Risk-based decision making in rats: Modulation by sex and amphetamine.

Decision-making is a complex process essential to daily adaptation in many species. Risk is an inherent aspect of decision-making and it is influenced by gonadal hormones. Testosterone and 17ß-estradiol may modulate decision making and impact the mesocorticolimbic dopamine pathway. Here, we explored sex differences, the effect of gonadal hormones and the dopamine agonist amphetamine on risk-based decision making. Intact or gonadectomised (GDX) male and female rats underwent to a probabilistic discounting task. High and low doses of testosterone propionate (1.0 or 0.2 mg) and 17ß-estradiol benzoate (0.3 µg) were administered to assess acute effects on risk-based decision making. After 3-days of washout period, intact and GDX rats received high or low (0.5 or 0.125 mg/kg) doses of amphetamine and re-tested in the probabilistic discounting task. Under baseline conditions, males made more risky choices during probability discounting compared to female rats, particularly in the lower probability blocks, but GDX did not influence risky choice. The high, but not the low dose, of testosterone modestly reduced risky decision making in GDX male rats. Conversely, 17ß-estradiol had no significant effect on risky choice regardless of GDX status in either sex. Lastly, a higher dose of amphetamine increased risky decision making in both intact males and females, but had no effect in GDX rats. These findings demonstrated sex differences in risk-based decision making, with males showing a stronger bias toward larger, uncertain rewards. GDX status influenced the effects of amphetamine, suggesting different dopaminergic regulation in risk-based choices among males and females.

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.

Sex and estrous cycle differences in immediate early gene activation in the hippocampus and the dorsal striatum after the cue competition task.

The hippocampus and dorsal striatum are important structures involved in place and response learning strategies respectively. Both sex and estrous cycle phase differences in learning strategy preference exist following cue competition paradigms. Furthermore, significant effects of sex and learning strategy on hippocampal neural plasticity have been reported. However, associations between learning strategy and immediate early gene (IEG) expression in the hippocampus and dorsal striatum are not completely understood. In the current study we investigated the effects of sex and estrous cycle phase on strategy choice and IEG expression in the hippocampus and dorsal striatum of rats following cue competition training in the Morris water maze. We found that proestrous rats were more likely to choose a place strategy than non-proestrous or male rats. Although male cue strategy users travelled greater distances than the other groups on the first day of training, there were no other sex or strategy differences in the ability to reach a hidden or a visible platform. Female place strategy users exhibited greater zif268 expression and male place strategy users exhibited greater cFos expression compared to all other groups in CA3. Furthermore, cue strategy users had greater expression of cFos in the dorsal striatum than place strategy users. Shorter distances to reach a visible platform were associated with less activation of cFos in CA3 and CA1 of male place strategy users. Our findings indicate multiple differences in brain activation with sex and strategy use, despite limited behavioral differences between the sexes on this cue competition paradigm.

Testosterone has antidepressant-like efficacy and facilitates imipramine-induced neuroplasticity in male rats exposed to chronic unpredictable stress.

Hypogonadal men are more likely to develop depression, while testosterone supplementation shows antidepressant-like effects in hypogonadal men and facilitates antidepressant efficacy. Depression is associated with hypothalamic-pituitary-adrenal (HPA) axis hyperactivity and testosterone exerts suppressive effects on the HPA axis. The hippocampus also plays a role in the feedback regulation of the HPA axis, and depressed patients show reduced hippocampal neuroplasticity. We assessed the antidepressant-like effects of testosterone with, or without, imipramine on behavioral and neural endophenotypes of depression in a chronic unpredictable stress (CUS) model of depression. A 21-day CUS protocol was used on gonadectomized male Sprague-Dawley rats treated with vehicle, 1mg of testosterone propionate, 10mg/kg of imipramine, or testosterone and imipramine in tandem. Testosterone treatment reduced novelty-induced hypophagia following CUS exposure, but not under non-stress conditions, representing state-dependent effects. Further, testosterone increased the latency to immobility in the forced swim test (FST), reduced basal corticosterone, and reduced adrenal mass in CUS-exposed rats. Testosterone also facilitated the effects of imipramine by reducing the latency to immobility in the FST and increasing sucrose preference. Testosterone treatment had no significant effect on neurogenesis, though the combination of testosterone and imipramine increased PSA-NCAM expression in the ventral dentate gyrus. These findings demonstrate the antidepressant- and anxiolytic-like effects of testosterone within a CUS model of depression, and provide insight into the mechanism of action, which appears to be independent of enhanced hippocampal neurogenesis.

