortex, whereas electrophysiological data suggest transient effects in hippocampus. Objectives are to 1) examine early morphological phases of the occipital cortical and hippocampal response to differential environmental complexity, when active synaptogenesis should be most easily distinguishable from constitutive turnover and synapse maturation effects will be minimized; 2) study the permanence of these morphological changes to determine whether they, like memories, are stable without continued differential experience and whether polyribosomal aggregate (PRA) location, which appears to indicate synaptogenesis, returns to a baseline state; 3) determine whether experience-induced increases in the hippocampal dentate gyrus response to afferent activity increase, reduce, or do not affect subsequent long term potentation, to assess whether these effects share a common mechanism; 4) study electrophysiological correlates of experience-induced differences in occipital cortical synaptic connectivity, to assess their role in brain function; and 5) to attempt to purify the mRNA associated with PRA located postsynaptically during synaptogenesis, to further understand synapse formation and its role in development and memory. Morphological procedures involve stereological analysis of electron and light microscopic data. Electrophysiological studies use isolated CNS preparations in vitro. Biochemical techniques involve density gradient centrifugation and affinity chromatography. Understanding mechanisms underlying developmental information storage and memory is essential to developing clinical treatments for learning and memory dysfunction, mental retardation, and related mental health problems.

As an approach to the neural substrates of memory, this project examines characteristics and functional roles of structural changes that occur in nerve cells in the forelimb region of rat motor-sensory cortex when they learn to reach into a chamber for food. Prolonged training increases dexterity and, when the innately nonpreferred forepaw is exclusively trained, paw preference for reaching is reversed. Dendritic fields of nerve cells in a motor-sensory cortex region that appears from lesion, electrical stimulation, unit recording and metabolic activity studies to be critically involved in this behavior increase in size with training. This suggests that new synapses are formed as a consequence of learning and by implication that synapse formation may be a basis for long term memory. To further test this hypothesis, we propose to: 1) delineate the pattern of changes across nerve cell types as a partial description of a "memory circuit", 2) determine the temporal sequence of the dendritic field changes for comparison with nerve cell recording studies of behavioral acquisition, 3) determine whether the structural changes persist beyond the training period, as the memory does, 4) ascertain whether training causes above background levels of formation of synapses in the motor-sensory cortex, and 5) determine where and when in the brain synthetic and energy-producing metabolic processes occur during acquisition and stable performance of the task. Results of these studies will provide evidence as to the involvement of synaptogenesis in the memory process and indicate whether learning (training) brings about active synapse formation.

This research addresses 1) age-related declines in the intrinsic capacity of the brain to exhibit plastic change of a type thought to be involved in memory formation, 2) effects of physical exercise upon the morphology of the aging brain, and 3) effects of mental activity the morphology of the brain. A central aspect of the approach is the increasingly strong evidence that the formation and/or stabilization of synaptic connections between nerve cells is involved in memory and related forms of brain information storage. In the aging human and animal brain, there is evidence that the declines apparent in memory are paralleled by the loss of synapses, a reduced ability to form new synapses, or both. The underlying causes of these changes in the aging brain are unknown, and determining what they are is the chief goal of this research project. The causes could be intrinsic to the brain or could involve physiological-metabolic support systems such as the cardiovascular system. The brain or peripheral systems could, as recent work suggests, be modulated by behavioral variables such as physical exercise or mental activity. The hypotheses to be tested involve the following questions: 1) does the aging brain have a diminished ability to generate new synaptic connections between neurons? 2) Does physical exercise affect number of or inducibility of synaptic connections, perhaps through general effects upon vascular or other metabolic support ? 3) Does physical exercise affect brain vasculature or metabolism in general? 4) Does motor learning (of an "acrobatic" task) affect the number of synaptic connections in brain regions likely to be heavy involved in performance of the task? 5) Does more general "mental exercise" arising from living in a complex environment affect brain metabolic or connectivity measures? And 6) Does additional physical exercise potentiate the effects of living in a complex environment? The hypotheses are to be tested using qantitative morphological methodology, combining light and electron microscopy to assess numbers of synapses per neuron, synaptic and neuronal density, vascular morphology, and mitochondrial volume fraction. These questions are critical to an understanding of the factors involved in the brain aging process and associated declines in learning, memory, and other aspects of mental performance and well-being.

