Peter D. Spear - US grants

The long-term objectives of the proposed research are to increase our understanding of the functions of extrastriate visual pathways in normal animals and to learn more about the mechanisms of compensatory changes that occur in these pathways following damage to visual cortical areas 17, 18 and 19 early in life. To accomplish these goals, a series of anatomical, electrophysiological, and behavioral studies will be carried out in cats. The studies will concentrate on the posteromedial lateral suprasylvian (PMLS) visual cortical area and its afferent pathways. The specific aims of the proposed experiments are: (1) Determine the properties of lateral geniculate neurons that provide enhanced projections to PMLS cortex following early visual cortex (areas 17, 18, and 19) damage and examine whether the information they provide to PMLS cortex differs from normal. (2) Carry out a quantitative analysis of the spatial receptive-field properties of PMLS neurons, determine the role of areas 17, 18, and 19 in the elaboration of those properties in normally reared cats, and determine if the residual properties differ in cats with early or adult visual cortex damage. (3) Study the behavioral psychophysical capacities of cats with early or adult visual cortex damage and directly assess whether PMLS cortex is involved in these capacities. (4) Determine whether the enhanced projections to PMLS cortex following early visual cortex damage require normal patterned visual experience to develop. (5) Determine whether functional vs. physical removal of inputs from visual cortex is necessary for physiological compensation in PMLS cortex and whether normal experience with stimulus movement is necessary for the compensation. (6) Determine whether callosal inputs are required for the development of physiological compensation In PMLS cortex following early visual cortex damage. (7) Investigate whether physiological compensation involves neural reorganization or a persistence of pre-existing properties and evaluate suggestions that the mechanisms differ for different properties. (8) Investigate the possibility that PMLS cortex normally is involved in the control of eye movements. (9) Carry out preliminary experiments to determine the neuropharmacological mechanisms of physiological compensation and investigate whether compensation can be made to occur following visual cortex damage in adult cats. Together, the proposed experiments will provide information about normal visual system organization and development and about the mechanisms of recovery from brain damage in neonates and adults.

The overall goals of the research are to learn more about the roles of the parallel X, Y, and W pathways in visual system function and development. These goals will be accomplished by studying visual system physiology in normal cats and cats that have been raised in an abnormal visual environment. In addition, we will continue our work to devise procedures to selectively eliminate particular components of the parallel visual pathways. The specific aims of the research are: 1) Investigate the nature of binocular interactions on neurons in the lateral geniculate nucleus (LGN). This will include a quantitative spatial frequency analysis of receptive-field properties through the non-dominant eye and a comparison of these properties for X, Y, and W cells in the LGN. In addition, it will include an analysis of the effects of non-dominant eye stimulation on specific receptive-field properties through the dominant eye. 2) Investigate the effects of early visual experience on the function of the W-cell pathway through the LGN. This will be accomplished by recording from neurons in the C laminae of the LGN in monocularly deprived cats. 3) Continue efforts to develop new and better methods for selectively eliminating retinal X, Y, or W cells and their projections to the brain. Three different approaches will be used to meet this aim. The first will asssess the possibility that monoclonal antibodies can be used, either alone or conjugated to a neurotoxin, to destroy a specific class of retinal ganglion cells. The second will determine whether retrogradely transported neurotoxins can be used to eliminate specific classes of retinal ganglion cells. The third will determine if selective photothermolysis can be used to eliminate specific classes of retinal ganglion cells. This project will help elucidate the brain mechanisms of both normal and abnormal vision.

The long-term objective of the proposed research are to understand the neural mechanisms of visual processing, how those mechanisms change, throughout life, and how they are altered to compensate for brain damage. Two specific projects are proposed for the renewal period. The first will continue our investigations of the mechanisms of neural compensation that occurs following visual cortex (VC) damage early in life. Anatomical studies will be carried out in cats to learn more about retinal inputs to the central visual pathways after VC damage, to investigate the nature and mechanisms of enhanced projections that develop from the lateral geniculate nucleus (LGN) to posteromedial lateral suprasylvian (PMLS) cortex following VC damage at different ages, and to determine whether other enhanced projections exist. We also will begin to investigate the biochemical bases of the compensation that occurs following early VC damage. Immunohistochemical studies of the distribution of nerve growth factor (NGF) receptors during normal development and after VC damage will be carried out to learn more about why there is greater potential for compensation in neonates than adults. In addition, we will investigate whether compensation can be increased by administering trophic factors. Together, these experiments will provide information about the mechanisms of recovery from brain damage and possible treatments to improve recovery. The second project will extend our previous work on early visual system development to include changes that occur during aging. Neurophysiological and anatomical studies will be carried out in the retina, LGN, and striate cortex of young adult and old monkeys. The results will be related to changes in human psychophysics during aging, and they will be used to test directly several hypotheses that have been proposed concerning the location and nature of the neural changes that underly vision deficits during aging. These studies will increase our understanding of the relationship between neural structure and function, of the neural mechanisms of declines in visual abilities during aging, and of the affects of aging on the brain in general.