Sex, drugs, and adult neurogenesis: sex-dependent effects of escalating adolescent cannabinoid exposure on adult hippocampal neurogenesis, stress reactivity, and amphetamine sensitization.

Cannabinoid exposure during adolescence has adverse effects on neuroplasticity, emotional behavior, cognition, and reward sensitivity in adult rats. We investigated whether escalating doses of the cannabinoid receptor 1 (CB1 R) agonist, HU-210, in adolescence would affect adult hippocampal neurogenesis and behavioral processes putatively modulated by hippocampal neurogenesis, in adult male and female Sprague-Dawley rats. Escalating doses of HU-210 (25, 50, and 100 µg/kg), or vehicle were administered from postnatal day (PND) 35 to 46. Animals were left undisturbed until PND 70, when they were treated with 5-bromo-2-deoxyuridine (BrdU; 200 mg/kg) and perfused 21 days later to examine density of BrdU-ir and BrdU/NeuN cells in the dentate gyrus. In another cohort, hypothalamic-pituitary-adrenal (HPA) axis reactivity to an acute restraint stress (30 min; PND 75) and behavioral sensitization to d-amphetamine sulfate (1-2 mg/kg; PND 105-134) were assessed in adulthood. Adolescent HU-210 administration suppressed the density of BrdU-ir cells in the dentate gyrus in adult male, but not adult female rats. Adolescent HU-210 administration also induced significantly higher peak corticosterone levels and reminiscent of the changes in neurogenesis, this effect was more pronounced in adult males than females. However, adolescent cannabinoid treatment resulted in significantly higher stereotypy scores in adult female, but not male, rats. Thus, adolescent CB1 R activation suppressed hippocampal neurogenesis and increased stress responsivity in adult males, but not females, and enhanced amphetamine sensitization in adult female, but not male, rats. Taken together, increased CB1 R activation during adolescence results in sex-dependent, long-term, changes to hippocampal structure and function, an effect that may shed light on differing vulnerabilities to developing disorders following adolescent cannabinoid exposure, based on sex.

Amyotrophic lateral sclerosis: exploring pathophysiology in the context of treatment.

Amyotrophic lateral sclerosis (ALS) is a complex, neurodegenerative disorder in which alterations in structural, physiological, and metabolic parameters act synergistically. Over the last decade there has been a considerable focus on developing drugs to slow the progression of the disease. Despite this, only four disease-modifying therapies are approved in North America. Although additional research is required for a thorough understanding of ALS, we have accumulated a large amount of knowledge that could be better integrated into future clinical trials to accelerate drug development and provide patients with improved treatment options. It is likely that future, successful ALS treatments will take a multi-pronged therapeutic approach, targeting different pathways, akin to personalized medicine in oncology. In this review, we discuss the link between ALS pathophysiology and treatments, looking at the therapeutic failures as learning opportunities that can help us refine and optimize drug development.

Neuroscientists' everyday experiences of ethics: the interplay of regulatory, professional, personal and tangible ethical spheres.

The ethical issues neuroscience raises are subject to increasing attention, exemplified in the emergence of the discipline neuroethics. While the moral implications of neurotechnological developments are often discussed, less is known about how ethics intersects with everyday work in neuroscience and how scientists themselves perceive the ethics of their research. Drawing on observation and interviews with members of one UK group conducting neuroscience research at both the laboratory bench and in the clinic, this article examines what ethics meant to these researchers and delineates four specific types of ethics that shaped their day-to-day work: regulatory, professional, personal and tangible. While the first three categories are similar to those identified elsewhere in sociological work on scientific and clinical ethics, the notion of 'tangible ethics' emerged by attending to everyday practice, in which these scientists' discursive distinctions between right and wrong were sometimes challenged. The findings shed light on how ethical positions produce and are, in turn, produced by scientific practice. Informing sociological understandings of neuroscience, they also throw the category of neuroscience and its ethical specificity into question, given that members of this group did not experience their work as raising issues that were distinctly neuro-ethical.

The neural plasticity theory of depression: assessing the roles of adult neurogenesis and PSA-NCAM within the hippocampus.

