ACTIVATION OF GABAA RECEPTORS AND INHIBITION OF NEUROSTEROID SYNTHESIS HAVE SEPARABLE ESTROUS-DEPENDENT EFFECTS ON BINGE DRINKING IN FEMALE MICE

poster abstractAlcohol concentrations relevant to the beginning stages of binge intoxica-tion may selectively activate GABAA receptor subtypes expressing δ-subunit proteins (δ-GABAAR). Indeed, administration of agonists that interact with these δ-GABAAR prior to alcohol access, can abolish binge drinking behavior (Melon and Boehm, 2011). Unfortunately, our ability to manipulate binge drinking in females is dependent upon estrous phase. The present experi-ments were designed to clarify the estrous-dependent effects of activation of δ-GABAAR on binge drinking. Specifically, we were interested in demonstrat-ing whether females display more persistent binge drinking as a function of cycle-dependent changes in the synthesis of endogenous neurosteroids that modulate δ-GABAAR. Using the Drinking-in-the-Dark binge-drinking model, regularly cycling female mice were given 2 hours of daily access to alcohol (20%v/v). Vaginal cytology was assessed after each drinking session to track estrous status. In experiment 1, animals were administered gaboxadol (an agonist with high affinity for δ-GABAAR) prior to their 8th day of access. In experiment 2, these methods were repeated, but mice received vehicle or finasteride (a neurosteroid synthesis inhibitor) 22hr prior to their 8th day of access. Results from experiment 1 demonstrated that diestrus females were insensitive to the significant gaboxadol-induced decrease in binge drinking observed for proestrus, estrus and metestrus females. In experiment 2, ve-hicle and finasteride treated diestrus females exhibited gaboxadol-induced reduction of their binge drinking. Surprisingly, finasteride pretreatment sig-nificantly reduced binge drinking for estrus females. These studies suggest that ovarian-linked changes to extrasynaptic GABAA R and to neurosteroid activity may be important factors in the binge consumption of alcohol for females. Future studies will further explore the role that acute stress during diestrus may play in inhibiting the effects of δ-GABAA R activation on binge drinking

Activation of extrasynaptic δ-GABAA receptors globally or within the posterior-VTA has estrous-dependent effects on consumption of alcohol and estrous-independent effects on locomotion

Recent reports support higher than expected rates of binge alcohol consumption among women and girls. Unfortunately, few studies have assessed the mechanisms underlying this pattern of intake in females. Studies in males suggest that alcohol concentrations relevant to the beginning stages of binge intoxication may selectively target tonic GABAergic inhibition mediated by GABAA receptor subtypes expressing the δ-subunit protein (δ-GABAARs). Indeed, administration of agonists that interact with these δ-GABAARs prior to alcohol access can abolish binge drinking behavior in male mice. These δ-GABAARs have also been shown to exhibit estrous-dependent plasticity in regions relevant to drug taking behavior, like the hippocampus and periaqueductal gray. The present experiments were designed to determine whether the estrous cycle would alter binge drinking, or our ability to modulate this pattern of alcohol use with THIP, an agonist with high selectivity and efficacy at δ-GABAARs. Using the Drinking-in-the-Dark (DID) binge-drinking model, regularly cycling female mice were given 2h of daily access to alcohol (20%v/v). Vaginal cytology or vaginal impedance was assessed after drinking sessions to track estrous status. There was no fluctuation in binge drinking associated with the estrous cycle. Both Intra-posterior-VTA administration of THIP and systemic administration of the drug was also associated with an estrous cycle dependent reduction in drinking behavior. Pre-treatment with finasteride to inhibit synthesis of 5α-reduced neurosteroids did not disrupt THIP's effects. Analysis of δ-subunit mRNA from posterior-VTA enriched tissue samples revealed that expression of this GABAA receptor subunit is elevated during diestrus in this region. Taken together, these studies demonstrate that δGABAARs in the VTA are an important target for binge drinking in females and confirm that the estrous cycle is an important moderator of the pharmacology of this GABAA receptor subtype

Subset of cortical layer 6b neurons selectively innervates higher order thalamic nuclei in mice

