Ovarian hormone deficiency of menopause brings on changes that can have far reaching consequences on the future health and well being of women. Nondemented postmenopausal women frequently note alterations in cognitive functions, particularly memory and attention. Determining the relationship between ovarian hormones and cognitive function in menopause can be difficult to study in women because of a variety of confounding factors. We have developed a monkey model of menopause that allows us to more rigorously control many of these factors and additionally, that has allowed us to begin to identify cholinergic mechanisms of ovarian hormone action in the primate brain. Our initial behavioral and neurobiological studies were performed in young ovariectomized monkeys so that we could determine the effects of estrogen therapy (ERT) without the influence of other confounding factors, including advanced age. However, there are many important questions that remain unanswered, including the effects of estrogen plus progesterone therapy (HRT) and the effects of ovarian hormones in monkeys of an age that more closely models that of the middle-aged postmenopausal woman. These issues will be addressed in middle-aged monkeys in the present project. Behavioral experiments in Specific Aim 1 will determine the cognitive effects of ovarian hormone replacement therapy (ERT and HRT) using a series of behavioral tasks that measure several different cognitive functions that rely on the cholinergic system.
In Specific Aim 2. functional imaging studies of the cholinergic system will be performed in the monkeys of Specific Aim 1 in parallel with their behavioral assessments to determine if measures of presynaptic cholinergic activity correlate with measures of cognitive function in monkeys treated with ovarian hormones.
In Specific Aim 3. pharmacological studies will be performed in the monkeys following their initial behavioral and imaging studies to determine the effects of cholinergic, muscarinic and nicotinic receptor blockade on cognitive function in monkeys treated with ovarian hormones. Thus, the overall objectives of the experiments proposed in this application are to extend and broaden our initial investigations in young monkeys by determining the effects of ovarian hormone replacement therapy on cognitive function and in vivo cholinergic system function in middle-aged surgically menopausal rhesus monkeys. The findings from these novel experiments in middle-aged monkeys will significantly advance our understanding of the effects of ovarian hormone therapy on cognitive and neurobiological profiles of primates.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG013204-09
Application #
6940742
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Monjan, Andrew A
Project Start
1996-05-01
Project End
2007-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
9
Fiscal Year
2005
Total Cost
$721,758
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Voytko, Mary Lou; Tinkler, Gregory Paul; Browne, Carole et al. (2009) Neuroprotective effects of estrogen therapy for cognitive and neurobiological profiles of monkey models of menopause. Am J Primatol 71:794-801
Browne, Carole; Tobin, Joseph R; Voytko, Mary Lou (2009) Effects of two years of conjugated equine estrogens on cholinergic neurons in young and middle-aged ovariectomized monkeys. Brain Res 1264:13-23
Voytko, Mary Lou; Murray, Rhonda; Higgs, Casey J (2009) Executive function and attention are preserved in older surgically menopausal monkeys receiving estrogen or estrogen plus progesterone. J Neurosci 29:10362-70