In order to optimize interdisciplinary approaches that capitalize upon new technical and theoretical developments, a Center for the Neurobiology of Learning and Memory is being established at the Beckman Institute (currently under construction) of the University of Illinois at Urbana-Champaign . This center will serve as 1) a Resource Center, providing advanced facilities for the study of the learning and memory process, including optical imaging (for histological studies), multi-electrode array recording (to allow functional patterns of interactions among neurons to be examined), and rapid tissue freezing (for assessment of sub-cellular dynamics); 2) a Research Center that fosters communication and collaboration among scientists pursuing common and related problems of memory and neural plasticity; 3) a Training Center which prepares graduate and postdoctoral investigators for research careers in learning and memory, and 4) a Recruiting Center that to attract outstanding young people to scientific careers. This program of scientific development and interaction is taking advantage of the unusual resources of the Beckman Institute and the University of Illinois Urbana-Champaign campus in neurobiology, interdisciplinary collaboration and cooperation, and strengths of the component disciplines of neural and behavioral sciences. Technical foci of the Center include large array neurophysiological recording facilities, with which the interactions among brain regions during learning are studied; rapid freezing facilities for examining brain slices in vitro, (with which the nature of plasticity at the level of the synapse is studied), and neuroanatomical imaging and analysis facilities (where memory processes are studied at levels ranging from the molecular to the morphological). Several types of learning are being studied, including discriminative conditioning, acquisition of motor skill, acquisition of acoustic discriminative ability, and the traditional psychological animal learning tasks such as mazes. In addition, current "models" of memory (such as long-term potentiation and kindling) are being examined. The function of the Center for the Neurobiology of Learning and Memory is to advance our knowledge of brain substrates of learning and memory from the cellular and molecular to the integrative brain system levels.

This award provides funds to establish an interdisciplinary site REU program in Neuroscience at the University of Illinois Neural and Behavioral Biology (NBB) Program, a Ph.D. granting interdisciplinary program begun in 1970. The common focus is neuroscience, the interdisciplinary field that seeks to understand the function of nerve cells and systems from the molecular and cellular levels to that of behavior. Faculty in the program that demonstrate an extensive history of involvement of undergraduate in laboratory research have been selected as co- Principal Investigators. Collectively, faculty in NBB have sent about 75 undergraduates who worked with them into scientific careers, including faculty positions at Harvard, Yale, Chicago, Stanford, and Pennsylvania. Even greater numbers have gone on to careers in Medicine and other professional Doctorate-level fields. Neuroscience subfields in which research experience will be offered included behavioral neuroscience, neural development and plasticity, molecular, cellular and genetic neuroscience, neurophysiology, neuroanatomy, computational neuroscience, and cognitive neuroscience.

This award will provide partial support for the conference Computations in Natural and Artificial Parallel Systems. This conference is interdisciplinary in nature, bringing together researchers from several different fields to focus on parallel computation systems, comparing the parallel circuit in the brain with that of parallel computer systems. The conference with be held September 27-30 at the Beckman Institute in Urbana-Champaign, Illinois.

This award will support course on stereology for North American neuroscientists. The techniques to be taught will allow for an unbiased quantitative analysis of morphological structures. Participants will be given first hand experience through lectures and laboratory exercises provided by scientists who are the forerunners of quantitative anatomy.

learning; neural plasticity; neuroanatomy; exercise; brain electrical activity; age difference; synapses; cerebellum; brain mapping; fragile X syndromes; computational neuroscience; behavioral /social science research tag; animal old age; laboratory rat; immunocytochemistry; histology;

