Cross-Talk Between Estrogen and Thyroid Hormones During Amphibian Development

It is generally thought that in amphibians, thyroid hormones (THs) regulate metamorphosis, while sex steroids (estrogens and androgens) regulate gonadal differentiation. However, inhibition of TH synthesis in frogs alters gonadal differentiation, suggesting instead that these two endocrine axes interact during development. Specifically, THs may be involved in male development, while estrogens may inhibit tadpole metamorphosis. However, we do not currently know the mechanisms that account for these interactions, let alone how such mechanisms may differ between species. To develop and test new hypotheses on the roles of sex steroids and THs, I first examined transcriptional profiles (mRNA) of enzymes and receptors related to sex steroids and THs during embryogenesis and metamorphosis in Silurana tropicalis. Tadpoles were exposed to either an estrogen synthesis inhibitor (fadrozole) or TH (triiodothyronine, T3) during early larval or tadpole development. Acute exposures of S. tropicalis to fadrozole or T3 during early development resulted in increased expression of androgen- and TH-related genes in whole body larvae, while chronic exposure to fadrozole during metamorphosis affected gonadal differentiation but did not affect tadpole development. On the other hand, acute exposure to T3 during metamorphosis increased the expression of androgen-related transcripts both in the brain and gonad. In S. tropicalis, the results suggested that cross-talk is primarily in one direction (i.e., effect of THs on the reproductive axis) with a strong relationship between TH and androgen status. Lastly, I established developmental transcript profiles and investigated T3 regulation of brain and gonad transcripts in Engystomops pustulosus. I then compared these results with S. tropicalis and an earlier study in Lithobates pipiens. While each species developed with similar profiles, they differed in their response to T3. Exposure to T3 resulted in either an increase in androgen-related genes (S. tropicalis) or a decrease in estrogen-related genes (E. pustulosus and L. pipiens). In conclusion, these data demonstrated that cross-talk mechanisms differ among these three evolutionary separate species, but in all cases, T3 appears to affect the balance of sex steroids, stimulating the androgen system and providing potential mechanisms of the masculinising effects of THs. These results will contribute to understanding the mechanisms of hormone interactions and their evolutionary basis in frogs

Beyond Sex Differences : Short and Long-Term Implications of Motherhood on Women’s Health

Sex differences exist in development, physiology, behaviour, disease prevalence, manifestation, and outcome. It is vitally important to consider sex differences in research towards a better understanding of precision medicine for both men and women. However, for substantial progress in women’s health we need to acknowledge that female physiology is different from males and uniquely female experiences such as pregnancy and motherhood can affect the physiology of females. Pregnancy is associated with dramatic changes in physiology (cardiac, pulmonary, immune, and metabolic) and endocrinology (steroids and peptide hormones, many of which are unique to pregnancy). Thus, it is not surprising that there can be repercussions both in the short and in the long-term for the health of the female. Here, we discuss research demonstrating that pregnancy and the postpartum period are associated with changes in neuroplasticity and cognition, and a greater risk of developing certain mental health disorders with some of these effects having lifelong consequences. As a potential implication, we also discuss how drug treatments may work differently in parous women. Finally, we argue that, in addition to sex differences, the physiological challenges unique to women need to be taken into consideration for a better understanding of women’s physiology and disease.Arts, Faculty ofMedicine, Faculty ofOther UBCPsychology, Department ofReviewedFacultyPostdoctoralGraduat

Hippocampal learning, memory, and neurogenesis : effects of sex and estrogens across the lifespan in adults

There are sex differences in hippocampus-dependent cognition and neurogenesis suggesting that sex hormones are involved. Estrogens modulate certain forms of spatial and contextual memory and neurogenesis in the adult female rodent, and to a lesser extent male, hippocampus. This review focuses on the effects of sex and estrogens on hippocampal learning, memory, and neurogenesis in the young and aged adult rodent. We discuss how factors such as the type of estrogen, duration and dose of treatment, timing of treatment and type of memory influence the effects of estrogens on cognition and neurogenesis. We also address how reproductive experience (pregnancy and mothering) and aging interact with estrogens to modulate hippocampal cognition and neurogenesis in females. Given the evidence that adult hippocampal neurogenesis plays a role in long-term spatial memory and pattern separation, we also discuss the functional implications of regulating neurogenesis in the hippocampus.Arts, Faculty ofMedicine, Faculty ofPsychology, Department ofReviewedFacultyPostdoctoralGraduat

Estradiol and GPER Activation Differentially Affect Cell Proliferation but Not GPER Expression in the Hippocampus of Adult Female Rats.

