Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Chronic high corticosterone reduces neurogenesis in the dentate gyrus of adult male and female rats

Adult neurogenesis in the dentate gyrus of the hippocampus is altered with stress exposure and has been implicated in depression. High levels of corticosterone (CORT) suppress neurogenesis in the dentate gyrus of male rats. However both acute and chronic stress do not consistently reduce adult hippocampal neurogenesis in female rats. Therefore, this study was conducted to investigate the effect of different doses of corticosterone on hippocampal neurogenesis in male and female rats. Rats received 21 days of s.c. injections of either oil, 10mg/kg or 40mg/kg CORT. Subjects were perfused 24h after the last CORT injection and brains were analyzed for cell proliferation (Ki67-labeling) or immature neurons (doublecortin-labeling). Results show that in both males and females high CORT, but not low CORT, reduced both cell proliferation and the density of immature neurons in the dentate gyrus. Furthermore, high CORT males had reduced density in immature neurons in both the ventral and dorsal regions while high CORT females only showed the reduced density of immature neurons in the ventral hippocampus. The high dose of CORT disrupted the estrous cycle of females. Further, the low dose of CORT significantly reduced weight gain and increased basal CORT levels in males but not females, suggesting a greater vulnerability in males with the lower dose of CORT. Thus we find subtle sex differences in the response to chronic CORT on both body weight and in the dorsal dentate gyrus that may play a role in understanding different vulnerabilities to stress-related neuropsychiatric disorders between the sexes.Arts, Faculty ofPsychology, Department ofReviewedFacultyPostdoctora

Chronic corticosterone during pregnancy and postpartum affects maternal care, cell proliferation and depressive-like behavior in the dam

Stress during pregnancy and the postpartum can influence the well-being of both the mother and her offspring. Prolonged elevated levels of glucocorticoids are associated with depression and we developed an animal model of postpartum depression/stress based on high levels of corticosterone (CORT) during the postpartum. Gestational stress is a risk factor for postpartum depression and prenatal and/or postnatal high levels of CORT may have differential effects on the mother. Thus the present study was conducted to investigate the effects of low (10mg/kg) or high levels of CORT (40mg/kg) given to dams either during gestation, postpartum or across both gestation and postpartum on maternal care, depressive-like behavior and hippocampal cell proliferation in the dam. Only the high dose of CORT administered during the postpartum increased depressive-like behavior in the dam. Furthermore the high dose of CORT altered maternal care (reduced time spent on the nest and nursing) regardless of whether administration of CORT was during gestation or postpartum. Gestational and/or postpartum treatment with high CORT and postpartum low CORT reduced cell proliferation in the dentate gyrus of postpartum dams compared to oil-treated controls. Thus prolonged treatment with high levels of CORT postpartum reduced maternal care, hippocampal cell proliferation and induced depressive-like behavior in the dam and therefore might be considered an animal model of postpartum depression. More research is needed to understand the effects of stress hormones during different phases of reproduction and how they affect the brain and behavior of the mother and her offspring.Arts, Faculty ofPsychology, Department ofReviewedFacultyPostdoctora

Estradiol content in adult brain tissue

In general, the behavioural and neural effects of estradiol administration to males and females differ. While much attention has been paid to the potential structural, cellular and sub-cellular mechanisms that may underlie such differences, as of yet there has been no examination of whether the differences observed may be related to differential uptake or storage of estradiol within the brain itself. We administered estradiol benzoate to gonadectomized male and female rats, and compared the concentration of estradiol in serum and brain tissue found in these rats to those of gonadectomized, oil-treated rats and intact rats of both sexes. Long-term gonadectomy (3 weeks) reduced estradiol concentration in the male and female hippocampus, but not in the male or female amygdala or in the female prefrontal cortex. Furthermore, exogenous treatment with estradiol increased estradiol content to levels above intact animals in the amygdala, prefrontal cortex and the male hippocampus. Levels of estradiol were undetectable in the prefrontal cortex of intact males, but were detectable in all other brain regions of intact rats. Here we demonstrate (1) that serum concentrations of estradiol are not necessarily reflective of brain tissue concentrations, (2) that within the brain, there are regional differences in the effects of gonadectomy and estradiol administration, and (3) that there is less evidence for local production of estradiol in males than females, particularly in the prefrontal cortex and perhaps the hippocampus. Thus there are regional differences in estradiol concentration in the prefrontal cortex, amygdala and hippocampus that are influenced by sex and hormone status.Arts, Faculty ofPsychology, Department ofReviewedFacultyGraduat

