Translational cognitive endocrinology: Designing rodent experiments with the goal to ultimately enhance cognitive health in women

Abstract

Understanding the cognitive impact of endogenously derived, and exogenously administered, hormone alterations is necessary for developing hormone treatments to support healthy brain function in women, especially during aging. The increasing number of studies in the burgeoning area of translational cognitive neuroendocrinology has revealed numerous factors that influence the extent and direction of female steroid effects on cognition. Here, we discuss the decision processes underlying the design of rodent hormone manipulation experiments evaluating learning and memory. It is noted that even when beginning with a clear hypothesis-driven question, there are numerous factors to consider in order to solidify a sound experimental design that will yield clean, interpretable results. Decisions and considerations include: age of animals at hormone administration and test, ovariectomy implementation, when to administer hormones relative to ovarian hormone loss, how and whether to monitor the estrous cycle if animals are ovary-intact, dose of hormone, administration route of hormone, hormone treatment confirmation protocols, handling procedures required for hormone administration and treatment confirmation, cognitive domains to be tested and which mazes should be utilized to test these cognitive domains, and control measures to be used. A balanced view of optimal design and realistic experimental practice and protocol is presented. The emerging results from translational cognitive neuroendocrinology studies have been diverse, but also enlightening and exciting as we realize the broad scope and powerful nature of ovarian hormone effects on the brain and its function. We must design, implement, and interpret hormone and cognition experiments with sensitivity to these tenets, acknowledging and respecting the breadth and depth of the impact gonadal hormones have on brain functioning and its rich plasticity.

Trajectories and phenotypes with estrogen exposures across the lifespan: What does Goldilocks have to do with it?

“…Other theories suggest that menopause is simply a result of physiological deterioration with age (Ward et al, 2009) or an artifact of an increased lifespan (Wu et al, 2005). However, this seems unlikely considering that women tend to live longer than men and that the average lifespan is increasing, yet the age of menopause onset has remained relatively stable (Amundsen and Diers, 1973, 1970; Mennenga and Bimonte-Nelson, 2013; Regan and Partridge, 2013; Seifarth et al, 2012; Sherwin, 2003), indicating that the number of reproductive-age years is not proportionally increasing along with the rising average lifespan. Additionally, the rate at which chimpanzees (the closest living relatives to humans) and human females’ ovarian follicles deplete is remarkably similar, yet a chimpanzee's lifespan is much shorter than modern humans and they lack an extended post-menopausal life stage, indicating that humans’ unique capacity for longevity evolved long ago (Gems, 2014).…”

“…That is, one dose and duration might be optimal for one woman, but suboptimal or even detrimental to another woman. In addition, the animal work indicates that there are a considerable number of potentially interactive factors to bear in mind, including, but certainly not limited to, the type of estrogen given, route of hormone administration, status of reproductive senescence/follicular depletion, age at which hormone is administered, presence or absence of a progestogen, and the presence or absence of ovaries (Acosta et al, 2013; Chisholm and Juraska, 2013; Luine, 2014; Mennenga and Bimonte-Nelson, 2013), as well as the appropriate battery of assessments to tap into estrogen-modulated systems.…”

“…Several animal models exist as translational tools to help us better understand aging and reproductive senescence (Acosta et al, 2013; Brinton, 2012; Mennenga and Bimonte-Nelson, 2013). Much of our understanding of the impact of estrogens on cognition comes from the “blank slate” Ovx rat model, in which the primary source of endogenous gonadal hormones, the ovaries, is removed before exogenous hormone therapies are administered 1 .…”

Contrasting effects of individual versus combined estrogen and progestogen regimens as working memory load increases in middle-aged ovariectomized rats: one plus one does not equal two

“…As early as the 1950s, studies have suggested a beneficial role of estrogens in cognitive and related molecular processes of the central nervous system (e.g., Bimonte and Denenberg, 1999; Caldwell and Watson, 1952; Komnenich et al, 2013; Matsumoto et al, 1985; Singh et al, 1995; Woolley and McEwen, 1993). Today, there are an extensive array of studies aimed at understanding the effects of E2 on learning and memory in humans as well as in animal models (for reviews: Frick, 2015; Koebele and Bimonte-Nelson, 2015; Korol and Pisani, 2015; Maki, 2012; Mennenga and Bimonte-Nelson, 2013; Sherwin, 2006). The ovariectomy (Ovx) model in rodents, whereby the primary source for circulating ovarian hormones, the ovaries, are surgically removed, provides a low circulating ovarian hormone profile or a ‘blank hormonal slate’.…”

Engineering poly(lactic-co-glycolic acid) (PLGA) micro- and nano-carriers for Controlled Delivery of 17β-Estradiol

“…In addition to its well-known role in female endocrinology, E2 is also recognized for its more broad neuroprotective effects, which suggests that hormone therapy could be of interest for treating conditions other than symptoms associated with menopause 8,27,33 For example, E2 has been shown to enhance normal cognitive function following the loss of circulating ovarian hormones, in both humans and in animal models 41,50,53 . E2 has also been examined as a potential therapeutic treatment for neurodegenerative diseases, such as Alzheimer’s disease (AD) 3,4,16,38,76,84 .…”