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Neuroplasticity, Hormones, and Cognition

Hippocampal Plasticity

We conducted some of the first studies of how sex, stress, and steroid hormones regulate adult hippocampal neurogenesis. Sex differences in neurogenesis (Galea & McEwen, 1999; Yagi et al., 2020) are related to estrogens in females (Ormerod and Galea, 2001; Barker and Galea, 2008; Green and Galea, 2008; Barha et al., 2009; Eid et al., 2020; Barha and Galea, 2013; Galea et al., 2018; Chan et al., 2014) and androgens in males (Spritzer and Galea, 2007; Duarte-Guterman et al., 2019; Hamson et al., 2013; Swift-Gallant et al., 2018). Our past work has examined estrogen receptor (ER) and androgen receptor (AR) involvement in neurogenesis in the hippocampus. ERα, ERβ and GPER differentially regulate neurogenesis (Mazzuco et al., 2009; Duarte-Guterman et al., 2015) in young adult female, but not male, rats (Barker and Galea, 2008). Androgens, on the other hand, increase neurogenesis in adult male but not females, but not middle-aged male rats 


via androgen receptors (Hamson et al., 2013; Swift-Gallant et al. 2018, Duarte-Guterman et al., 2019). We also see differences in how females respond to estrogens based on their past reproductive history. Overall, although we and others have found no sex differences in the levels of neurogenesis, the maturation rate and attrition rate of new neurons are very different between the sexes (Yagi et al., 2020). Our most recent publications show that there are sex differences in the level of engagement of different ages of new neurons during memory retrieval (Yagi et al., 2022).  Our work, funded by NSERC and the Cure for AD Foundation, is to examine the mechanisms of hormone-induced neuroprotection via cell signaling proteins during normal aging and in an animal model of sporadic AD in both sexes, stemming from our findings that androgens, but not estrogens, increase neuroplasticity in males, a pattern reversed in females and with aging.

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My NSERC program centers on understanding how estrogens and sex influence cognitive processes using learning tasks that rely on different brain regions and circuits, Our NSERC-related work has identified that estrogens dose-dependently regulate memory, neurogenesis, expression of synaptic proteins and immediate early genes in the hippocampus (Barha et al., 2007; Barha and Galea, 2011; McClure et al., 2013; Yagi et al., 2017; Yagi et al in prep). Collectively, we found that high E2 impaired performance in a variety of hippocampus-dependent tasks in female rodents but low E2 facilitated performance on hippocampus-dependent and prefrontal cortex (PFC)-dependent tasks (Sinopoli et al., 2006; Uban et al., 2011; Holmes et al., 2002). In addition, we found that high ovarian steroids are associated with spatial strategy use (Rummel et al., 2010; Yagi et al., 2016, 2017). Further, our work suggests E2 affects mesolimbic-dependent decision-making and hippocampus-dependent memory via genomic and non-genomic mechanisms (Islas et al., 2020; Sinopoli et al., 2006; Uban et al., 2012; Wide et al., 2004). 

Overall, higher E2 impairs both working and reference memory, while low E2 facilitates working memory in females (Holmes et al., 2002; Uban et al., 2012). We also find that a different estrogen, estrone dose-dependently impairs cognition (Barha et al., 2010; Galea et al., 2018) in female rats. We also found that E2 increased neurogenesis in the DG after Morris Water Maze learning but not after estrone-treatment (McClure et al., 2013), and that proestrus (high E2) increased cfos expression in the DG after cue competition (Yagi et al., 2017). Preliminary evidence suggests low E2 increased neurogenesis but high E2 reduced neurogenesis in spatial strategy users after pattern separation (Yagi et al, in prep). Therefore, estrogens modulate learning and neuroplasticity depending on type, dose, and brain regions targeted in females. Our continuing work in this area is to examine how sex and different doses of estrogens influence neural correlates (including neurogenesis) and functional connectivity after memory retrieval. We recently showed that although there are no sex differences in neurogenesis in the hippocampus of adult rats, there are differences in the maturation pathways that males and females use to establish those new neurons (Yagi et al., 2020).  Males show greater proliferation and faster maturation, but higher attrition of new neurons than females. These findings suggest that if stimulating neurogenesis is warranted, different systems (treatments) would need to be targeted in males versus females. Indeed, we also found sex differences in functional connectivity with contextual pattern separation and greater new neuron activation in females compared to males, as well as different patterns of functional connectivity with these activated new neurons (Yagi et al., 2022).  Ongoing work is now examining this in females with different estrogens and we find that estradiol accelerates the maturation of new neurons which depends on the duration of estradiol treatment in young adult ovariectomized rats (Yagi et al., in prep). These findings have implications for hormone therapy and its effects on memory and neuroplasticity.

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