Associative nictitating membrane (NM), or eyeblink, conditioning in the rabbit will be used to examine alterations in the structural organization of the cerebellum and associated brainstem structures that occur as a result of learning. The substrates of learning are believed to be fundamental mechanisms of brain information storage that are involved in brain development, memory, recovery from brain damage, as well as in certain pathological conditions, perhaps including epileptogenesis. Associative conditioning involves the pairing of a conditioned stimulus (CS) tone with the delivery of an unconditioned stimulus (US) puff of air to the cornea of the eye over repeated trials such that a conditioned eyeblink response (CR) comes to be elicited by the tone alone. Comparison with rabbits that experience tones and airpuffs at random intervals allows identification of brain changes specific to associative learning and exclusion of brain changes brought about by exposure to the stimuli or emission of the motor response. In addition, as conditioning occurs unilaterally, a within-animal control exists for nonassociative responses to the conditioning process (e.g. stress [which is not particularly evident in the subjects], extraneous motor activity, other general metabolic changes induced by conditioning). Considerable research has elucidated brainstem and cerebellar structures that mediate the conditioning process. Prior data indicates that structural changes in Purkinje and probably stellate neurons occurs in the cerebellar (lobule HVI) hemisphere that mediates the conditioned response, while no structural effects are evident in animals receiving random stimulus presentation. The goal of this proposal is to discern the types of morphological changes at the cellular (neuronal) that occur both in cerebellar cortex and deep nuclei and in brainstem structures that carry input and output information that is critical to the acquisition and performance of the conditioned response. Other structures to be investigated are the dorsal accessory olive, source of US information, and the red nucleus, the primary post-cerebellar structure along the CR pathway. The methods to be employed include quantitative analysis of neurons impregnated by the Golgi techniques and unbiased stereological estimation of synaptic numerical change.

Neuronal pattern analysis (NPA) documents the dynamic brain processes of sensation, perception, learning and cognition by recording the electrical activity of brain neurons. Recent advances in multi-array recording technologies have greatly expanded the rate at which NPA data can be obtained, and these technologies have fostered means not previously available to study the intercorrelations of dynamic activities in neuronal networks. Computational modeling of brain dynamic activity has fostered major increment in the requirements of data processing due to the need to analyze simulated neuronal spike trains and to compare real and simulated neuronal data. These developments call for parallel development of adequate database systems for organization, rapid access, and sharing of NPA data. This project will establish a database system (DBS) for time series neurophysiological data recorded in experiments of members of the University of Illinois Beckman Institute Neuronal Pattern Analysis Group. System design and implementation will be carried out with consultation and guidance of the National center for Supercomputer Applications. This proposed system will foster community-wide sharing of times series and other forms of neural data, proved a model DBS that can generalize to other neuroscience groups, and enhance the research in the involved laboratories.

DESCRIPTION (provided by applicant): This project explores continuing post-developmental neurogenesis and non-neuronal cytogenesis as processes that could be harnessed to aid in rehabilitation of the fetal alcohol-damaged brain. We have found that the capacity for post-weaning cytogenesis in adolescence and young adulthood is present, even enhanced, in the motor cortex of rats given binge-like alcohol exposure during the neonatal period of rapid brain growth, compared to unexposed controls. However, the alcohol-exposed rats fall behind their controls in preserving these newly-generated cells as they grow older. In the dentate gyrus of the hippocampus, a region known to generate new neurons post-developmentally and into adulthood, the number of adult-generated cells was similar in alcohol-exposed and control rats, but the alcohol-exposed rats again failed to preserve these new cells in the long term, falling behind their unexposed control counterparts. Overall, early alcohol exposure did not prevent genesis of new cells, but affected neurogenesis in dentate gyrus, and fewer of these cells survived. In contrast, increased voluntary physical exercise in adolescent rats (under social housing conditions) in a running wheel did increase cytogenesis and neurogenesis both in alcohol-exposed and control animals, but these new cells persisted less well in the alcohol-exposed rats than in controls. The goal of the proposed work is to determine whether and, if so, how combinations of experience, including physical exercise and learning in a physically stimulating toy-equipped environment, can be used to drive cell genesis and promote survival of newly-generated cells in a manner that positively influences brain function. The effects of these manipulations will be assessed both histologically in terms of the relative numbers of neurons and non- neuronal cells, and functionally in terms of performance on a set of behavioral tasks that depend on functional or structural plasticity in the hippocampus. Histological measures will use homologs to BrdU that are independently immuno-detectable, allowing populations of cells generated at different times to be independently assessed. Behavioral tests appropriate to the assessment of hippocampal function will be assessed in independent sets of animals, including trace eyeblink conditioning, trace fear conditioning (both contextual and CS-elicited fear), and spatial working memory in a water maze task. By combining age-specific markers of neurogenesis during the post-weaning intervention period with assessment of subsequent behavioral performance on hippocampal-dependent tasks, it will be possible to identify potential links between experience-dependent promotion of neurogenesis in the dentate gyrus and improved outcomes in cognitive behavior relevant to fetal alcohol spectrum disorders. PUBLIC HEALTH RELEVANCE Fetal alcohol spectrum disorders is a leading cause of developmental disability and mental retardation both in the US and in many other countries. Effective rehabilitative strategies directed at the damaged brain are at present not known. This project, using a rodent model of fetal alcohol damage, focuses on the capacity of some post-developmental brain regions to generate new neurons or other cell types and searches for ways to harness this capacity as a route to effective rehabilitative intervention.

