Mice behaviorally selected for high Pavlovian fear memory exhibit fear generalization, HPA-axis alterations and increased basal activity in cortico-limbic circuits

Biological factors underlying individual variability in fearfulness and anxiety have important implications for stress-related psychiatric illness including PTSD and major depression. Using an advanced intercross line (AIL) derived from C57BL/6 and DBA/2J mouse strains and behavioral selection over 3 generations, we established two lines exhibiting High or Low fear behavior after fear conditioning. Across the selection generations, the two lines showed clear differences in training and tests for contextual and conditioned fear. Before fear conditioning training, there were no differences between lines in baseline freezing to a novel context. However, after fear conditioning High line mice demonstrated pronounced freezing in a new context suggestive of poor context discrimination. Fear generalization was not restricted to contextual fear. High fear mice froze to a novel acoustic stimulus while freezing in the Low line did not increase over baseline. Enhanced fear learning and generalization are consistent with transgenic and pharmacological disruption of the hypothalamic-pituitary-adrenal axis (HPA-axis) (Brinks, 2009, Thompson, 2004, Kaouane, 2012). To determine whether there were differences in HPA-axis regulation between the lines, morning urine samples were collected to measure basal corticosterone. Levels of secreted corticosterone in the circadian trough were analyzed by corticosterone ELISA. High fear mice were found to have higher basal corticosterone levels than low line animals. Examination of hormonal stress response components by qPCR revealed increased expression of CRH mRNA and decreased mRNA for MR and CRHR1 in hypothalamus of high fear mice. These alterations may contribute to both the behavioral phenotype and higher basal corticosterone in High fear mice. To determine basal brain activity in vivo in High and Low fear mice we used manganese-enhanced magnetic resonance imaging (MEMRI). Analysis revealed a pattern of basal brain activity made up of amygdala, cortical and hippocampal circuits that was elevated in the High line. Ongoing studies also seek to determine the relative balance of excitatory and inhibitory tone in the amygdala and hippocampus and the neuronal structure of its neurons. While these heterogeneous lines are selected on fear memory expression, HPA-axis alterations and differences in hippocampal activity segregate with the behavioral phenotypes. These differences are detectable in a basal state strongly suggesting these are biological traits underlying the behavioral phenotype (Johnson et al, 2011).

Single voxel Magnetic Resonance Spectroscopic (1H-MRS) analysis of deep brain structures after traumatic prefrontal brain injury (TBI) in rat

Chronic difficulties arising from mild brain injury (TBI) are difficult to predict because the processes underlying changes after TBI are poorly understood. In mild brain injury the extent of neuropsychiatric and cognitive symptoms correspond poorly to overt tissue loss (Barth 1983; Liu 2010). Cellular, immune and hormonal cascades occurring after injury and continuing during the healing process may impact uninjured brain regions sensitive to the effects of physiological and emotional stress, which receive projections from the injury site. Changes in these most basic properties due to injury or disease have profound implications for virtually every aspect of brain function through disruption of neurotransmitter, neuroendocrine and metabolic systems. In order to screen for changes in transmitter and metabolic activity, in this study we developed Single voxel proton Magnetic Resonance Spectroscopy (1H-MRS) for use in both injured and control animals. We first evaluated if 1H-MRS could be used to evaluate in vivo, alterations in brain metabolism and catabolism of the prefrontal cortex, amygdala and ventral hippocampus in both control and injured animals after controlled cortical impact injury to the rat prefrontal cortex. We found that metabolite measurements for Myo-Inositol, Choline, creatine, Glutamate+Glutamine, and N-acetyl-acetate are attainable in deep brain structures in vivo in injured and controls rats. We next seek to evaluate longitudinally, in vivo, alterations in brain metabolism and catabolism of the prefrontal cortex, amygdala and ventral hippocampus during the first month after controlled cortical impact injury to the rat prefrontal cortex. These ongoing studies will provide data on the changes in transmitters and metabolites over time in injured and non-injured subjects. These studies address some of the fundamental questions about how mild brain injury has such diverse effects on overall brain health and function.

