FKBP51 in a dynamic environment

Mental health disorders are a pressing global health-threat, affecting millions of people world-wide, which has already cost the world economy over 2.5 trillion dollars, making it a critical burden to society. These psychiatric disorders, including major depressive disorders, anxiety disorders and posttraumatic stress disorders, commonly arise as a combination of genetic and environmental factors. In the past decades, these gene by environment interactions (GxE) have increasingly been studied in both clinical and pre-clinical settings. Exposure to early life adversity has often been associated with negative outcomes on brain and behaviour and it has frequently been described as a risk factor for developing psychiatric disease. Nevertheless, there is also cumulative evidence that exposure to early life stress (ELS) in a milder form can result in adaptive responses that prepare an individual to cope with future life challenges. One gene that has repeatedly been implicated in the risk for psychiatric disease development is the FK506-binding protein 5 (FKBP5) gene, that encodes the glucocorticoid receptor (GR) co-chaperone FKBP51. FKBP51 plays an important role in regulating the sensitivity of the GR to the stress-hormone cortisol in humans or corticosterone in rodents. Interestingly, polymorphisms in the FKBP5 gene were found to interact with traumatic early life events to increase the risk for developing psychiatric disorders. In recent years, FKBP51 has extensively been studied in relation to stress resilience and vulnerability, however the mechanisms by which it contributes to these processes, particularly in combination with ELS, are not yet fully understood. Apart from genetic factors and early life events, there are a number of additional environmental factors that can be of great influence on mental health, such as age or sex. In fact, research from the past decades has shed an increasing light on the pivotal role that sex plays in the resilience to (early life) stress. Nevertheless, since many studies historically only included males, there is unfortunately still a large gap in information on the female sex when it comes to stress resilience and vulnerability mechanisms. In this thesis, the importance of including both sexes in rodent stress research study designs is emphasized, by demonstrating sex-differential phenotypes of chronic social defeat stress using a recently developed hands-on protocol for chronic social defeat in females. Moreover, using genetic mouse models, this thesis demonstrates not only clear sex-dependent, but also cell-type specific functionality of FKBP51, either under baseline conditions in an older aged sample or in interaction with ELS stress exposure. Furthermore, it underlines the FKBP51-mediated beneficial effects of ELS exposure in female mice and proposes novel underlying pathways in this process. Ultimately, this thesis corroborates the notion that FKBP5 is not per se a psychiatric risk factor, but rather a highly dynamic stress-responsive gene that interacts with the environment in shaping stress resilience

The Raven knows my name: Contemplation and practice on an off-grid island

Students often confront grief, anxiety, and despair as they learn about ecological decline and their complicity in a deleterious system. Ecological grief afflicts students even as the world requires much of them by way of action and reform. However, the middle and upper-class in modern Western societies, accustomed to comfort and consumption, often find it hard to diminish their ecological impact. This dissertation explores the following question: How do we do what we are not inclined to do even as we suffer from ecological grief? Informed by Zen tradition and practice, the author explores contemplation as a way of dealing with ecological pain. Working through Pierre Bourdieu’s theory of habitus, the suite of ruling dispositions shaped by practice, the author examines how inclinations are shaped by everyday activities. The research project involves a ten-and-a-half-month retreat on an off-grid island on the West Coast of British Columbia. Using a combination of contemplative practice, phenomenological inquiry and portraiture, the author documents the disruptions to his urban habitus, the practices related to living in a wild place, and how such practices are relevant to educators aiming to promote dispositions that cohere with a more ecologically sound way of life. Through stories and reflections from each season, the author relates experiences of living in the woods and interprets their significance to environmental education. Significant themes include: embodiment, awareness, water, askesis, time, and contemplation. The author also describes discontinuities and adjustments upon his return to the city and elaborates on their significance in relation to ecological grief and habitus. The last chapter explores the dimensions of ecological grief and suggests approaches to working with anxieties, ambivalences, and aspirations associated with the ecological decline. This study presents an analysis of the various dimensions of practice and suggests profiles of practice to help reshape existing dispositions

Behavioral and histochemical characterization of a novel BACE Knockout x PDAPP mouse model of Alzheimer's Disease: examination of potential effects of BACE inhibition on Alzheimer's Disease and the role of APP, Aβ and BACE in normal and pathological memory function