The purpose of this proposal is to request funds for the purchase of a Philips CM- 200 Transmission Electron Microscope to be housed in the Visualization Facility (BVF) of the Beckman Institute on the University of Illinois campus. The Principal Investigators will be using this electron microscope for a variety of studies including (i) neuroplasticity and its relationship to underlying cellular and system level processes (William Greenough), (ii) the study of monodisperse rod-coil block copolymers (Samuel Stupp), (iii) analysis of nuclear and chromosome architecture (Andrew Belmont), (iv) sex differences in the organization and behavioral function of the brain (Janice Juraska), and (v) the characterization of morphological and functional abnormalities in cerebellar neural circuitry in a genetic animal model of movement dysfunction (Louise Abbott). In addition to these core projects there are 6 other research projects from a variety of disciplines for which this instrument provides immediate or long term benefits. The purpose of obtaining a new instrument is twofold. Firstly it will provide access to an intermediate voltage instrument for biological research on the UIUC campus. The only intermediate voltage instruments in this region are exclusively devoted to material science research and biologists with projects for which higher voltages are necessary have to travel to remote sites. Secondly it will replace an existing 18 year old instrument currently located in the BVF that is suffering increasingly from age related problems. In addition to providing unique capabilities for imaging thicker specimens this microscope will have a number of other important advantages over the existing instrument. The ability to control the instrument through a computer interface and to collect micrographs using a CCD camera will greatly aid, and in certain cases be essential for several applications. Specifically, for techniques such as serial sectioning, quantitative stereology and single axis tomography which involve the collection or examination of large numbers of images, semi-automatic acquisition procedures can be devised that not only simplify the process but also ensure that the electron dose is minimized and the region of interest is maximized. Furthermore, certain applications of these 3-dimensional reconstruction techniques require literally hundreds of images per data set and these applications for practical considerations will only be feasible given the availability of direct digital data acquisition. These control and imaging capabilities will also greatly improve the routine acquisition of high quality images. Further advantages of the new microscope arise from the advances in technology over the past 20 years. These have led to simplification of alignment procedures, improvements in beam coherence, lenses and goniometer stages and the implementation of techniques for acquiring images at low doses in order to limit beam damage. The microscope will be located in the Beckman Visualization Facility which houses a number of other related instruments (including a confocal microscope, a stereology workstation and various light microscopes) as well as supporting equipment (wet lab, microtomes, darkrooms) and excellent facilities for the digital processing and analysis of images. The location of the microscope in the multi- disciplinary environment of the Beckman Institute, which also includes part of the National Center for Supercomputing Applications, provides an excellent environment to take advantage of some of the latest technology available for the on- line processing and analysis of electron micrographs. We are strongly committed to providing access to this instrument and its associated, special facilities to the campus wide user group whose research wholly or partly depends on the application of electron microscopy. There is enthusiastic commitment to this project from both the Beckman In stitute and the University as a whole. This has been demonstrated by the contribution of 50% matching funds for the project as well as the supporting infrastructure for the equipment provided by the Beckman Institute Visualization Facility.

technology /technique development; cognition; psychology; nervous system; nuclear magnetic resonance spectroscopy; biomedical resource; Mammalia; cardiovascular system; growth factor; magnetic resonance imaging; behavioral /social science research tag;

technology /technique development; cognition; psychology; nervous system; nuclear magnetic resonance spectroscopy; biomedical resource; Mammalia; bioengineering /biomedical engineering; cardiovascular system; growth factor; magnetic resonance imaging; behavioral /social science research tag;

Exercise results in long-term perfusion changes in regions of the rat brain. These can be measured by MRI methods, and the contributions of new blood vessel formation to the process analyzed.