Marginal costs of hospital-acquired conditions : information for priority-setting for patient safety programmes and research

Objective: To estimate the relative inpatient costs of hospital-acquired conditions. Methods: Patient level costs were estimated using computerized costing systems that log individual utilization of inpatient services and apply sophisticated cost estimates from the hospital's general ledger. Occurrence of hospital-acquired conditions was identified using an Australian ‘condition-onset' flag for diagnoses not present on admission. These were grouped to yield a comprehensive set of 144 categories of hospital-acquired conditions to summarize data coded with ICD-10. Standard linear regression techniques were used to identify the independent contribution of hospital-acquired conditions to costs, taking into account the case-mix of a sample of acute inpatients (n = 1,699,997) treated in Australian public hospitals in Victoria (2005/06) and Queensland (2006/07). Results: The most costly types of complications were post-procedure endocrine/metabolic disorders, adding AU$21,827 to the cost of an episode, followed by MRSA (AU$19,881) and enterocolitis due to Clostridium difficile (AU$19,743). Aggregate costs to the system, however, were highest for septicaemia (AU$41.4 million), complications of cardiac and vascular implants other than septicaemia (AU$28.7 million), acute lower respiratory infections, including influenza and pneumonia (AU$27.8 million) and UTI (AU$24.7 million). Hospital-acquired complications are estimated to add 17.3% to treatment costs in this sample. Conclusions: Patient safety efforts frequently focus on dramatic but rare complications with very serious patient harm. Previous studies of the costs of adverse events have provided information on ‘indicators’ of safety problems rather than the full range of hospital-acquired conditions. Adding a cost dimension to priority-setting could result in changes to the focus of patient safety programmes and research. Financial information should be combined with information on patient outcomes to allow for cost-utility evaluation of future interventions.

Enhanced preference for high-fat foods following a simulated night shift

Objectives Shift workers are prone to obesity and associated co-morbidities such as diabetes and cardiovascular disease. Sleep restriction associated with shift work results in dramatic endocrine and metabolic effects that predispose shift workers to these adverse health consequences. While sleep restriction has been associated with increased caloric intake, food preference may also play a key role in weight gain associated with shift work. This study examined the impact of an overnight simulated night shift on food preference. Methods Sixteen participants [mean 20.1, standard deviation (SD) 1.4 years; 8 women] underwent a simulated night shift and control condition in a counterbalanced order. On the following morning, participants were provided an opportunity for breakfast that included high- and low-fat food options (mean 64.8% and 6.4% fat, respectively). Results Participants ate significantly more high-fat breakfast items after the simulated night shift than after the control condition [167.3, standard error of the mean (SEM 28.7) g versus 211.4 (SEM 35.6) g; P=0.012]. The preference for high-fat food was apparent among the majority of individuals following the simulated night shift (81%), but not for the control condition (31%). Shift work and control conditions did not differ, however, in the total amount of food or calories consumed. Conclusions A simulated night shift leads to preference for high-fat food during a subsequent breakfast opportunity. These results suggest that food choice may contribute to weight-related chronic health problems commonly seen among night shift workers.

Néstor-Guillermo Progeria Syndrome: a biochemical insight into Barrier-to-Autointegration Factor 1, alanine 12 threonine mutation

Background Premature aging syndromes recapitulate many aspects of natural aging and provide an insight into this phenomenon at a molecular and cellular level. The progeria syndromes appear to cause rapid aging through disruption of normal nuclear structure. Recently, a coding mutation (c.34G > A [p.A12T]) in the Barrier to Autointegration Factor 1 (BANF1) gene was identified as the genetic basis of Néstor-Guillermo Progeria syndrome (NGPS). This mutation was described to cause instability in the BANF1 protein, causing a disruption of the nuclear envelope structure. Results Here we demonstrate that the BANF1 A12T protein is indeed correctly folded, stable and that the observed phenotype, is likely due to the disruption of the DNA binding surface of the A12T mutant. We demonstrate, using biochemical assays, that the BANF1 A12T protein is impaired in its ability to bind DNA while its interaction with nuclear envelope proteins is unperturbed. Consistent with this, we demonstrate that ectopic expression of the mutant protein induces the NGPS cellular phenotype, while the protein localizes normally to the nuclear envelope. Conclusions Our study clarifies the role of the A12T mutation in NGPS patients, which will be of importance for understanding the development of the disease.