This dissertation describes the phenotypic characterization of a BACE knockout (KO) x PDAPP transgenic mouse line, utilizing behavioral, histochemical, and pharmacologic methods. Overproduction and accumulation of the amyloid-|3 (A|3) peptide in the brain has been implicated as one of the causal factors in the development of Alzheimer's Disease (AD). Based on this concept, several transgenic mouse models have been created that overexpress human mutant Amyloid Precursor Protein (hAPP) that reproduces many of the cognitive and histopathological features of AD. Recently, the (3-site cleaving enzyme (BACE) responsible for the first proteolytic cleavage of APP has been characterized, and subsequent research has led to the propagation of BACE inhibition as a prime experimental strategy for AD therapy.Currently, there are many academic and pharmaceutical company laboratories actively engaged in developing therapeutic inhibitors of BACE for AD. However, the theoretical repercussions of BACE activity reduction have not yet been fully addressed in an in vivo model. Indeed, although overproduction of A|3 leads to neuroanatomical and cognitive pathology in human patients and animal models, lack ofA|3 may also result in deleterious cognitive effects. Examining the behavioral and histological phenotypes of BACE KO animals on normal and hAPP overexpressing backgrounds is an effective way to assess whether the inhibition of BACE is a reasonable strategy for the treatment of AD.To examine this issue a series of behavioral studies were conducted using homozygous and hemizygous BACE KO mice, PDAPP mice, and BACE KO; PDAPP lines together with relevant controls. The studies included various protocols in a cued and spatial watermaze task and detailed analysis of the occurrence of epileptiform seizures. Objective methods were used to analyse the changes in learning ability and the frequency of seizures.The results from the characterization of the BACE KO x PDAPP mouse line indicate that the absolute loss of BACE and A|3 caused profound spatial memory deficits, sometimes greater even than that of hAPP mice alone. In addition, absolute BACE KO was associated with spontaneous seizures as well as greater seizure activity in drug-induced seizure experiments. However, the partial hemizygous deletion of the BACE gene on a hAPP background appeared to improve spatial memory performance on certain measures and protect against drug-induced seizure responses relative to hAPP mice. The research described in this dissertation is consistent with the notion that, under certain circumstances, therapeutic inhibition of BACE may prove to be a valuable strategy for treatment of AD. In addition, these studies also support an important role for the [3-amyloid processing pathway in "normal" learning and memory processes, possibly by regulating neuronal activity levels

Wastewater irrigation and health: assessing and mitigating risk in low-income countries

Wastewater irrigation / Public health / Health hazards / Risk assessment / Epidemiology / Sewage sludge / Excreta / Diseases / Vegetables / Leaf vegetables / Economic impact / Wastewater treatment / Irrigation methods / Developing countries

The new technique for accurate estimation of the spinal cord circuitry:recording reflex responses of large motor unit populations

We propose and validate a non-invasive method that enables accurate detection of the discharge times of a relatively large number of motor units during excitatory and inhibitory reflex stimulations. HDsEMG and intramuscular EMG (iEMG) were recorded from the tibialis anterior muscle during ankle dorsiflexions performed at 5%, 10%, and 20% of the maximum voluntary contraction (MVC) force, in 9 healthy subjects. The tibial nerve (inhibitory reflex) and the peroneal nerve (excitatory reflex) were stimulated with constant current stimuli. In total, 416 motor units were identified from the automatic decomposition of the HDsEMG. The iEMG was decomposed using a state-of-the-art decomposition tool and provided 84 motor units (average of two recording sites). The reflex responses of the detected motor units were analyzed using the peri-stimulus time histogram (PSTH) and the peri-stimulus frequencygram (PSF). The reflex responses of the common motor units identified concurrently from the HDsEMG and the iEMG signals showed an average disagreement (the difference between number of observed spikes in each bin relative to the mean) of 8.2±2.2% (5% MVC), 6.8±1.0% (10% MVC), and 7.5±2.2% (20% MVC), for reflex inhibition, and 6.5±4.1%, 12.0±1.8%, 13.9±2.4%, for reflex excitation. There was no significant difference between the characteristics of the reflex responses, such as latency, amplitude and duration, for the motor units identified by both techniques. Finally, reflex responses could be identified at higher force (four of the nine subjects performed contraction up to 50% MVC) using HDsEMG but not iEMG, because of the difficulty in decomposing the iEMG at high forces. In conclusion, single motor unit reflex responses can be estimated accurately and non-invasively in relatively large populations of motor units using HDsEMG. This non-invasive approach may enable a more thorough investigation of the synaptic input distribution on active motor units at various force levels

Quality of drinking and recreational water in the Hunter New England region of New South Wales: bridging the gap between research, practice and policy