We recently obtained evidence in an in vitro synaptoneurosome preparation for the rapid translation of the mRNA at the synapse, under metabotropic glutamate receptor control. We also have found that "knockout" mice that cannot produce this protein exhibit immature synapse morphology and produce or retain excess numbers of spine synapses into adulthood. Our preliminary data indicates regulation of cortical FMRP expression by motor skill training in adult rats. These findings complete other work on the fragile X gene (FMR1) and syndrome (FraXS) to suggest as a "working hypothesis" that FMRP may play a role in the process whereby synaptic activity during development results in structural maturation of the synapse, and may be necessary for the normal developmental synapse elimination process. We process a series of basic studies of rodent brain designed to further explore 1) the cellular and subcellular localization of FMRP with regard to both macro (soma, dendrite) and micro (organelle) structures, as a further source of clues to the possible cellular function of the protein, 2) the spatiotemporal pattern of expression during development and it is possible correlation with other major developmental processes such as synaptogenesis, to explore possible reasons for the pathological effects of fragile X deficiencies on brain development, 3) the effects of electrical stimulation of axonal pathways on its expression in target neurons to determine if it us under synaptic control in vivo, and 4) the effects of behavioral experience, ranging from monocular visual deprivation to complex rearing environments and motor skill learning upon its expression in brain regions known to exhibit plasticity in response to those manipulations. We also response to examine 5) development and adult morphology, 6) effects of experience, and 7) the elimination of multiple innervation of Purkinje cells by climbing fibers in a recently developed transgenic fragile X knockout mouse. Fragile X syndrome, which can arise from a mutations that prevents gene expression or from point mutations affecting the structure of the protein, is the leading inherited cause of human mental retardation and is also frequently associated with Autism and Attentional Deficit/Hyperactivity Disorder. Knowledge of the mechanism of action of the gene product may well give rise to treatments of these syndromes.

DESCRIPTION (provided by applicant): This proposal requests support for a 5 year continuation of the Banbury Conferences on Fragile X syndrome (FXS). Including an initial conference, six such meetings have been held at Banbury Conference Center at Cold Spring Harbor Laboratory on Long Island NY. We propose a series of five annual interdisciplinary conferences on basic and clinical research relevant to fragile X syndrome (FXS). The conferences are intended to bring together a broad range of scientists, both those working on FXS and others in allied, relevant fields. Another goal is to introduce young scientists, including females and minorities, to the area. Fragile X syndrome is the most common inherited cause of mental retardation. It arises due to expansion of an unstable region of trinucleotide repeats in the 5'untranslated promoter region of the FMR-1 gene, causing hypermethylation of cytosine residues and, generally, silencing of the gene. A number of mouse FMR-1 knockout models for the syndrome have or are about to become available. The function of the fragile X mental retardation protein (FMRP) is believed to be the transport and translational regulation of a subset of mRNAs with a diverse set of cellular functions. FMRP appears to be translated at synapses in response to activation of metabotropic glutamate receptors. Relatively subtle phenotypic effects of the disorder are seen in the gross size of several brain regions and in the fine structure of synapses in humans and in the knockout mouse model. As the Banbury Conferences have made clear (summarized in Sec. C), advances in our knowledge of this disorder are occurring very rapidly. There is no other meeting devoted exclusively to basic and clinical research on FXS, and the participants consistently report the Banbury Conference to be extremely valuable.

