Effect of Ovarian Hormone Therapy on Cognition in the Aged Female Rhesus Macaque

Studies of the effect of hormone therapy on cognitive function in menopausal women have been equivocal, in part due to differences in the type and timing of hormone treatment. Here we cognitively tested aged female rhesus macaques on (1) the delayed response task of spatial working memory, (2) a visuospatial attention task that measured spatially and temporally cued reaction times, and (3) a simple reaction time task as a control for motor speed. After task acquisition, animals were ovariectomized (OVX). Their performance was compared with intact controls for 2 months, at which time no group differences were found. The OVX animals were then assigned to treatment with either a subcutaneous sham implant (OVX), 17-β estradiol (E) implant (OVX+E) or E implant plus cyclic oral progesterone (OVX+EP). All groups were then tested repeatedly over 12 months. The OVX+E animals performed significantly better on the delayed response task than all of the other groups for much of the 12 month testing period. The OVX+EP animals also showed improved performance in the delayed response task, but only at 30 s delays and with performance levels below that of OVX+E animals. The OVX+E animals also performed significantly better in the visuospatial attention task, particularly in the most challenging invalid cue condition; this difference also was maintained across the 12 month testing period. Simple reaction time was not affected by hormonal manipulation. These data demonstrate that chronic, continuous administration of E can exert multiple beneficial cognitive effects in aged, OVX rhesus macaque females. SIGNIFICANCE STATEMENT Hormone therapy after menopause is controversial. We tested the effects of hormone replacement in aged rhesus macaques, soon after surgically-induced menopause [ovariectomy (OVX)], on tests of memory and attention. Untreated ovarian-intact and OVX animals were compared with OVX animals receiving estradiol (E) alone or E with progesterone (P). E was administered in a continuous fashion via subcutaneous implant, whereas P was administered orally in a cyclic fashion. On both tests, E-treated animals performed better than the other 3 experimental groups across 1 year of treatment. Thus, in this monkey model, chronic E administered soon after the loss of ovarian hormones had long-term benefits for cognitive function

Why primate models matter.

Research involving nonhuman primates (NHPs) has played a vital role in many of the medical and scientific advances of the past century. NHPs are used because of their similarity to humans in physiology, neuroanatomy, reproduction, development, cognition, and social complexity-yet it is these very similarities that make the use of NHPs in biomedical research a considered decision. As primate researchers, we feel an obligation and responsibility to present the facts concerning why primates are used in various areas of biomedical research. Recent decisions in the United States, including the phasing out of chimpanzees in research by the National Institutes of Health and the pending closure of the New England Primate Research Center, illustrate to us the critical importance of conveying why continued research with primates is needed. Here, we review key areas in biomedicine where primate models have been, and continue to be, essential for advancing fundamental knowledge in biomedical and biological research

Brain volumetric and microstructural correlates of executive and motor performance in aged rhesus monkeys

The aged rhesus macaque exhibits brain atrophy and behavioral deficits similar to normal aging in humans. Here we studied the association between cognitive and motor performance and anatomic and microstructural brain integrity measured with 3T magnetic resonance imaging in aged monkeys. About half of these animals were maintained on moderate calorie restriction, the only intervention shown to delay the aging process in lower animals. T1-weighted anatomic and diffusion tensor images were used to obtain gray matter volume, and fractional anisotropy and mean diffusivity, respectively. We tested the extent to which brain health indexed by gray matter volume, fractional anisotropy, and mean diffusivity were related to executive and motor function, and determined the effect of the dietary intervention on this relationship. We hypothesized that fewer errors on the executive function test and faster motor times would be correlated with higher volume, higher fractional anisotropy, and lower mean diffusivity in frontal areas that mediate executive function, and in motor, premotor, subcortical, and cerebellar areas underlying goal-directed motor behaviors. Higher error percentage on a cognitive conceptual shift task was significantly associated with lower gray matter volume in frontal and parietal cortices, and lower fractional anisotropy in major association fiber bundles. Similarly, slower performance time on the motor task was significantly correlated with lower volumetric measures in cortical, subcortical, and cerebellar areas and decreased fractional anisotropy in several major association fiber bundles. Notably, performance during the acquisition phase of the hardest level of the motor task was significantly associated with anterior mesial temporal lobe volume. Finally, these brain-behavior correlations for the motor task were attenuated in calorie restricted animals compared to controls, indicating a potential protective effect of the dietary intervention