Estradiol increases cell proliferation in the dentate gyrus of the female rodent but it is not known whether the G protein-coupled estrogen receptor (GPER), a membrane receptor, is involved in this process, nor whether there are regional differences in estradiol's effects on cell proliferation. Thus, we investigated whether estradiol exerts its effects on cell proliferation in the dorsal and ventral dentate gyrus through GPER, using the GPER agonist, G1, and antagonist, G15. Ovariectomized adult female rats received a single injection of either: 17β-estradiol (10 μg), G1 (0.1, 5, 10 μg), G15 (40 μg), G15 and estradiol, or vehicle (oil, DMSO, or oil+DMSO). After 30 min, animals received an injection of bromodeoxyuridine (BrdU) and were perfused 24 h later. Acute treatment with estradiol increased, while the GPER agonist G1 (5 μg) decreased, the number of BrdU+ cells in the dentate gyrus relative to controls. The GPER antagonist, G15 increased the number of BrdU+ cells relative to control in the dorsal region and decreased the number of BrdU+ cells in the ventral region. However, G15 treatment in conjunction with estradiol partially eliminated the estradiol-induced increase in cell proliferation in the dorsal dentate gyrus. Furthermore, G1 decreased the expression of GPER in the dentate gyrus but not the CA1 and CA3 regions of the hippocampus. In summary, we found that activation of GPER decreased cell proliferation and GPER expression in the dentate gyrus of young female rats, presenting a potential and novel estrogen-independent role for this receptor in the adult hippocampus

G1 and G15 regulate expression of GPER in the granule cell layer (GCL) but not the CA1 and CA3 regions of the hippocampus.

<p>Optical density (OD) was measured in the entire GCL, and in the CA1 and CA3 regions (using circles as shown in B and D). Photomicrograph of a representative section showing GPER expression in the GCL, CA1, and hilus (A) and the CA1 and CA3 regions (C). Thesholded images showing regions expressing GPER above the threshold (B and D). Mean (+SEM) optical density after 24 h of estradiol, G1 or G15 treatments in the total GCL including the subgranular zone (E-F), in the total CA1 (G-H) and total CA3 (I-J) regions. Rats were given either estradiol (E2, 10 μg), one of the doses of G1 (L, low, 0.1 μg; M, medium, 5 μg; H, high, 10 μg) or G15 (40 μg) alone or in combination with E2. Vehicles were either oil, DMSO, or a combination of both (oil+DMSO). Asterisks denote significant differences between treatment groups (*<i>p</i><0.05; **<i>p</i><0.01).</p

Mean ± SEM body mass of ovariectomized female rats the day of perfusion for Experiment 1 and 2.

<p>No significant effects of treatment on body mass were observed.</p><p>Mean ± SEM body mass of ovariectomized female rats the day of perfusion for Experiment 1 and 2.</p

Mean ± SEM volume of the granule cell layer (GCL) and the hilus (mm³) in female ovariectomized rats from Experiment 1 and 2 exposed to estradiol (E2), the GPER agonist G1, and the GPER antagonist G15.

<p>There were no significant differences between treatments observed in the volume of the GCL or hilus.</p><p>Mean ± SEM volume of the granule cell layer (GCL) and the hilus (mm³) in female ovariectomized rats from Experiment 1 and 2 exposed to estradiol (E2), the GPER agonist G1, and the GPER antagonist G15.</p

Estradiol, GPER agonist G1, and GPER antagonist G15 affect cell proliferation in the hippocampus.