DESCRIPTION (provided by applicant): This program is designed to train 5 predoctoral and 3 postdoctoral trainees, at anyone time, for research and training careers in developmental psychobiology and neurobiology. It is our belief that, since behavioral development rests upon the development of the nervous system, an understanding of the psychological development process requires an integrated knowledge of both behavioral and neural development. Thus an integrated interdisciplinary training program is proposed. Trainees will be admitted via one of two degree-granting units: the Neuroscience Program (NP) and the Biological Psychology Division of the Department of Psychology. In conjunction with the College of Medicine (Urbana-Champaign) a joint MD/PhD degree is also offered through both Programs. The philosophy underlying the design of this program includes the following: 1) because "chance favors the mind prepared", scientists can be more productive if their perspective is broadly interdisciplinary; 2) because the primary goal of this training program is development of research skills, students should be immersed, with strong mentor support, in research throughout their graduate training; 3) the ability to learn and develop critical new methodologies is important, and research training must prepare one for new skills as well as hone those current; 4) presentation skills, communicating ideas to students, colleagues, evaluative arenas and the public is a crucial part of being a good scientist, and 5) good professional ethics requires judgment asmuch as knowledge of the rules, which must be learned both through formal example and through in-laboratory experience with good mentors. Faculty range from behaviorally-oriented psychologists to molecularly-oriented biologists. Members of this group have proven themselves exceptionally capable of cooperation and collaboration, despite their diversity of background. This broad buffet of knowledge allows for a unique program of training that can equip its product to deal with the broad range of phenomena that fall under the heading "neuroscience". Careful attention to a core set of concepts, breadth of knowledge, centered appropriately around the trainee's focus of interest, and productive interactions among trainees and multiple faculty in multiple disciplines characterize our training.

0619257
Boppart

This Instrument Development proposal details the construction, integration, and application of a novel multimodality microscope technology that will be enabling for a wide range of biological and medical investigations. A state-of-the-art multimodality microscope is proposed that combines the emerging technology of optical coherence tomography (microscopy) (OCT/OCM) with advanced multiphoton microscopy (MPM). This instrument is greater than the sum of its parts by providing complementary data on both the structure (OCM) and function (MPM) of biological systems.

[unreadable] DESCRIPTION (provided by applicant): This proposal requests continued support of a highly successful interdisciplinary training grant in Developmental Psychobiology and Neurobiology under the auspices of the MENTOR award program. Pre-doctoral and postdoctoral trainees are prepared for research and teaching careers. Former trainees have an excellent track record in obtaining academic or in some cases industry positions. Broad and deep knowledge of research literature and methodological sophistication are emphasized in the training program, in which students are enrolled in the Neuroscience or Biological Psychology Ph.D. programs at the University of Illinois at Urbana-Champaign. A faculty committee guides the training of each pre-doctoral and postdoctoral trainee, developing an individualized training program appropriate to the trainee's current state of preparation and future goals. To build skills in oral communication, each trainee will present at least one seminar each year describing her/his research and activities to a seminar group that includes other trainees and [unreadable] their advisors and members of the trainee's committee. All faculty in the training program are [unreadable] members of the Neuroscience Program. Two of the primary faculty, including the PI/PD, are [unreadable] members of the National Academy of Sciences, and many others have received fellow status or other indications of accomplishment within their professional organizations. The PD is very well known in the field of neural development and plasticity and provides "translational" experience through his work on fragile X syndrome. Several other faculty are similarly developing translational lines of research. Instruction in the Responsible Conduct of Science includes both enrollment in a graduate course, MCB 580 - "Research Ethics and Responsibilities" and individual training by the faculty mentor. Substantial efforts have allowed us to attract outstanding minority trainees, and a number of former minority trainees have successfully obtained faculty positions at major universities. [unreadable] [unreadable] [unreadable]