Love hurts: The costly reality of online romance fraud

Online dating and romance scams continue to lure in Australians with figures this week showing people have lost more than A$23 million this year alone, with average individual losses at A$21,000 – three times higher than other types of fraud. The Australian Competition and Consumer Commission (ACCC) set up the Scam Disruption Project in August to help target those it believes have been caught in such scams. Over three months it sent 1,500 letters to potential victims in New South Wales and the Australian Capital Territory. The figures released this week show that 50 people have been scammed, losing a total A$1.7 million – that’s an average of A$34,000 per victim. Almost three quarters of the scams were dating and romance related, which saw it evolve into the number one category of fraud victimisation. Romance scams continue to pose a problem – despite the efforts of the police and ACCC – so why is it that people continue to fall for them?

Slippage: Reclaiming personal family history through contemporary photomedia

This paper addresses the role of photography as a documentary medium and how this forms a basis for my practice-led studio investigations. In it, I will explore how photography is used to create histories and sustain specific notions of ‘legacy’ within the context of the family photo album. Family history is often based on stories to which the photo album provides a visual point of reference. Despite the ostensible ‘objectivity’ of the family photograph though it is nonetheless as subjective as the stories that surround it. In this way, the photo album perpetuates a hegemony of truth that obscures the fragmentary and highly selective nature of these documents and stories. The result is that every photo album implicitly documents the gaps or voids present in understandings of our own histories. Homi Bhabha refers to these kinds of voids as ‘disjunctive historical spaces’ – spaces of slippage that create the opportunity for new narratives and understandings to occur. Using Bhabha’s ideas as a chief point of reference, I will explore how these voids or gaps in information – and the opportunities for re-examination that they open up - can be explored through contemporary photomedia. Digital technologies such as camera phones and scanners generate a space in which photography’s own documentary conventions can be turned in on themselves to create a subterfuge. My current studio-based research involves using the scanner to navigate through my family’s sometimes-‘occulted’ history, in order to explore, document and recover my connection to this narrative. I am primarily interested in the scanner as a tool for capturing not simply surfaces, but objects, moments or movements in time. Objects or moments captured by the scanner can often be simultaneously distorted and consolidated, blurred and sharpened. This paper will propose that this ‘slippage’, literally expressed in the disruption of the pixelated field, can be used to create a space in which alternative readings or understandings of past events can be explored and new narratives produced.

The combination of plant-expressed cellobiohydrolase and low dosages of cellulases for the hydrolysis of sugar cane bagasse

Background The expression of biomass-degrading enzymes (such as cellobiohydrolases) in transgenic plants has the potential to reduce the costs of biomass saccharification by providing a source of enzymes to supplement commercial cellulase mixtures. Cellobiohydrolases are the main enzymes in commercial cellulase mixtures. In the present study, a cellobiohydrolase was expressed in transgenic corn stover leaf and assessed as an additive for two commercial cellulase mixtures for the saccharification of pretreated sugar cane bagasse obtained by different processes. Results Recombinant cellobiohydrolase in the senescent leaves of transgenic corn was extracted using a simple buffer with no concentration step. The extract significantly enhanced the performance of Celluclast 1.5 L (a commercial cellulase mixture) by up to fourfold on sugar cane bagasse pretreated at the pilot scale using a dilute sulfuric acid steam explosion process compared to the commercial cellulase mixture on its own. Also, the extracts were able to enhance the performance of Cellic CTec2 (a commercial cellulase mixture) up to fourfold on a range of residues from sugar cane bagasse pretreated at the laboratory (using acidified ethylene carbonate/ethylene glycol, 1-butyl-3-methylimidazolium chloride, and ball-milling) and pilot (dilute sodium hydroxide and glycerol/hydrochloric acid steam explosion) scales. We have demonstrated using tap water as a solvent (under conditions that mimic an industrial process) extraction of about 90% recombinant cellobiohydrolase from senescent, transgenic corn stover leaf that had minimal tissue disruption. Conclusions The accumulation of recombinant cellobiohydrolase in senescent, transgenic corn stover leaf is a viable strategy to reduce the saccharification cost associated with the production of fermentable sugars from pretreated biomass. We envisage an industrial-scale process in which transgenic plants provide both fibre and biomass-degrading enzymes for pretreatment and enzymatic hydrolysis, respectively.