<p>A photomicrograph of a representative section of (A) the dorsal dentate gyrus with the supra- and infra-pyramidal blades labelled and (B) cluster of BrdU+ cells (black arrows) in the subgranular zone of the dentate gyrus 24 h after BrdU injection. Mean (+SEM) total number of BrdU+ cells in the granule cell layer (GCL) and hilus of the dorsal (C and E) and ventral (D and F) dentate gyrus. For Experiment 1 (C-D), rats were given either estradiol (E2, 10 μg), one of the doses of G1 (M, medium, 5 μg; H, high, 10 μg) or one of the vehicles (oil or DMSO). Estradiol significantly increased cell proliferation in both dorsal and ventral regions, while G1-M decreased cell proliferation in the dorsal region only. DMSO alone significantly increased the number of BrdU+ cells in the ventral, but not dorsal GCL, compared to the oil group (P = 0.003, P = 0.021 respectively; dorsal not significant due to Bonferroni correction). For Experiment 2 (E-F), rats were given either estradiol (E2, 10 μg) or G15 (40 μg) alone or in combination with E2. Vehicle was a combination of oil and DMSO. E2+DMSO increased cell proliferation compared to control (oil+DMSO) in the dorsal GCL. G15 increased the number of BrdU+ cells relative to control in the dorsal region and decreased the number of BrdU+ cells in the ventral region compared to oil+DMSO. Asterisks denote significant differences between control and treatment groups (*<i>p</i><0.05; **<i>p</i><0.01; ***<i>p</i><0.001).</p

Sex, hormones, and neurogenesis in the hippocampus : Hormonal modulation of neurogenesis and potential functional implications

The hippocampus is an area of the brain that undergoes dramatic plasticity in response to experience and hormone exposure. The hippocampus retains the ability to produce new neurons in most mammalian species and is a structure that is targeted in a number of neurodegenerative and neuropsychiatric diseases, many of which are influenced by both sex and sex hormone exposure. Intriguingly, gonadal and adrenal hormones affect the structure and function of the hippocampus differently in males and females. Sex differences in the effects of steroid hormones to modulate hippocampal plasticity should not be completely surprising as the physiology of males and females is different, with the most notable difference that the females gestate and nurse the offspring. Furthermore, reproductive experience (pregnancy and mothering) results in permanent changes to the maternal brain, including the hippocampus in females. Adult neurogenesis in the hippocampus is regulated by both gonadal and adrenal hormones in a sex and experience-dependent way. This review outlines the ability of gonadal and stress hormones to modulate multiple aspects of neurogenesis (cell proliferation and cell survival) in both male and female rodents. The function of adult neurogenesis in the hippocampus is linked to spatial memory and depression and this review provides early evidence of the functional links between hormonal modulation of neurogenesis to regulate cognition and stress.Arts, Faculty ofOther UBCPsychology, Department ofReviewedFacultyPostdoctora

Premarin has opposing effects on spatial learning, neural activation, and serum cytokine levels in middle-aged female rats depending on reproductive history

Menopause is associated with cognitive decline, and hormone therapies (HT) may improve cognition depending on type, and timing of HT. Previous parity may influence cognition in later life. We investigated how primiparity and long-term ovariectomy influence cognition, neurogenesis, hormones, cytokines, and neuronal activation in middle-aged rats in response to Premarin, an HT. Nulliparous and primiparous rats were sham-ovariectomized or ovariectomized, administered vehicle or Premarin six months later, and all rats were trained in the Morris water maze. Premarin improved spatial learning and memory in nulliparous rats, but impaired early learning in primiparous rats. With training, primiparity increased hippocampal neurogenesis, and Premarin decreased immature neurons, regardless of parity. Moreover, Premarin increased serum tumor necrosis factor (TNF) α and the CXC chemokine ligand 1 (CXCL1) in nulliparous, but not primiparous, trained rats. However, Premarin decreased the expression of the immediate early gene zif268 in the dorsal CA3 region in primiparous rats after training. Thus, primiparity alters how Premarin affects spatial learning, neuronal activation, and serum cytokines. These findings have implications for the treatment of age-associated cognitive decline in women.Arts, Faculty ofMedicine, Faculty ofPsychology, Department ofReviewedFacultyResearcherPostdoctoralGraduat