The overarching goal of my research is to understand how sex steroid hormones shape the neural circuitry underlying higher order cognitive functions. This includes defining the role of sex steroids in the healthy adult brain and, in turn, exploring how the loss of gonadal hormones during reproductive aging influences memory circuitry. I use a multi-tier approach that includes fMRI, molecular PET imaging, neuroendocrinology and imaging genetics.

1. Hormonal regulation of memory circuitry

The brain is a major target of sex steroids, yet relatively little is known about how these hormones shape brain function beyond their role in reproduction. A rapidly growing body of work from rodents and nonhuman primates has established estradiol’s influence on synaptic organization within the hippocampus and prefrontal cortex. Despite significant implications for human health, few laboratories are examining these relationships at a human cognitive neuroscience level. Capitalizing on convergent techniques from cognitive neuroscience, neuroendocrinology and imaging genetics, my graduate work identified estradiol’s impact on prefrontal cortex function and working memory performance in women. This research revealed that estradiol’s impact on prefrontal cortex function is not uniform across women, but depends in part on individual differences in genetic variability within the dopamine system. More broadly, these findings suggest that dopamine’s influence on cognition cannot be fully understood without taking estradiol into account (Jacobs & D’Esposito, J. Neuroscience, 2011; for related work see Jacobs, Weinberger, Jagust & D’Esposito, in prep; and Jacobs et al, Neuropsychopharmacology, 2015).

This work was funded by a National Science Foundation Graduate Research Fellowship.

2. Impact of reproductive aging on memory circuitry

Given accumulating evidence of estradiol’s regulation of memory circuitry, the loss of ovarian estrogens during the menopausal transition may play a significant role in shaping early age-related neural changes in women. In collaboration with Professor Jill Goldstein (K12 mentor), I am currently investigating this in a large-scale, population-based fMRI study of mid-life men and women. Results from the study suggest that the natural depletion of sex steroid hormones in midlife alters neural mechanisms of working memory. For example, despite very little difference in chronological age (<1 year) and task performance, postmenopausal women recruit dorsolateral PFC more strongly than pre- and perimenopausal women and men, perhaps reflecting a successful compensatory response for maintaining working memory performance at a level commensurate with the other groups. Current analyses are characterizing the changes in functional connectivity between dorsolateral PFC, superior parietal cortex and the hippocampus that occur as estradiol levels decline during reproductive senescence.

This work is supported by an NIH K12 Career Development award. Recent findings will be presented at SfN (nanosymposium, November 2014) and ACNP (“Hot Topics” Symposium, December 2014).

3. Relationship between neural and chromosomal aging

As a Robert Wood Johnson Foundation Health and Society Scholar (2010-2012), I broadened my focus to examine the relationship between cellular and neural aging. In collaboration with Elissa Epel and Elizabeth Blackburn at UCSF and Natalie Rasgon at Stanford, we showed that cellular markers of aging reflect early structural brain changes in memory circuitry (Jacobs et al., JAMA Neurology 2014). Next, we found that APOE-ε4 (a major genetic risk factor for cognitive decline, dementia, and early mortality) is associated with accelerated biological aging in humans. Despite the fact that the adults in our sample were currently healthy, ε4-carriers exhibited the equivalent of one decade of additional cell aging compared to non-carriers during the two-year study. Further, the data suggested that hormone therapy may buffer against cell aging in a genotype-dependent manner (Jacobs et al., Plos One 2013, Faculty of 1000 selection).

This work was supported by the Robert Wood Johnson Foundation.

4. Fetal origins of neural and cellular aging

Capitalizing on a 50-year neuroimaging follow-up study of a prenatal cohort, Professor Goldstein and I are currently investigating whether exposure to prenatal stress accelerates chromosomal and neural indices of aging. Participants are part of a community-based sample called the New England Family Study, which originally enrolled 17,000 pregnant women from the greater Boston area. The offspring, now midlife, have been followed since 2nd trimester in utero. This large-scale population-based neuroimaging study combines structural and functional brain imaging in the adult offspring with prenatal serologic indicators of maternal-fetal stress (e.g. inflammatory cytokines and adrenal stress hormones). Current analyses are examining whether prenatal stress accelerates age-related neurodegeneration and memory circuitry dysfunction, and whether these relationships vary by sex. We are also exploring whether prenatal stress has an enduring effect on cellular aging. Animal studies provide substantial evidence that exposure to early life stress can program the developing hypothalamic-pituitary-adrenal axis and disrupt the structure and function of brain regions densely populated with stress hormone receptors. Now, for the first time, we have the unique ability to examine these relationships prospectively in humans.

This work is supported by an NIH K12 Career Development award.