Working as one: A road map to disaster resilience for Australia

Natural disasters cause widespread disruption, costing the Australian economy $6.3 billion per year, and those costs are projected to rise incrementally to $23 billion by 2050. With more frequent natural disasters with greater consequences, Australian communities need the ability to prepare and plan for them, absorb and recover from them, and adapt more successfully to their effects. Enhancing Australian resilience will allow us to better anticipate disasters and assist in planning to reduce losses, rather than just waiting for the next king hit and paying for it afterwards. Given the scale of devastation, governments have been quick to pick up the pieces when major natural disasters hit. But this approach (‘The government will give you taxpayers’ money regardless of what you did to help yourself, and we’ll help you rebuild in the same risky area.’) has created a culture of dependence. This is unsustainable and costly. In 2008, ASPI published Taking a punch: building a more resilient Australia. That report emphasised the importance of strong leadership and coordination in disaster resilience policymaking, as well as the value of volunteers and family and individual preparation, in managing the effects of major disasters. This report offers a roadmap for enhancing Australia’s disaster resilience, building on the 2011 National Strategy for Disaster Resilience. It includes a snapshot of relevant issues and current resilience efforts in Australia, outlining key challenges and opportunities. The report sets out 11 recommendations to help guide Australia towards increasing national resilience, from individuals and local communities through to state and federal agencies.

Radial glia phagocytose axonal debris from degenerating overextending axons in the developing olfactory bulb

Axon targeting during the development of the olfactory system is not always accurate, and numerous axons overextend past the target layer into the deeper layers of the olfactory bulb. To date, the fate of the mis-targeted axons has not been determined. We hypothesized that following overextension, the axons degenerate, and cells within the deeper layers of the olfactory bulb phagocytose the axonal debris. We utilized a line of transgenic mice that expresses ZsGreen fluorescent protein in primary olfactory axons. We found that overextending axons closely followed the filaments of radial glia present in the olfactory bulb during embryonic development. Following overextension into deeper layers of the olfactory bulb, axons degenerated and radial glia responded by phagocytosing the resulting debris. We used in vitro analysis to confirm that the radial glia had phagocytosed debris from olfactory axons. We also investigated whether the fate of overextending axons was altered when the development of the olfactory bulb was perturbed. In mice that lacked Sox10, a transcription factor essential for normal olfactory bulb development, we observed a disruption to the morphology and positioning of radial glia and an accumulation of olfactory axon debris within the bulb. Our results demonstrate that during early development of the olfactory system, radial glia play an important role in removing overextended axons from the deeper layers of the olfactory bulb.

Neurodevelopmental animal models of schizophrenia: Effects on prepulse inhibition

Epidemiological studies have shown increased incidence of schizophrenia in patients subjected to different forms of pre- or perinatal stress. However, as the onset of schizophrenic illness does not usually occur until adolescence or early adulthood, it is not yet fully understood how disruption of early brain development may ultimately lead to malfunction years later. In order to elucidate a possible role for neurodevelopmental factors in the pathogenesis of schizophrenia and to highlight potential new treatments, animal models are needed. Prepulse inhibition (PPI) is a model of sensorimotor gating mechanisms in the brain. It is disrupted in schizophrenia patients and the disruption can be reversed with atypical antipsychotics. It has been widely used in animal studies to explore central mechanisms possibly involved in schizophrenia. There has been a recent surge of behavioural and neurochemical animal studies on neurodevelopmental models, particularly on the effects of postweaning isolation, maternal separation and neonatal lesions of the hippocampus. In these models, long lasting alterations in behaviour and/or molecular changes in specific brain regions are observed, comparable to those seen in schizophrenia. The aim of this article is to critically review the available literature on such neurodevelopmental animal models with special focus on the effects on PPI and brain regions that are putatively involved in regulation of PPI.