Repeated estradiol administration alters different aspects of neurogenesis and cell death in the hippocampus of female, but not male, rats

Estradiol has been shown to have neuroprotective effects, and acute estradiol treatment enhances hippocampal neurogenesis in the female brain. However, little is known about the effects of repeated administration of estradiol on the female brain, or about the effects of estradiol on the male brain. Gonadectomized male and female adult rats were injected with BrdU (200 mg/kg), and then 24 h later were given a s.c. injection of either estradiol benzoate (33 g/kg) or vehicle daily for 15 days. On day 16, animals were perfused and the brains processed to examine cells expressing Ki-67 (cell proliferation), BrdU (cell survival), doublecortin (young neuron production), pyknotic morphology (cell death), activated caspase-3 (apoptosis), and Fluoro-Jade B (degenerating neurons) in the dentate gyrus. In female rats, repeated administration of estradiol decreased the survival of new neurons (independent of any effects on initial cell proliferation), slightly increased cell proliferation, and decreased overall cell death in the dentate gyrus. In male rats, repeated administration of estradiol had no significant effect on neurogenesis or cell death. We therefore demonstrate a clear sex difference in the response to estradiol of hippocampal neurogenesis and apoptosis in adult rats, with adult females being more responsive to the effects of estradiol than males.Arts, Faculty ofMedicine, Faculty ofPsychology, Department ofReviewedFacultyGraduat

Sex differences in contextual fear

Estradiol affects the structure and function of the hippocampus. We have found that repeated estradiol affects neurogenesis and cell death in the hippocampus of adult female, but not male rats. In the present study we sought to determine whether using the same regimen of estradiol would influence hippocampus-dependent behaviour. Adult male and female rats were given estradiol or sesame oil for 15 days, and then tested using a contextual pre-exposure paradigm in which performance depends on the hippocampus. The time spent freezing displayed by rats was scored on subsequent days in (1) the training context, (2) a novel context in which rats had never been shocked, and (3) the training context a second time. Irrespective of treatment, males showed stronger memory for the context by exhibiting greater freezing in both the training context exposures and the novel context. Previous estradiol treatment, in either sex, did not affect the ability to learn and retain information about the training context. However, female rats treated with estradiol and exposed to a novel context after fear conditioning exhibited less freezing behaviour than controls. Taken together, our results demonstrate that gonadectomized male rats outperform females, regardless of previous treatment with estradiol, on a hippocampus-contextual fear conditioning test, and that previous estradiol treatment has a subtle effect on performance in female but not male rats.Arts, Faculty ofMedicine, Faculty ofPsychology, Department ofReviewedFacultyGraduat

Sex Hormones and Adult Hippocampal Neurogenesis : Regulation, Implications, and Potential Mechanisms