Objectives To understand the neural bases of visual deficits that occur during aging and to use the primate visual system as a model system for answering general questions about the effects of aging on the brain. ABSTRACT:Neuroanatomical studies carried out during the current year showed that there are no significant differences between young adult and old rhesus monkey retinae in the total number of ganglion cells, in the number of ganglion cells in particular retinal locations, or in ganglion-cell soma sizes. Comparisons between mean totals of LGN neurons and their input retinal ganglion cells indicated that there is about one ganglion cell for each LGN neuron. However, among the individual animals examined, there was no significant correlation between the numbers of these cells. Quantitative neuroanatomical measures in the rhesus monkey striate cortex suggest that there are no significant differences between young adult and old animals in areal density of cytochrome oxidase blobs. Neuron soma sizes also did not differ significantly between young adult and old animals or between blob and interblob regions. In addition, neuron density was not significantly different between young adult and old animals. However, there were significantly higher densities of neurons in interblobs than in blobs. Together with our previous studies, these results suggest that the peripheral parts of the visual pathways are relatively unaffected by aging in the rhesus monkey. We also carried out noninvasive electrophysiological studies in the rhesus monkey visual system to assess visual function of individual animals. Preliminary results for both young adult and old animals indicate that swept spatial frequency visual evoked cortical potentials (VECP) and pattern electroretinogram (PERG) estimates of spatial acuities are in close agreement. Both PERG and VECP estimates of spatial acuity are reduced in old animals in good ocular health, although there is some overlap with acuity values in the young adult animals. To complement the sweep-VEP method, we have begun training monkeys so that we can carry out behavioral psychophysical tests of vision. Keywords vision, visual cortex, retina, lateral geniculate nucleus, visual evoked cortical potentials, pattern electroretinogram, visual psychophysics, quantitative neuroanatomy

PROJECT SUMMARY
What is the intellectual merit of the proposed activity?
Wisconsin (WI) is a state with a rapidly changing ethnic and racial demography. The number of Hispanics has more than doubled in the last decade to over 200,000, there are over 400,000 acres of American Indian tribal lands, and 25% of the nearly one million residents in the large urban area around Milwaukee are African American. While not counted in tallies of underrepresented minorities for this proposal, WI also has the third largest population of Hmong in the United States, a group also underrepresented in higher education. This proposal would establish the Wisconsin Alliance for Minority Participation (Wisc-AMP)through the NSF Louis Stokes Alliance for Minority Participation (LSAMP) Program. Wisc-AMP brings together 21 public and private institutions of higher education in Wisconsin committed to collectively doubling the number of underrepresented minority students (URMS) receiving baccalaureate degrees in science and engineering majors. Wisc-AMP partners are also committed to the more fundamental goal of transforming the culture of our institutions to support and sustain diversity at all levels. The University of Wisconsin-Madison (UW-Madison) will be the lead institution. Few universities can equal UW-Madison's capacity to enroll large numbers of students or match the breadth and depth of its cutting-edge research rograms in science and engineering. Through individual interviews, data gathering, and document analysis, it was determined that the support provided through LSAMP would be best leveraged in two ways: 1) address retention and persistence of URMS in science or engineering majors at UW-Madison by expanding and improving on successful models already in place and 2) build the alliance. The initiatives at UW-Madison focus on several aspects of academic enhancement especially in the gatekeeping courses with new efforts to tutor not only those struggling but those who can be pushed to excellence as well as an enhanced summer research experience that encourages undergraduate students to share personal experiences and scientific inquiries with a network of peers and trains graduate students to be more effective mentors to undergraduate URMS. Alliance building involves several efforts aimed at developing a Network of Champions at participating sites as well as a Small Grants Program to facilitate collaboration and encourage individual partners to customize initiatives to their local environments. Wisc-AMP will be administered jointly by the Diversity Affairs Office and the Women in Science and Engineering Leadership Institute in the College of Engineering at UW-Madison. A Governing Board consists of Provosts/Vice Chancellors/Presidents from Wisc-AMP partners, students, an industry representative, and selected academic and community leaders in education and research. Increasing the recruitment and retention of URMS in science and engineering with the goal of transforming the institution involves buy-in from many departments and units. Therefore, at UW-Madison, the Provost is the principal investigator and two well-respected faculty members are co-principal investigators, faculty in prestigious positions are members of an internal Advisory Committee, staff who have been in the trenches working on the issues and administrators from the Admissions Office and the Registrars Office who are at key student entry points are involved as co-investigators or advisors. Formal evaluation of Wisc-AMP will use quantitative and qualitative methods to identify if and how well the goal of the program is met and which aspects of Wisc-AMP work.

What are the broader impacts of the proposed activity?
As the United States becomes an increasingly diverse society, it is imperative that institutions of higher education train a similarly diverse workforce. NSF has publicly proclaimed its commitment to broadening opportunities and enabling participation of all citizens as essential to the health and vitality of science and engineering. By investing in efforts to increase the number of URMS graduating with baccalaureate degrees in science or engineering, this proposal directly aligns with NSF's goal. Project innovations will be disseminated locally through meetings, discussions, and presentations; regionally through the alliance structure; and nationally through publications in scientific journals, proceedings of scientific meetings, and participation in annual LSAMP meetings. The results of Wisc-AMP's formal evaluation can be used to continue or re-direct proposed efforts and to advise developing alliances on successful and unsuccessful elements of each initiative.