James G. Herndon, PhD - US grants

cognition; psychology; nervous system; Mammalia; aging; Primates; behavioral /social science research tag;

The goal of this project is to study the role of central oxytocin pathways in the mediation of social attachment. This project uses molecular, cellular, and behavioral techniques with a focus on monogamous mammals. The major finding is that the oxytocin receptor appears to be distributed in markedly different patterns across species, leading to different functional effects of the peptide. In monogamous species, oxytocin receptors are found in pathways implicated in reward. The species differences in receptor distribution are not associated with variations in the coding sequence of the receptor gene but may be due to extensive variation in the promoter. Recently, anatomic and molecular studies in monkeys have been undertaken prior to investigating the human brain. A related receptor, the V1a receptor, has been found in select regions of the rhesus forebrain with binding and in situ hybridization and, based on its pattern of expression, may have an important rol e in memor y. The ultimate purpose of this research is to identify the neural circuitry for attachment behavior, providing a potential map of areas for study in human disorders of social attachment, such as autism. FUNDING NIH / RO1MH56538-02 $149,619 1/01/97 - 12/31/01 PUBLICATIONS Insel, T.R. Towards a neurobiology of attachment. Review of General Psychology (In press). Insel, T.R., O'Brien, D.J. and Leckman, J.F. Oxytocin, vasopressin, and autism. Is there a connection? Biological Psychiatry (In press). Insel, T.R. and Winslow, J.T. Serotonin and neuropeptides in affiliative behaviors. Biological Psychiatry 44:207-219, 1998. Insel, T.R. and Winslow, J.T. The neurobiology of social attachment, in Charney D.S., Nestler, E.J., and Bunney, B.S. (Eds.) Neurobiology of Mental Illness, Oxford University Press, New York (In press). Insel, T.R., Winslow, J.T., Wang, Z. and Young, L.J. Oxytocin, vasopressin, and the neuroendocrine basis of pair bond formation, in Zingg, H.H., Bourque, C.W., and Bichet, D.G. (Eds.) Vasopressin and Oxytocin Molecular, Cellular, and Clinical Advances, Plenum Press, New York, pp. 215-224, 1998. Sanchez, M., Young, L.J., Plotsky, P. and Insel, T.R. Autoradiographic and in situ hybridization localization of corticotropin-releasing factor 1 and 2 receptors in nonhuman primate brain. J. Comp. Neurol. (In press). Wang, Z., Young, L.J., De Vries, G. J. and Insel, T.R. Voles and vasopressin A review of molecular, cellular, and behavioral studies of pair bonding and paternal behaviors, in Urban, I.J.A., Burback, J.P.H., and De Wied, D. (Eds.) Brain Vasopressin and Related Peptides, Signpost (In press). Young, L.J., Toloczko, D. and Insel, T.R. Localization of V1a receptor binding and mRNA in the rhesus monkey brain. J. Neuroendo. (In press). Young, L.J., Wang, Z. and Insel, T.R. Neuroendocrine bases of monogamy. Trends in Neuroscience 21(2):71-75, 1998. P51RR00165-38 1/1/98 - 12/31/98 Yerkes Regional Primate Research Center

Unfortunately, prolongation of life in AIDS sufferers may lead to a higher incidence of AIDS-related cognitive deficits. It is, therefore, extremely important to develop an animal model of human AIDS-related cognitive impairment. A neurotropic variant of SIV is being tested in pigtail macaques that have been trained on a battery of cognitive tasks. If this variant produces cognitive deficits, then the SIV-infected pigtail macaque may provide the needed model for future studies of possible treatments of AIDS-related dementias.