The thalamus receives input from 3 distinct cortical layers, but input from only 2 of these has been well characterized. We therefore investigated whether the third input, derived from layer 6b, is more similar to the projections from layer 6a or layer 5. We studied the projections of a restricted population of deep layer 6 cells (“layer 6b cells”) taking advantage of the transgenic mouse Tg(Drd1a-cre)FK164Gsat/Mmucd (Drd1a-Cre), that selectively expresses Cre-recombinase in a subpopulation of layer 6b neurons across the entire cortical mantle. At P8, 18% of layer 6b neurons are labeled with Drd1a-Cre::tdTomato in somatosensory cortex (SS), and some co-express known layer 6b markers. Using Cre-dependent viral tracing, we identified topographical projections to higher order thalamic nuclei. VGluT1+ synapses formed by labeled layer 6b projections were found in posterior thalamic nucleus (Po) but not in the (pre)thalamic reticular nucleus (TRN). The lack of TRN collaterals was confirmed with single-cell tracing from SS. Transmission electron microscopy comparison of terminal varicosities from layer 5 and layer 6b axons in Po showed that L6b varicosities are markedly smaller and simpler than the majority from L5. Our results suggest that L6b projections to the thalamus are distinct from both L5 and L6a projectionsZ.M.’s laboratory is supported by Medical Research Council (G00900901), Biotechnology and Biological Sciences Research Council (BB/1021833) and The Wellcome Trust (092071/Z/10/Z). E.G. held an MRC Doctoral Studentship; S.H. is supported from Daiichi Sankyo Foundation of Life Science, Japan, L.U. is supported by OXION Wellcome Trust Initiative, Oxford. Y.K. is supported from the Pennsylvania Department of Health using Tobacco CURE Funds SAP#4100062216; P.K. from National Institutes of Health (NIH) R01DC009607 and a visiting Fellowship at St. Catherine’s College, Oxford. F.C.’s laboratory is supported by Human Brain Project (European Flagship, Ref. GA 604102 and Ministerio de Economia y Competitividad MINECO (Spain; Grant BFU2017-88549-P)

Crossâ Network Directory Service: Infrastructure to enable collaborations across distributed research networks

IntroductionExisting largeâ scale distributed health data networks are disconnected even as they address related questions of healthcare research and public policy. This paper describes the design and implementation of a fully functional prototype openâ source tool, the Crossâ Network Directory Service (CNDS), which addresses much of what keeps distributed networks disconnected from each other.MethodsThe set of services needed to implement a Crossâ Directory Service was identified through engagement with stakeholders and workgroup members. CNDS was implemented using PCORnet and Sentinel network instances and tested by participating data partners.ResultsWeb services that enable the four major functional features of the service (registration, discovery, communication, and governance) were developed and placed into an openâ source repository. The services include a robust metadata model that is extensible to accommodate a virtually unlimited inventory of metadata fields, without requiring any further software development. The user interfaces are programmatically generated based on the contents of the metadata model.ConclusionThe CNDS pilot project gathered functional requirements from stakeholders and collaborating partners to build a software application to enable crossâ network data and resource sharing. The two partnersâ one from Sentinel and one from PCORnetâ tested the software. They successfully entered metadata about their organizations and data sources and then used the Discovery and Communication functionality to find data sources of interest and send a crossâ network query. The CNDS software can help integrate disparate health data networks by providing a mechanism for data partners to participate in multiple networks, share resources, and seamlessly send queries across those networks.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149237/1/lrh210187.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149237/2/lrh210187_am.pd

Integrating plant physiology into simulation of fire behavior and effects

Wildfires are a global crisis, but current fire models fail to capture vegetation response to changing climate. With drought and elevated temperature increasing the importance of vegetation dynamics to fire behavior, and the advent of next generation models capable of capturing increasingly complex physical processes, we provide a renewed focus on representation of woody vegetation in fire models. Currently, the most advanced representations of fire behavior and biophysical fire effects are found in distinct classes of fine-scale models and do not capture variation in live fuel (i.e. living plant) properties. We demonstrate that plant water and carbon dynamics, which influence combustion and heat transfer into the plant and often dictate plant survival, provide the mechanistic linkage between fire behavior and effects. Our conceptual framework linking remotely sensed estimates of plant water and carbon to fine-scale models of fire behavior and effects could be a critical first step toward improving the fidelity of the coarse scale models that are now relied upon for global fire forecasting. This process-based approach will be essential to capturing the influence of physiological responses to drought and warming on live fuel conditions, strengthening the science needed to guide fire managers in an uncertain future