Depression is a devastating and prevalent disease, with profound effects on neural structure and function; however the etiology and neuropathology of depression remain poorly understood. Though antidepressant drugs exist, they are not ideal, as only a segment of patients are effectively treated, therapeutic onset is delayed, and the exact mechanism of these drugs remains to be elucidated. Several theories of depression do exist, including modulation of monoaminergic neurotransmission, alterations in neurotrophic factors, and the upregulation of adult hippocampal neurogenesis, and are briefly mentioned in the review. However none of these theories sufficiently explains the pathology and treatment of depression unto itself. Recently, neural plasticity theories of depression have postulated that multiple aspects of brain plasticity, beyond neurogenesis, may bridge the prevailing theories. The term "neural plasticity" encompasses an array of mechanisms, from the birth, survival, migration, and integration of new neurons to neurite outgrowth, synaptogenesis, and the modulation of mature synapses. This review critically assesses the role of adult hippocampal neurogenesis and the cell adhesion molecule, PSA-NCAM (which is known to be involved in many facets of neural plasticity), in depression and antidepressant treatment.

Androgens Enhance Adult Hippocampal Neurogenesis in Males but Not Females in an Age-Dependent Manner.

Androgens (testosterone and DHT) increase adult hippocampal neurogenesis by increasing survival of new neurons in male rats and mice via an androgen receptor pathway, but it is not known whether androgens regulate neurogenesis in female rats and whether the effect is age-dependent. We investigated the effects of DHT, a potent androgen, on neurogenesis in young adult and middle-aged male and female rats. Rats were gonadectomized and injected with the DNA synthesis marker bromodeoxyuridine (BrdU). The following day, rats began receiving daily injections of oil or DHT for 30 days. We evaluated cell proliferation (Ki67) and survival of new neurons (BrdU and BrdU/NeuN) in the hippocampus of male and female rats by using immunohistochemistry. As expected, DHT increased the number of BrdU+ cells in young males but surprisingly not in middle-aged males or in young and middle-aged females. In middle age, DHT increased the proportion of BrdU/NeuN cells, an effect driven by females. Androgen receptor expression also increased with aging in both female and male rats, which may contribute to a lack of DHT neurogenic effect in middle age. Our results indicate that DHT regulates adult hippocampal neurogenesis in a sex- and age-dependent manner.

Shifting paradigms? Reflections on regenerative medicine, embryonic stem cells and pharmaceuticals.

Will human embryonic stem (hES) cells lead to a revolutionary new regenerative medicine? We begin to answer this question by drawing on interviews with scientists and clinicians from leading labs and clinics in the UK and the USA, exploring their views on the bench-bedside interface in the fields of hES cells, neuroscience and diabetes. We employ Bourdieu's concepts of field, habitus and capital in order to understand stem cell science and cell transplantation. We also build on research on the sociology of expectations, and explore expectations of pharmaceutical approaches in hES research through our concept of 'expectational capital'. In the process we discuss emerging expectations within stem cell research, most especially the 'disease in a dish' approach, where hES cells will be used as tools for unravelling the mechanisms of disease to enable the development of new drugs. We argue that experts' persuasive promises advance their interests in the uncertain stem cell field, and explore how this performative strategy might stabilise the emerging 'disease in a dish' model of translational research.

A qualitative study exploring patients perceived quality of life following an emergency liver transplant for acute liver failure.

Liver transplantation is now an accepted and successful therapy for both acute and chronic liver diseases. Whilst the study of health related quality of life (HRQoL) post-transplantation for chronic liver disease (CLD) has been well documented, there is little data measuring HRQoL following liver transplantation for acute liver failure (ALF), despite super urgent transplantation constituting 16.6% of all United Kingdom liver transplantation. Therefore, the aim of the present study was to document the HRQoL in patients who have received an emergency liver transplant for ALF. Data collection employed between method triangulation, using the Short Form 36 quality of life health questionnaire for both ALF (n=47) and CLD (n=49), and six semi-structured interviews. Only the qualitative element of the study is reported here. Phenomenological analysis of the semi-structured interviews identified four themes relating to the physical changes encountered (inactivity), physical recovery (health transition); changes made to the transplant recipients life styles (modification); and outlook. The majority of transplanted ALF transplant recipients' stated that they have a good quality of life, which was often comparable to their pretransplantation lifestyle. However, the initial recovery process was often difficult and was related to the physical changes instigated from their multi-organ failure and intensive care stay, which can present numerous physical and emotional challenges.

From bench to bedside? Biomedical scientists' expectations of stem cell science as a future therapy for diabetes.

The movement of scientific research from the bench to the bedside is becoming an increasingly important aspect of modern 'biomedical societies'. There is, however, currently a dearth of social science research on the interaction between the laboratory and the clinic. The recent upsurge in global funding for stem cell research is largely premised on the promise of translating scientific understanding of stem cells into regenerative medicine. In this paper, we report on the views of biomedical scientists based in the United Kingdom who are involved in human embryonic stem cell research in the field of diabetes. We explore their views on the prospects and problems of translational research in the field of stem cell science. We discuss two main themes: institutional influences on interactions between scientists and clinicians, and stem cell science itself as the major barrier to therapies. We frame our discussion within the emerging literature of the sociology of expectations.