Estradiuol (E2) replacement therapy (ERT) in menopausal women has protective effects on a variety of age-related diseases, including osteoporosis, cardiovascular diseases, age-related memory impairments, and development of dementia. However, ERT, even with progestin co- treatment, induces precancerous changes in the tissues of the breast and uterus. A new group of non-steroidal estrogens, deemed Selective Estrogen Receptor Modulators (SERMs) has been developed as a possible alternative to ERT but without the adverse proliferative effects on breast and endometrial tissues, while retaining some of the positive effects of E2. Yet, despite the well-documented efficacy of these compounds in peripheral target tissues, their influence in the brain, and especially upon cognitive function, is not known. Clearly brain and cognitive effects of SERMs must be understood in order to determine their desirability as an alternative to ERT in hypoestrogenic women. We will use the ovariectomized rhesus monkey as a model of human low-estrogen conditions, such as menopause, to examine the effects of SERMs on female cognition. This project will first determine whether the SERMs tamoxifen and raloxifene are E2 agonists or E2 antagonists in a variety of cognitive domains in Ovariectomized female rhesus monkeys. Monkeys will be repeatedly tested with a computerized touch- screen system on a battery of four memory and attentional tasks while undergoing E2, SERMs, or placebo treatments. Specific Aim 2ill use the same battery of tasks to determine whether SERMs, in the presence of E2, act as E2 antagonists on cognitive function. Specific Aim 3 will use positron emission tomography (PET) and the glucose metabolic tracer [18F]fluorodeoxyglucose (18F FDG) to determine whether E2 increases activation of specific brain regions following performance on the cognitive task most improved by ERT. Specific Aim 1 will determine whether SERMs mimic E2 in enhancing object recognition memory, attention, and working memory, while impairing spatial memory functions in ovariectomized female rhesus monkeys. Specific Aim 2 will determine whether SERMs, in the presence of E2, act a sE2 antagonists in cognitive function/ Specific Aim 3 will use PET and the 18F FDG tracer to evaluate the relationships between rCMRglc, ERT, and cognitive performance on a specific task. These data in the rhesus monkey will provide valuable information on the efficacy of SERMs on female cognition and will help in evaluating the risks and benefits of using these compounds in hypoestrogenic women.

raloxifene; female; psychopharmacology; cognition; estrogens; Macaca mulatta; animal colony; animal old age;

[unreadable] DESCRIPTION (provided by applicant): Among all female primates, only women are infertile for as much as 30 to 50 % of their lifetimes. One evolutionary theory of aging, the "grandmother hypothesis," holds that post-reproductive longevity of women provided a selective advantage because assistance in child-rearing provided by grandmothers led to higher rates of lifetime fertility in their daughters. Humans are also uniquely susceptible to Alzheimer's disease (AD) and its presumed precursor Mild Cognitive Impairment (MCI). We believe that these unique human characteristics, particularly as they occur in women, can best be understood by comparing human's brain and cognitive aging with the same features in our closest relative, the chimpanzee, and in the most widely studied biomedical model of human aging, the rhesus monkey. Accordingly, we propose to study longitudinally cognitive function, emotional processing, brain aging, and of aging in normally aging women, women with AD and MCI, and female rhesus monkeys and chimpanzees. The research program consists of 3 projects. Project 1 will study cognitive and motoric aging in the 3 species and will determine how well classic nonhuman primate tests of cognitive function measure the same capabilities in humans. Project 2 will examine the effects of aging on social cognition and emotional processing in female primates. Project 3 will define the human-specific pattern of brain aging by comparing age-related changes in brain structure in humans, chimpanzees, and macaques, using in vivo imaging and histologic techniques. The projects will be supported by the Administrative and Data Analysis Core, which will have responsibility for storage and analysis of data on a project-wide basis, and by the Animal Core, which will coordinate selection and use of the nonhuman subjects for all projects. The Imaging Core will provide expertise and assistance in collecting and analyzing brain images. Finally, the Reproductive Status Core will monitor subjects' endocrine status during testing. We anticipate that the data will provide new insights into the biological basis of age-related functional decline in female primates, and into the factors that govern successful versus unsuccessful aging. This comparative analysis also can illuminate the origins of human age-related neurodegenerative disorders such as AD, facilitating the development of treatments for this disease. [unreadable] [unreadable]

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This project compares brain and cognitive decline in female Homo sapiens, Pan troglodytes and Macaca mulatta. We have collected behavioral data from 436 healthy human females on tasks derived for nonhuman primates (NHPs). Results confirm that humans show age-related decline on NHP-derived tasks designed to measure visual recognition memory, spatial working memory, motor function, and executive function. Parallel studies on rhesus monkeys (n=24) have confirmed the expected pattern of decline in monkeys. However, results in chimpanzees (n=36) have been surprising in that the chimpanzee appears to be somewhat resistant to age-related changes in some tests. Thus, while all three species show deficits in executive function, as measured by our computerized Conceptual Set Shifting Task, only humans and rhesus monkeys, but not chimpanzees, show a decline in spatial working memory. Another aim of this project is to assess cognitive function in AD and MCI patients, enrolled as subjects in the Emory Alzheimer Disease Research Center (ADRC), which has also made progress. Twenty-six ADRC subjects have been enrolled, and preliminary results confirm that they too show age-related decline in the CSST and DRST tasks. Additional subjects are now being tested. Many theories of aging suggest that the human's aging phenotype, including impairment and the uniquely human susceptibility to Alzheimer Disease, is a result of selection pressure that shaped our species. This unique study of the differences among three primates will help us understand evolutionary and physiological processes that may paradoxically underlie both our uniquely human longevity and our susceptibility to age-related decline.