The embodied nurse: Interdisciplinary knowledge exchange between compassionate nursing and recent developments in embodied leadership studies

Aims: To report a potential knowledge exchange between nursing studies and the results obtained from a study conducted into the attributes of embodied leadership. Background: Leadership theories have been applied to evaluate, improve, and train nursing practitioners in several previous studies. However, leadership research has entered a new phase where the focus is to produce sustainable leaders through authenticity and compassion, the same two characteristics identified as being of most success in emergent nursing practice. There are few studies that have indicated a knowledge exchange between the latest developments in leadership studies and nursing. Design: An exploratory and qualitative study. Methods: Between February 2012 - July 2012, a focused sample of 14 medical care professionals was interviewed across a chain of hospitals. The aim was to evaluate embodied leadership characteristics and understand the factors that contribute to the manifestation of these characteristics. The transcribed interviews were analysed using thematic analysis. Findings: Several factors that contribute to the characteristics of embodied leadership have been identified in the interviews and in subsequent literature searches on the characteristics and contributing factors found to be associated with nursing research. These could prompt a knowledge exchange. Conclusion: The results suggest common ground between nursing and contemporary leadership research in the exposition of behaviours; namely, being non-judgmental, listening actively, reflective practice and embracing uncertainty. Several implications can therefore be expected through the exchange of knowledge resulting from collaboration between researchers in the two disciplines

Can We Modify the Intrauterine Environment to Halt the Intergenerational Cycle of Obesity?

Child obesity is a global epidemic whose development is rooted in complex and multi-factorial interactions. Once established, obesity is difficult to reverse and epidemiological, animal model, and experimental studies have provided strong evidence implicating the intrauterine environment in downstream obesity. This review focuses on the interplay between maternal obesity, gestational weight gain and lifestyle behaviours, which may act independently or in combination, to perpetuate the intergenerational cycle of obesity. The gestational period, is a crucial time of growth, development and physiological change in mother and child. This provides a window of opportunity for intervention via maternal nutrition and/or physical activity that may induce beneficial physiological alternations in the fetus that are mediated through favourable adaptations to in utero environmental stimuli. Evidence in the emerging field of epigenetics suggests that chronic, sub-clinical perturbations during pregnancy may affect fetal phenotype and long-term human data from ongoing randomized controlled trials will further aid in establishing the science behind ones predisposition to positive energy balance

A redox-active switch in fructosamine-3-kinases expands the regulatory repertoire of the protein kinase superfamily

Aberrant regulation of metabolic kinases by altered redox homeostasis substantially contributes to aging and various diseases, such as diabetes. We found that the catalytic activity of a conserved family of fructosamine-3-kinases (FN3Ks), which are evolutionarily related to eukaryotic protein kinases, is regulated by redox-sensitive cysteine residues in the kinase domain. The crystal structure of the FN3K homolog from Arabidopsis thaliana revealed that it forms an unexpected strand-exchange dimer in which the ATP-binding P-loop and adjoining β strands are swapped between two chains in the dimer. This dimeric configuration is characterized by strained interchain disulfide bonds that stabilize the P-loop in an extended conformation. Mutational analysis and solution studies confirmed that the strained disulfides function as redox “switches” to reversibly regulate the activity and dimerization of FN3K. Human FN3K, which contains an equivalent P-loop Cys, was also redox sensitive, whereas ancestral bacterial FN3K homologs, which lack a P-loop Cys, were not. Furthermore, CRISPR-mediated knockout of FN3K in human liver cancer cells altered the abundance of redox metabolites, including an increase in glutathione. We propose that redox regulation evolved in FN3K homologs in response to changing cellular redox conditions. Our findings provide insights into the origin and evolution of redox regulation in the protein kinase superfamily and may open new avenues for targeting human FN3K in diabetic complications