Neurogenesis within the adult hippocampus is modulated by endogenous and exogenous factors. Here, we review the role of sex hormones in the regulation of adult hippocampal neurogenesis in males and females. The review is framed around the potential functional implications of sex hormone regulation of adult hippocampal neurogenesis, with a focus on cognitive function and mood regulation, which may be related to sex differences in incidence and severity of dementia and depression. We present findings from preclinical studies of endogenous fluctuations in sex hormones relating to reproductive function and ageing, and from studies of exogenous hormone manipulations. In addition, we discuss the modulating roles of sex, age, and reproductive history on the relationship between sex hormones and neurogenesis. Because sex hormones have diverse targets in the central nervous system, we overview potential mechanisms through which sex hormones may influence hippocampal neurogenesis. Lastly, we advocate for a more systematic consideration of sex and sex hormones in studying the functional implications of adult hippocampal neurogenesis.Arts, Faculty ofPsychology, Department ofMedicine, Faculty ofReviewedFacultyPostdoctoralGraduat

Chronic aromatase inhibition increases ventral hippocampal neurogenesis in middle-aged female mice

Letrozole, a third-generation aromatase inhibitor, prevents the production of estrogens in the final step in conversion from androgens. Due to its efficacy at suppressing estrogens, letrozole has recently taken favor as a first-line adjuvant treatment for hormone-responsive breast cancer in middle-aged women. Though patient response to letrozole has generally been positive, there is conflicting evidence surrounding its effects on the development of depression. It is possible that the potential adverse effects of letrozole on mood are a result of the impact of hormonal fluctuations on neurogenesis in the hippocampus. Thus, to clarify the effects of letrozole on the hippocampus and behavior, we examined how chronic administration affects hippocampal neurogenesis and depressive-like behavior in middle-aged, intact female mice. Mice were given either letrozole (1mg/kg) or vehicle by injection (i.p.) daily for 3 weeks. Depressive-like behavior was assessed during the last 3 days of treatment using the forced swim test, tail suspension test, and sucrose preference test. The production of new neurons was quantified using the immature neuronal marker doublecortin (DCX), and cell proliferation was quantified using the endogenous marker Ki67. We found that letrozole increased DCX and Ki67 expression and maturation in the dentate gyrus, but had no significant effect on depressive-like behavior. Our findings suggest that a reduction in estrogens in middle-aged females increases hippocampal neurogenesis without any adverse impact on depressive-like behavior; as such, this furthers our understanding of how estrogens modulate neurogenesis, and to the rationale for the utilization of letrozole in the clinical management of breast cancer.Arts, Faculty ofMedicine, Faculty ofOther UBCPsychology, Department ofReviewedFacultyGraduat

Gestational and postpartum corticosterone exposure to the dam affects behavioral and endocrine outcome of the offspring in a sexually-dimorphic manner

Exposure to high levels of glucocorticoids in utero and during the postpartum period has a detrimental effect on brain development. We created an animal model of postpartum stress/depression based on administering high levels of corticosterone (CORT) to the dams during the postpartum period which caused behavioral changes and reduced hippocampal cell proliferation in the offspring. As the consequences of early exposure to glucocorticoids may depend on the dose and the developmental stage of the offspring, the present study was conducted to investigate the effects of low (10mg/kg) or high levels of CORT (40mg/kg) given to dams either during gestation, postpartum or across both gestation and postpartum on the outcome of the offspring. Male and female offspring were weighed throughout the experiment, tested in a series of behavioral tests (forced swim test, open field, elevated plus maze) and basal and restraint stress CORT levels were examined in adolescence or young adulthood. Results show that maternal CORT exposure, regardless of when administered, significantly attenuated body weight gain until adulthood in the offspring. Offspring exposed to low maternal CORT, but not high maternal CORT, during the postpartum had higher basal levels of CORT as young adults. Further, male and female offspring of dams exposed to high maternal CORT in utero showed more depressive-like behavior in the forced swim test, while males of dams exposed to high maternal CORT postpartum exhibited more anxiety-like behavior in the elevated plus maze. Taken together, maternal glucocorticoid exposure have long lasting effects on male and female offspring‟s behavioral and neuroendocrine measures in adolescence and adulthood depending on the time of exposure to glucocorticoids.Arts, Faculty ofOther UBCPsychology, Department ofReviewedFacultyPostdoctora

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