Ovarian hormones, but not fluoxetine, impart resilience within a chronic unpredictable stress model in middle-aged female rats.

Depression is more prevalent in women than in men, and women are at a heightened risk for depression during the postpartum and perimenopause. There is also evidence to suggest that the ovarian hormone milieu may dictate antidepressant efficacy. Thus, it is important to investigate the role of ovarian hormones in the pathogenesis of depression and in the mechanisms that may underlie antidepressant efficacy. In the present study, we used 10-month-old female Sprague-Dawley rats to examine the effects of long-term ovarian hormone deprivation on the development of depressive-like endophenotypes after chronic stress, and on antidepressant efficacy. Four months following ovariectomy (OVX) or sham surgery, all rats were subjected to 6 weeks of chronic unpredictable stress (CUS). During the last 3 weeks of CUS, rats received daily injections of fluoxetine (5 mg/kg) or vehicle. All rats were assessed on measures of anxiety- and depressive-like behavior, hypothalamic-pituitary-adrenal (HPA) negative feedback inhibition, and on markers of neurogenesis and microglia in the dentate gyrus. Our findings demonstrate that long-term ovarian hormone deprivation increased anxiety and depressive-like behavior, as seen by increased immobility in the forced swim test and latency to feed in the novelty suppressed feeding test, and decreased sucrose preference. Further, long-term OVX resulted in impaired HPA negative feedback inhibition, as seen in the dexamethasone suppression test. Fluoxetine treatment showed limited behavioral and neuroendocrine efficacy, however it reduced microglial (Iba-1) expression, and increased cell proliferation, neurogenesis (via cell survival), and the expression of the polysialylated neuronal cell adhesion molecule (PSA-NCAM) in the dentate gyrus, although these effects varied by region (dorsal, ventral) and ovarian status. Taken together, our findings demonstrate that ovarian hormones may impart resilience against the behavioral and neuroendocrine consequences of chronic unpredictable stress, and may modulate the effects of fluoxetine on cell proliferation, neurogenesis, and PSA-NCAM in the middle-aged female.

Enzymatic Depletion of the Polysialic Acid Moiety Associated with the Neural Cell Adhesion Molecule Inhibits Antidepressant Efficacy.

Antidepressant drugs are too often ineffective, the exact mechanism of efficacy is still ambiguous, and there has been a paucity of novel targets for pharmacotherapy. In an attempt to understand the pathogenesis of depression and subsequently develop more efficacious antidepressant drugs, multiple theories have been proposed, including the modulation of neurotransmission, the upregulation of neurogenesis and neurotrophic factors, normalizing hypothalamic-pituitary-adrenal reactivity, and the reduction of neuroinflammation; all of which have supporting lines of evidence. Therefore, an ideal molecular target for novel pharmaceutical intervention would function at the confluence of these theories. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) functions broadly, serving to mediate synaptic plasticity, neurogenesis, neurotrophic factor signaling, and inflammatory signaling throughout the brain; all of which are associated with the pathophysiology and treatment of depression. Moreover, the expression of PSA-NCAM is reduced by depression, and conversely enhanced by antidepressant treatment, particularly within the hippocampus. Here we demonstrate that selectively cleaving the polysialic acid moiety, using the bacteriophage-derived enzyme endoneuraminidase N, completely inhibits the antidepressant efficacy of the selective-serotonin reuptake inhibitor fluoxetine (FLX) in a chronic unpredictable stress model of depression. We also observe a corresponding attenuation of FLX-induced hippocampal neuroplasticity, including decreased hippocampal neurogenesis, synaptic density, and neural activation. These data indicate that PSA-NCAM-mediated neuroplasticity is necessary for antidepressant action; therefore PSA-NCAM represents an interesting, and novel, target for pharmacotherapy.

Fractured identities: injury and the balletic body.

