Florey Department of Neuroscience and Mental Health - Research Publications

Permanent URI for this collection

http://hdl.handle.net/11343/269

Search Results

Now showing 1 - 4 of 4

The Effects of Ethinylestradiol and Progestins ("the pill") on Cognitive Function in Pre-menopausal Women

Gogos, A ; Wu, YC ; Williams, AS ; Byrne, LK (SPRINGER/PLENUM PUBLISHERS, 2014-12)

Oral contraceptives (OCs), often referred to as "the pill", are the most commonly employed form of reversible contraception. OCs are comprised of combined synthetic estrogen and progestin, which work to suppress ovulation and subsequently protect against pregnancy. To date, almost 200 million women have taken various formulations of OC, making it one of the most widely consumed classes of medication in the world. While a substantial body of literature has been dedicated to understanding the physical effects of OCs, much less is known about the long term consequences of OC use on brain anatomy and the associated cognitive effects. Accumulating evidence suggests that sex hormones may significantly affect human cognition. This phenomenon has been commonly studied in older populations, such as in post-menopausal women, while research in healthy, pre-menopausal women remains limited. The current review focused on the effects of OCs on human cognition, with the majority of studies comparing pre-menopausal OC users to naturally cycling women. Human neuroimaging data and animal studies are also described herein. Taken together, the published findings on OC use and human cognition are varied. Of those that do report positive results, OC users appear to have improved verbal memory, associative learning and spatial attention. We recommend future research to employ blinding procedures and randomised designs. Further, more detailed information pertaining to the specific generation and phasic type of OCs, as well as menstrual cycle phase of the OC non-users should be considered to help unmask the potential impact of OC use on human cognition.
Analyzing the influence of BDNF heterozygosity on spatial memory response to 17β-estradiol

Wu, YWC ; Du, X ; van den Buuse, M ; Hill, RA (NATURE PUBLISHING GROUP, 2015-01-20)

The recent use of estrogen-based therapies as adjunctive treatments for the cognitive impairments of schizophrenia has produced promising results; however the mechanism behind estrogen-based cognitive enhancement is relatively unknown. Brain-derived neurotrophic factor (BDNF) regulates learning and memory and its expression is highly responsive to estradiol. We recently found that estradiol modulates the expression of hippocampal parvalbumin-positive GABAergic interneurons, known to regulate neuronal synchrony and cognitive function. What is unknown is whether disruptions to the aforementioned estradiol-parvalbumin pathway alter learning and memory, and whether BDNF may mediate these events. Wild-type (WT) and BDNF heterozygous (+/-) mice were ovariectomized (OVX) at 5 weeks of age and simultaneously received empty, estradiol- or progesterone-filled implants for 7 weeks. At young adulthood, mice were tested for spatial and recognition memory in the Y-maze and novel-object recognition test, respectively. Hippocampal protein expression of BDNF and GABAergic interneuron markers, including parvalbumin, were assessed. WT OVX mice show impaired performance on Y-maze and novel-object recognition test. Estradiol replacement in OVX mice prevented the Y-maze impairment, a Behavioral abnormality of dorsal hippocampal origin. BDNF and parvalbumin protein expression in the dorsal hippocampus and parvalbumin-positive cell number in the dorsal CA1 were significantly reduced by OVX in WT mice, while E2 replacement prevented these deficits. In contrast, BDNF(+/-) mice showed either no response or an opposite response to hormone manipulation in both behavioral and molecular indices. Our data suggest that BDNF status is an important biomarker for predicting responsiveness to estrogenic compounds which have emerged as promising adjunctive therapeutics for schizophrenia patients.
Sex differences in the adolescent developmental trajectory of parvalbumin interneurons in the hippocampus: A role for estradiol

Wu, YC ; Du, X ; van den Buuse, M ; Hill, RA (PERGAMON-ELSEVIER SCIENCE LTD, 2014-07)

