Current Lines of Research
Sex steroid hormones
The primary goal of our laboratory is to pinpoint the molecules and cellular processes through which estrogens and progestins enhance memory consolidation throughout the female lifespan. We are particularly interested in how hormones affect memory in older women, because the decline of estrogens and progestins at menopause dramatically increases a woman’s risk of memory loss and Alzheimer’s disease. Because traditional hormone therapies increase risks of cancer, heart disease, and stroke, they are not recommended to treat age-related cognitive decline in women. However, the development of novel treatments that mimic the beneficial effects of estrogens and progestins in the brain, but do not produce their harmful side effects, could prevent or reverse age-related cognitive decline, thereby improving the quality of life for millions of older women. A critical step towards the development of such treatments is the discovery of the underlying molecular mechanisms in the hippocampus through which estrogens and progestins regulate memory formation (for reviews, see Frick, 2009; Frick, 2010; Frick, 2012; Frick, 2013; Fortress & Frick, 2014; Tuscher et al., 2015; Frick et al, 2015; Frick, 2015; Fortress & Frick, 2016).
Our studies focus on the hippocampus, a brain region necessary for memory formation that deteriorates in aging and Alzheimer’s disease. Our current working model of how the potent estrogen 17beta-estradiol (E2) enhances memory in the dorsal hippocampus is illustrated below (Frick, 2015). We have discovered that several membrane-associated receptors are necessary for E2 to enhance object recognition and spatial memory, including ERalpha, ERbeta, metabotropic glutamate receptors, and NMDA receptors (Boulware et al., 2013; Lewis et al., 2008). Activation of these receptors in the dorsal hippocampus triggers the rapid activation of numerous cell-signaling pathways, including ERK and mTOR. This activation is necessary for E2 to enhance hippocampal memory in young and middle-aged female mice (Fernandez et al., 2008; Fan et al., 2010; Lewis et al., 2008; Fortress et al., 2013b). In recent collaborative work with Drs. Vicky Luine (Hunter College) and Maya Frankfurt (Hofstra North Shore-LIJ School of Medicine), we also recently found that dorsal hippocampal ERK and mTOR activation are necessary for E2 to increase dendritic spine density in both the dorsal hippocampus and medial prefrontal cortex of young female mice (Tuscher et al., 2016a). Interestingly, activation of the membrane estrogen receptor GPER enhances hippocampal memory formation via JNK signaling, rather than ERK signaling (Kim et al., 2016), suggesting that GPER may not function as an estrogen receptor in the hippocampus.
Our recent findings that canonical Wnt signaling is necessary for memory consolidation (Fortress et al., 2013a) raise the possibility that Wnt signaling may also play a role in E2-induced memory enhancement. These findings form the basis of our new grant from the National Institute of Mental Health to study the roles of canonical Wnt signaling and the neurotrophin BDNF in mediating the effects of E2 on memory consolidation in both female and male mice.
Downstream from cell signaling, we have found that the ability of E2 to enhance memory in young and middle-aged females depends on rapid activation of the epigenetic processes histone acetylation and DNA methylation (Zhao et al., 2010; Zhao et al., 2012; Fortress et al., 2014). Other work from the lab has identified genes in the dorsal hippocampus whose expression is regulated by E2 (Pechenino & Frick, 2009). Most recently, we used chromatin immunoprecipitation (ChIP) to show that E2 increases acetylation of promoters of the BDNF gene (Fortress et al., 2014). In a related project, we are collaborating with Drs. Mahmun Hossain and Douglas Steeber of UWM’s Chemistry and Biological Sciences departments to study the effects on memory of selective histone deacetylase inhibitors.
In collaboration with Dr. Luke Remage-Healey (University of Massachusetts Amherst), we have also begun to examine the role of E2 synthesized within the dorsal hippocampus in memory formation. Our recent data suggest that hippocampally-synthesized E2 is necessary for the formation of object recognition and spatial memories in female mice (Tuscher et al., 2016b). This work also suggests that object learning may trigger hippocampal E2 synthesis, which could explain why exogenous E2 treatments are so effective at regulating memory formation.