1-(3,4-dihydroxyphenyl)ethane-1,2-diol; 2'-Nor-2'-deoxyguanosine; 2'NDG; 2-Amino-1,9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]-6H-purin-6-one; 3,4-dihydroxyphenylglycol; 6H-Purin-6-one, 2-amino-1,9-dihydro-9-((2-hydroxy-1-(hydroxymethyl)ethoxy)methyl)-; 9-[(1,3-Dihydroxy-2-propoxy)methyl]guanine; Address; Affect; Alternate Splicing; Alternative Splicing; Ammon Horn; Au element; Biologic Marker; Biological Markers; Body Tissues; Brain; Cell Communication and Signaling; Cell Signaling; Cells; Characteristics; Collaborations; Complex; Cornu Ammonis; DHPG; DOPEG; Dendritic Spines; Dentate Fascia; Dentate Gyrus; Development; ERK 1; ERK1 Kinase; Encephalon; Encephalons; Escalante syndrome; Extracellular Signal-Regulated Kinase 1; FMR1; FMR1 Gene; FMRP; Fascia Dentata; Florida; Fmr1 gene,; Fmr1,; Fragile X; Fragile X Gene; Fragile X Mental Retardation 1 Gene; Fragile X Syndrome; Future; Ganciclovir; Gancyclovir; Gene Delivery; Gene Transfer Clinical; Gene Transfer Procedure; Gene-Tx; Genes; Genetic; Genetic Intervention; Goals; Gold; Gyrus Dentatus; Hereditary; Hippocampus; Hippocampus (Brain); Image; Individual; Inherited; Injection of therapeutic agent; Injections; Intervention, Genetic; Intracellular Communication and Signaling; Investigation; Isoforms; Knock-out; Knockout; Knowledge; Label; MAP Kinase 3; MAPK3 Mitogen-Activated Protein Kinase; Mammals, Mice; Martin-Bell Syndrome; Martin-Bell-Renpenning syndrome; Measures; Medicine; Meiosis-Activated Myelin Basic Protein Kinase p44(mpk); Mental Retardation; Methods; Mice; Mice, Mutant Strains; Microscopic; Microtubule-Associated Protein-2 Kinase; Mitogen-Activated Protein Kinase 3; Modeling; Molecular Biology, Gene Therapy; Molecular Configuration; Molecular Conformation; Molecular Marker; Molecular Stereochemistry; Morphology; Murine; Mus; Mutant Strains Mice; NRVS-SYS; Neocortex; Nerve Cells; Nerve Transmitter Substances; Nerve Unit; Nervous System; Nervous System, Brain; Nervous system structure; Neural Cell; Neurocyte; Neurologic Body System; Neurologic Organ System; Neurons; Neurotransmitters; Nordeoxyguanosine; Outcome Study; P44MAPK; PSTkinase p44mpk; Performance; Pharmacological Treatment; Phenotype; Phosphorylation; Play; Predisposition; Promoter; Promoters (Genetics); Promotor; Promotor (Genetics); Property; Property, LOINC Axis 2; Protein Isoforms; Protein Phosphorylation; Protein-Serine-Threonine Kinase p44(mpk); Proteins; Pyramidal neuron; RNA Splicing; RNA Splicing, Alternative; Range; Renpenning syndrome 2; Research; Role; Science of Medicine; Shapes; Signal Transduction; Signal Transduction Systems; Signaling; Signature Molecule; Slice; Spinal Column; Spine; Splicing; Staging; Standards; Standards of Weights and Measures; Structure of dentate gyrus; Study, Outcome; Susceptibility; Symptoms; System; System, LOINC Axis 4; Therapy, DNA; Time; Tissues; Universities; Variant; Variation; Vertebral column; Vibrissae; Viral; Viral Vector; Whiskers; Work; X-linked mental deficiency-megalotestes syndrome; X-linked mental retardation with fragile X syndrome; X-linked mental retardation-fragile site 1 syndrome; animal tissue; audiogenic seizure; autism-fragile X (AFRAX) syndrome; autism-fragile X syndrome; backbone; biological signal transduction; biomarker; college; conformation; conformational state; dendrite spine; density; dentate gyrus; dihydroxyphenylethylene glycol; dihydroxypropoxymethylguanine; fra(X) syndrome; fra(X)(28) syndrome; fra(X)(q27) syndrome; fra(X)(q27-28) syndrome; fragile X mental retardation 1; fragile X-mental retardation syndrome; fragile Xq syndrome; fragile site mental retardation 1; fragile x [{C0016667}]; fragile x syndromes; gene function; gene product; gene therapy; genetic therapy; hippocampal; hippocampal pyramidal neuron; homotypical cortex; imaging; isocortex; macro-orchidism-marker X (MOMX) syndrome; macro-orchidism-marker X syndrome; mar(X) syndrome; marker X syndrome; mental retardation-macroorchidism syndrome; mouse model; mouse mutant; neocortical; neopallium; neuronal; p44 (MAPK); p44 MAPK; response; restoration; social role; somatosensory; theories; two-photon

Developmental Disabilities; FMRP; Phenotype; Protein Isoforms; Research; RNA Splicing; Variant