Effects of Immediate or Delayed Estradiol on Behavior in Old Menopausal Macaques on Obesogenic Diet

Abstract

Macaques have served as effective models of human disease, including pathological processes associated with obesity and the metabolic syndrome. This study approached several questions: (1) does a western-style diet (WSD) contribute to sedentary behavior or is sedentary behavior a consequence of obesity and (2) does estradiol (E) hormone therapy offset WSD or ameliorate sedentary behavior? We further questioned whether the timing of E administration (immediately following hysterectomy, ImE; or after a 2-year delay, DE) would impact behavior. Focal observations were taken on the animals in social housing over a period of 2.5 years before and after initiation of the WSD and hysterectomy. In addition, anxiety was assessed through the Human Intruder and Novel Object Tests. All animals gained weight, but ImE delayed the time to maximum weight achieved at 18 months. Over the course of the study, ImE-treated monkeys spent more time “alone” and less time in “close social” contact than placebo-controls. The DE-treated monkeys were not different from placebo-controls in these 2 outcomes. The placebo-control group exhibited more “self-groom” behavior, an indicator of anxiety, than did the ImE-treated group, and DE-treated animals approached levels observed in the ImE-treated animals. All animals exhibited an increase in “consume” behavior over time with no statistical difference between the groups. By the end of the protocol, the placebo-control group exhibited less activity compared to ImE + DE-treated animals combined. Animals also showed increased anxiety after starting on the WSD in the Human Intruder Test and the Novel Object Test. In summary, the data indicated that WSD per se promoted increased consummatory behavior, sedentary behavior, and anxiety-type behaviors, whereas ImE promoted activity. Thus, WSD may precipitate the behaviors observed in humans who then become obese, sedentary, anxious, and socially isolated. ImE replacement ameliorates some of these behaviors, but not all.

Longitudinal Effects of Immediate and Delayed Estradiol on Cognitive Performance in a Spatial Maze and Hippocampal Volume in Menopausal Macaques Under an Obesogenic Diet

“…Recently, Coleman et al (16) reported on the effects of both delayed and immediate estrogen replacement on behavior performance compared to placebo-controls after OvH in the same aged rhesus macaques under obesogenic diets involved in the present study (16). Their results demonstrated that macaques under an obesogenic diet exhibited increased sedentary and anxiety-like behaviors, but that immediate estrogen replacement promoted activity and ameliorated anxiety-like behavior.…”

“…Hippocampal and prefrontal ROIs were defined specifically because of their hypothesized role in spatial maze performance. The amygdala ROI was defined because a previous study on these monkeys ( 16 ) observed treatment differences in anxiety-type behaviors which we hypothesized could both affect performance on the task and could manifest anatomically as differential relative amygdala sizes. A motor ROI was defined as a region that we did not expect to be substantially involved in treatment effects on cognitive performance to serve as an anatomical control for the other anatomical analyses.…”

“…The animals and experimental treatment paradigm are as described previously by Coleman et al (16). Briefly, aged female rhesus macaques of 17 years old or older were socially housed in groups of 2-4 animals throughout the study in indoor pens (∼3.7 × 2.1 × 2.1 m) and provided with enrichment such as toys and foraging devices.…”

“…Little is known about how WSDs interact with hormone replacement therapy in menopause. There is some evidence indicating that the effectiveness of HRT on behavioral and cognitive performance is modulated by an obesogenic diet in macaques (16) as well as in rodent models (17), but the mechanisms that may contribute to this diet-HRT interaction on cognition are not known.…”