Social worlds shape human bodies and so it is inevitable that there are strong relationships between the body, professional dance and identity. In this article we draw on Bourdieu's notions of habitus, and various forms of capital, as the main theoretical framework for our discussion. Our ethnography of the balletic body elicited dancers and ex-dancers' perceptions of their bodies and sought to reveal some of the facets of their embodied habitus. The sheer physicality of their working lives - of feeling exhausted, sweaty and out of breath - is something dancers (like all athletes) become 'addicted to'. Ageing and injury can reveal this compulsion to dance and so dancers invariably find it very difficult to, for example, give up class once they retire from the stage; or miss a performance if they have a 'slight injury'. In other words, the vocational calling to dance is so overwhelming that their balletic body is their identity. In addition, there is an unremitting loop between individual habitus and institutional habitus (the ballet company), which affects both the meaning and management of injury. All our informants at the Royal Ballet (London: n = 20) had suffered dance injuries. The injured, dancing body is perceived as an inevitable part of a career in ballet. Everyone spoke of the improved athleticism of dancers, and of the expansion in facilities to maintain healthy dancers. However, most dancers can expect several major injuries during their careers. Such epiphanies force dancers to confront their embodiment, and their thoughts invariably turn to their body, career and self. Critical injuries threaten to terminate a dancer's career and so endanger their embodied sense of self. On a more everyday level, dancing and performing with painful, niggling injuries is the norm.

Analysing data using grounded theory.

Grounded theory is a systematic research approach for the collection and analysis of qualitative data. The aim of the grounded theory approach is to generate an explanatory theory from the data being analysed, rather than trying to 'fit' the data into an existing theoretical framework ( 1 , 2 ).

On being a (modern) scientist: risks of public engagement in the UK interspecies embryo debate.

In 2006, a small group of UK academic scientists made headlines when they proposed the creation of interspecies embryos - mixing human and animal genetic material. A public campaign was fought to mobilize support for the research. Drawing on interviews with the key scientists involved, this paper argues that engaging the public through communicating their ideas via the media can result in tensions between the necessity of, and inherent dangers in, scientists campaigning on controversial issues. Some scientists believed that communicating science had damaged their professional standing in the eyes of their peers, who, in turn, policed the boundaries around what they believed constituted a "good" scientist. Tensions between promoting "science" versus promotion of the "scientist;" engaging the public versus publishing peer-reviewed articles and winning grants; and building expectations versus overhyping the science reveal the difficult choices scientists in the modern world have to make over the potential gains and risks of communicating science. We conclude that although scientists' participation in public debates is often encouraged, the rewards of such engagement remain. Moreover, this participation can detrimentally affect scientists' careers.

Hypogonadism predisposes males to the development of behavioural and neuroplastic depressive phenotypes.

The incidence of depression is 2-3× higher in women particularly during the reproductive years, an occurrence that has been associated with levels of sex hormones. The age-related decline of testosterone levels in men corresponds with the increased acquisition of depressive symptoms, and hormone replacement therapy can be efficacious in treating depression in hypogonadal men. Although it is not possible to model depression in rodents, it is possible to model some of the symptoms of depression including a dysregulated stress response and altered neuroplasticity. Among animal models of depression, chronic mild unpredictable stress (CMS) is a common paradigm used to induce depressive-like behaviours in rodents, disrupt the hypothalamic-pituitary adrenal axis and decrease hippocampal neuroplasticity. The purpose of this study was to assess the effect of hypogonadism, produced by gonadectomy, on the acquisition of depressive-like behaviours and changes in hippocampal neuroplasticity in adult male Sprague-Dawley rats. A 21-day unpredictable CMS protocol was used on gonadectomised (GDX) and sham-operated males which produced an attenuation of weight gain in the GDX males receiving CMS treatment (GDX-CMS). Behavioural analysis was carried out to assess anxiety- and depressive-like behaviours. The combination of GDX and CMS produced greater passive behaviours within the forced swim test than CMS exposure alone. Similarly, hippocampal cell proliferation, neurogenesis and the expression of the neuroplastic protein polysialated neural cell adhesion molecule (PSA-NCAM) were all significantly reduced in the GDX-CMS group compared to all other treatment groups. These findings indicate that testicular hormones confer resiliency to chronic stress in males therefore reducing the likelihood of developing putative physiological, behavioural or neurological depressive-like phenotypes.

Towards the applied: the construction of ethical positions in stem cell translational research.

This paper aims to make an empirically informed analytical contribution to the development of a more socially embedded bioethics. Drawing upon 10 interviews with cutting edge stem cell researchers (5 scientists and 5 clinicians) it explores and illustrates the ways in which the role positions of translational researchers are shaped by the [Symbol: see text]normative structures' of science and medicine respectively and in combination. The empirical data is used to illuminate three overlapping themes of ethical relevance: what matters in stem cell research, experimental treatment, and responsible claim making (as contrasted with [Symbol: see text]hype'). Finally, we suggest that this kind of [Symbol: see text]descriptive' ethical analysis has potential relevance for understanding other substantive areas of stem cell ethics in practice, and we briefly consider the questions our analysis raises about role positions and ethical agency, and the implications for bioethics as a field of scholarship.