Introduction Population health research may include primary data collection and analysis; analysis of existing data; and systematic reviews for problem definition, solution generation, and evaluation. The main objective of this thesis was to analyse routinely collected data and primary data to assess drinking and recreational water quality management in the Hunter New England region of New South Wales (NSW), Australia. This research was practitionerled and designed to bridge the gap between research and policy in drinking water management in NSW. When used with a specific research goal, routinely collected data obtained for performance monitoring purposes is an important tool for improving the quality of water supplies. Such practitioner-led research may be directly translated into local practice to improve public health service delivery. Continuous interactions between practitioner-researchers, academics, decision makers and other stakeholders throughout the research process provided impetus for evidence adoption through sustained evaluation of public health benefits. This thesis provides a firm foundation for the design of future environmental health interventions for the translation of research evidence to policy decision outcomes, leading to improved water quality and public health in rural areas. Setting In NSW, the NSW Public Health Act 2010 (NSW Government, 2010) regulates water suppliers to provide safe water to consumers. NSW Health provides drinking water supply protocols that include monitoring, reporting, and public notifications. The NSW Health's Drinking Water Monitoring Program provides free water testing for suppliers throughout the state. Public water suppliers (utilities) are allocated barcoded-labels for the recommended number of samples for each water supply system each year. Compliance is measured by the adequacy of sampling, in which at least 98% should yield no E. coli detections. The Program centrally manages the internet-based NSW Drinking Water Database, which has recorded more than 20 000 sample results per year since 2001. Therefore, there is sufficient routinely collected data to assess drinking water quality in NSW. Method A Participatory Action Research (PAR) process was applied using a mixed methods framework. The practitioner researcher's research and collaborations with academics, policy makers and stakeholders from the planning through to the implementation of projects ensured that expectations were clear. An 'adopt and intervene as-we-go' philosophy was applied. The evidence was interrogated and areas of intervention were applied. Further projects were then designed to evaluate the identified areas of intervention. Four approaches were taken to explore and bring about change in drinking water quality management through advocacy: • Working with departmental staff to analyse routinely collected microbiological water quality data for reticulated water supplies to improve drinking water quality management within existing work budgets; • Working with recreational parks authorities to collect and analyse data to assess and improve private drinking water management; • Working with an Aboriginal community to assess reticulated drinking water supply quality and acceptance and promote consumption of safe drinking water; and • Working with departmental staff to pilot Enterococci testing to assess recreational swimming water quality at popular swimming sites to design new policy to reduce public health risk. Regular research briefs and reports to share findings, dissemination and advocacy through peer reviewed journal articles and presentations at professional conferences were used to share the research evidence to stakeholders, policy-makers and peer environmental health practitioners. Results and outcomes Public drinking water sampling adequacy significantly improved (p = 0.002) during the study period. Sampling adequacy was significantly lower in smaller populations (p = 0.013). E. coli detections significantly improved (p < 0.0001) but were significantly higher in smaller communities (p< 0.001). There was a strong inverse correlation between sampling compliance and E. coli detection (p<0.001; R² Linear = 0.72). NSW Health has assisted utilities to develop and implement Drinking Water Management Systems throughout the State. All recreational parks developed and implemented drinking water quality assurance programs. All recreational parks that provided water but do not treat or regularly monitor the quality of the water supplies have installed appropriate warning signs by the NSW Private Water Supply Guidelines, to warn visitors. Private drinking water supplies have now been included in the NSW Public Health Act, and Private Drinking Water Supply Guidelines were amended to include the development and implementation of drinking water quality assurance plans. Aesthetic factors such as water hardness, taste, colour, odours and societal values influence perceptions of risk and quality. Plans are underway to soften town water supply, as requested by the participating Aboriginal community, as this was a major barrier to consumption. All swimming sites exceeded the threshold NHMRC Enterococci illness transmission recreational level of 40 CFU/100 ml. There is a need for risk-based water quality management at informal recreational swimming sites. Conclusion The research demonstrated that improving drinking water sampling frequency was associated with enhanced microbiological water safety. However, there is room for improvement in sampling adequacy and water quality (E. coli detections) in smaller communities. Further dialogue, research, and policy focus is needed that includes partnerships with discrete NSW Aboriginal communities, in order to develop a deeper understanding of their perceptions of drinking water and to encourage consumption of safe water. This research promoted interaction between practitioners, managers and academics in environmental health program development to promote public health. The research clearly demonstrated how using routinely collected data coupled with primary data collection results in strong environmental health practitioner-led research with important policy outcomes. Future research should build on these key strengths, linking environmental health practitioners' fieldwork with productive collaborative networks between academics and policy makers, to promote the development of knowledge that provides evidence-based policy changes for public health benefit

Characterization of an animal model of cognitive impairment associated with schizophrenia. Effets of alpha2-adrenoceptor compounds.

382 p.Schizophrenia is a multi multifaceted, heterogeneous, chronic and debilitating disorder triggered by a series of interacting genetic, developmental and environmental factors. Cognitive impairment is considered a core feature of this disorder and highly dependent on the correct functioning of the prefrontal cortex, however, current antipsychotics lack efficacy for treating this condition. Prenatal exposure to infection is contemplated as one the most significant environmental risk factors for developing schizophrenia in the offspring. In this context, maternal immune activation animal models produce neurochemical and behavioral alterations considered relevant for the study of schizophrenia dysfunctions.The first part of this thesis consists of a neurochemical and behavioral characterization of an animal model of cognitive impairment associated with schizophrenia by the administration of the immunostimulant agent Poly (I:C). The second part involves the study of the effects of ¿2-adrenoceptor compounds on cognitive performance in the offspring. Finally, selective targeting of the locus coeruleus-prefrontal cortex circuit by different optogenetic approaches was performed.The Poly (I:C) animal model shows a catecholaminergic hypofunction in the prefrontal cortex with marked cognitive deficits, which are reversed by the administration of 2A-adrenoceptor agonist guanfacine and the 2C-adrenoceptor antagonist MK-912.These results support the important role of the noradrenergic system in the prefrontal cortex-dependent cognitive functions and the Poly (I:C) animal model as a promising translational model of cognitive impairment associated with schizophrenia