In 2013, we collaborated with Dr. Devin Mueller (now of Ponce University School of Medicine) to show that E2 is necessary for the extinction of a cocaine-induced place preference in female rats (Twining et al., 2013). Our current work pinpointing the molecular basis of this effect is supported by a grant from the National Institute on Drug Abuse.
We are also currently collaborating with Drs. Daniel Sem (Concordia University Wisconsin) and William Donaldson (Marquette University) to study the effects on memory of specific estrogen receptor beta agonists. This work is supported by a grant from the National Institute of General Medical Sciences.
As part of a new collaboration with Dr. Mary Jo LaDu (University of Illinois at Chicago), we have received one of nine inaugural “SAGA” (Sex and Gender in Alzheimer’s) grants from the Alzheimer’s Association to study the effect of apolipoprotein E genotype, sex, and E2 treatment on memory in mouse model of Alzheimer’s disease.
Finally, although much of our work has focused on E2, a similar line of research demonstrates that progesterone can also rapidly enhance memory consolidation in female mice throughout adulthood (e.g., Harburger et al., 2008, 2009; Lewis et al., 2008; Orr et al., 2009), and do so rapidly via ERK and mTOR activation in the dorsal hippocampus (Orr et al., 2012). Our most recent findings demonstrate that these effects are mediated via membrane progesterone receptors, whereas intracellular progesterone receptors appear to regulate memory consolidation by activating canonical Wnt signaling (Fortress et al., 2015).
Our early work on sex differences in memory highlighted the existence of sex differences in age-related memory and neurochemical decline in mice (e.g., Frick et al., 2000; Frick et al., 2002) and demonstrated that young male mice outperform young female mice in object recognition (Frick & Gresack, 2003) and working memory (Gresack & Frick, 2003) tasks. Interestingly, our work with human subjects shows a different pattern of sex differences. In Yale undergraduates, we found that spatial memory tested in a virtual radial arm maze does not differ between men and women, whereas object memory is superior in women relative to men (Levy et al., 2005). Whether a sex differences in observed in a particular test of learning and memory is influenced by numerous factors, including experimental methodology and stress. This latter point is highlighted in our recent study showing that prenatal stress impairs spatial memory in both adult male and female mice, but induces greater epigenetic and corticosterone alterations in the hippocampus of females (Benoit et al., 2015). We discuss these issues in a recent review paper published as part of a special issue on sex differences (Koss & Frick, in press).
We are also beginning to examine the molecular bases of sex differences in memory. In one previous study, we found that a sex difference (favoring males) in contextual fear conditioning is associated with increased activation of ERK in the ventral, but not dorsal, hippocampus in males relative to females (Gresack et al., 2009). Unpublished data from the lab suggest that dorsal hippocampal infusion of E2 enhances hippocampal memory consolidation similarly in male and female mice, but that it may do so via different cell-signaling mechanisms. Ongoing studies are being conducted as part of our NIMH grant to identify the cell-signaling mechanisms underlying estrogenic regulation of memory in males.
Finally, we also have a long-standing interest in studying how various types of environmental stimulation affect the response to aging, hormone treatment, and stress. We have found that environmental enrichment, consisting of both cognitive stimulation and physical exercise, can improve various types of hippocampal-dependent memory (e.g., spatial and object memory) and enhance hippocampal function (e.g., synaptic protein levels, growth factor levels) in young, middle-aged, and aged male and female mice (e.g., Frick et al., 2003; Frick & Fernandez, 2003; Lambert et al., 2005; Bennett et al., 2006). These studies demonstrate somewhat different effects of enrichment in males and females, with respect to both memory and synaptic protein levels (Harburger et al., 2007a). We have also tried to determine which aspects of the enriched environment are particularly important for cognition enhancement. Our data, thus far, indicate that exercise most effectively improves spatial memory in young and middle-aged females, whereas both exercise and cognitive stimulation are effective for aged females (Lambert et al., 2005; Harburger et al., 2007b). Finally, we have also shown that enrichment reduces the ability of E2 to enhance memory in young and middle-aged female mice (Gresack & Frick, 2004; Gresack et al., 2007).