OBJECTIVE: Gender differences in the neurodevelopmental disorder, schizophrenia, have been described for nearly all features of the illness. Reduced hippocampal expression of the GABAergic interneuron marker, parvalbumin (PV), and GABA synthesizing enzyme, GAD67, are consistently reported in schizophrenia. However, little is known of the expression patterns of hippocampal PV and GAD67 during adolescence and their interaction with sex steroid hormones during adolescent development. This study examined the effects of altered sex steroid hormone levels during adolescence on protein levels of PV, GAD67 and estrogen receptors (ERα/β) in the hippocampus of mice. METHODS: Protein expression of PV and GAD67 was measured in the dorsal (DHP) and ventral (VHP) hippocampus of female and male C57Bl/6 mice by Western blot in a week by week analysis from pre-pubescence to adulthood (week 3-12). Fluorescent immunohistochemistry (IHC) was used to investigate the relationship between ERs and PV(+) cells in the hippocampus of female mice at young adulthood (week 10-11). To further examine the role of sex steroid hormones on PV and GAD67 expression, gonadectomy and hormone replacement was done at 5 weeks of age. RESULTS: Female mice showed a significant gradual increase in PV expression from 3 to 12 weeks of age in the DHP and VHP which correlated with serum 17β-estradiol levels. Fluorescent IHC showed approximately 30-50% co-localization of ER-α in PV(+) cells in the female DHP and VHP (dentate gryus/hilus and CA1-CA3). Adolescent ovariectomy significantly reduced PV expression in the DHP but not VHP of female mice, while 17β-estradiol replacement prevented this deficit in DHP PV levels. ER-α expression, but not ER-β, was also reduced in the DHP following ovariectomy with no significant effect of 17β-estradiol replacement. In contrast to female mice, male mice did not show any significant changes in hippocampal PV/GAD67 expression throughout adolescent development. Furthermore, adolescent castration and treatment with testosterone or dihydrotestosterone produced no changes in PV/GAD67 expression. CONCLUSIONS: Our data suggest a differential developmental trajectory of PV expression between the sexes and manipulating circulating levels of sex steroid hormones by ovariectomy alters this trajectory in a region-dependent manner. This may be mediated via ER-α signaling as this receptor was found to be co-localized with PV(+) cells in the female mouse hippocampus. Alternative mechanisms of 17β-estradiol-induced regulation of PV expression are also discussed herein. Together, results from the present study may offer more insight into neurodevelopmental disorders, including schizophrenia, where sex steroid hormones and GABAergic markers are implicated in the pathophysiology of the illness.
Sex-dependent alterations in BDNF-TrkB signaling in the hippocampus of reelin heterozygous mice: a role for sex steroid hormones

Hill, RA ; Wu, Y-WC ; Gogos, A ; van den Buuse, M (WILEY, 2013-08)

Neurodevelopmental psychiatric disorders such as schizophrenia may be caused by a combination of gene × environment, gene × gene, and/or gene × sex interactions. Reduced expression of both Reelin and Brain-Derived Neurotrophic factor (BDNF) has been associated with schizophrenia in human post-mortem studies. However, it remains unclear how Reelin and BDNF interact (gene × gene) and whether this is sex-specific (gene × sex). This study investigated BDNF-TrkB signaling in the hippocampus of male and female Reelin heterozygous (Rln(+/-) ) mice. We found significantly increased levels of BDNF in the ventral hippocampus (VHP) of female, but not male Rln(+/-) compared to wild-type (WT) controls. While levels of TrkB were not significantly altered, phosphorylated TrkB (pTrkB) levels were significantly lower, again only in female Rln(+/-) compared to WT. This translated to downstream effects with a significant decrease in phosphorylated ERK1 (pERK1). No changes in BDNF, TrkB, pTrkB or pERK1/2 were observed in the dorsal hippocampus of Rln(+/-) mice. Ovariectomy (OVX) had no effect in WT controls, but caused a significant decrease in BDNF expression in the VHP of Rln(+/-) mice to the levels of intact WT controls. The high expression of BDNF was restored in OVX Rln(+/-) mice by 17β-estradiol treatment, suggesting that Rln(+/-) mice respond differently to an altered estradiol state than WT controls. In addition, while OVX had no significant effect on TrkB or ERK expression/phosphorylation, OVX + estradiol treatment markedly increased TrkB and ERK1 phosphorylation in Rln(+/-) and, to a lesser extent in WT controls, compared to intact genotype-matched controls. These data may provide a better understanding of the interaction of Reelin and BDNF in the hippocampus, which may be involved in schizophrenia.