An upstream open reading frame is essential for feedback regulation of ascorbate biosynthesis in arabidopsis

Ascorbate (vitamin C) is an essential antioxidant and enzyme cofactor in both plants and animals. Ascorbate concentration is tightly regulated in plants, partly to respond to stress. Here, we demonstrate that ascorbate concentrations are determined via the posttranscriptional repression of GDP-l-galactose phosphorylase (GGP), a major control enzyme in the ascorbate biosynthesis pathway. This regulation requires a cis-acting upstream open reading frame (uORF) that represses the translation of the downstream GGP open reading frame under high ascorbate concentration. Disruption of this uORF stops the ascorbate feedback regulation of translation and results in increased ascorbate concentrations in leaves. The uORF is predicted to initiate at a noncanonical codon (ACG rather than AUG) and encode a 60- to 65-residue peptide. Analysis of ribosome protection data from Arabidopsis thaliana showed colocation of high levels of ribosomes with both the uORF and the main coding sequence of GGP. Together, our data indicate that the noncanonical uORF is translated and encodes a peptide that functions in the ascorbate inhibition of translation. This posttranslational regulation of ascorbate is likely an ancient mechanism of control as the uORF is conserved in GGP genes from mosses to angiosperms.

Exercise-induced DNA damage: Is there a relationship with inflammatory responses?

Both a systemic inflammatory response as well as DNA damage has been observed following exhaustive endurance exercise. Hypothetically, exercise-induced DNA damage might either be a consequence of inflammatory processes or causally involved in inflammation and immunological alterations after strenuous prolonged exercise (e.g. by inducing lymphocyte apoptosis and lymphocytopenia). Nevertheless, up to now only few studies have addressed this issue and there is hardly any evidence regarding a direct relationship between DNA or chromosomal damage and inflammatory responses in the context of exercise. The most conclusive picture that emerges from available data is that reactive oxygen and nitrogen species (RONS) appear to be the key effectors which link inflammation with DNA damage. Considering the time-courses of inflammatory and oxidative stress responses on the one hand and DNA effects on the other the lack of correlations between these responses might also be explained by too short observation periods. This review summarizes and discusses the recent findings on this topic. Furthermore, data from our own study are presented that aimed to verify potential associations between several endpoints of genome stability and inflammatory, immune-endocrine and muscle damage parameters in competitors of an Ironman triathlon until 19 days into recovery. The current results indicate that DNA effects in lymphocytes are not responsible for exercise-induced inflammatory responses. Furthermore, this investigation shows that inflammatory processes, vice versa, do not promote DNA damage, neither directly nor via an increased formation of RONS derived from inflammatory cells. Oxidative DNA damage might have been counteracted by training- and exercise-induced antioxidant responses. However, further studies are needed that combine advanced -omics based techniques (transcriptomics, proteomics) with state-of-the-art biochemical biomarkers to gain more insights into the underlying mechanisms.

Gene network effects on brain microstructure and intellectual performance identified in 472 twins

A major challenge in neuroscience is finding which genes affect brain integrity, connectivity, and intellectual function. Discovering influential genes holds vast promise for neuroscience, but typical genome-wide searches assess approximately one million genetic variants one-by-one, leading to intractable false positive rates, even with vast samples of subjects. Even more intractable is the question of which genes interact and how they work together to affect brain connectivity. Here, we report a novel approach that discovers which genes contribute to brain wiring and fiber integrity at all pairs of points in a brain scan. We studied genetic correlations between thousands of points in human brain images from 472 twins and their nontwin siblings (mean age: 23.7 2.1 SD years; 193 male/279 female).Wecombined clustering with genome-wide scanning to find brain systems withcommongenetic determination.Wethen filtered the image in a new way to boost power to find causal genes. Using network analysis, we found a network of genes that affect brain wiring in healthy young adults. Our new strategy makes it computationally more tractable to discover genes that affect brain integrity. The gene network showed small-world and scale-free topologies, suggesting efficiency in genetic interactions and resilience to network disruption. Genetic variants at hubs of the network influence intellectual performance by modulating associations between performance intelligence quotient and the integrity of major white matter tracts, such as the callosal genu and splenium, cingulum, optic radiations, and the superior longitudinal fasciculus.

Progressive dysgraphia in a case of posterior cortical atrophy

Dysgraphia (agraphia) is a common feature of posterior cortical atrophy (PCA). However, detailed analyses of these spelling and writing impairments are infrequently conducted. LM is a 59-year-old woman with dysgraphia associated with PCA. She presented with a two-year history of decline in her writing and dressmaking skills. A 3D T1-weighted MRI scan confirmed selective bi-parietal atrophy, with relative sparing of the hippocampi and other cortical regions. Analyses of LM's preserved and impaired spelling abilities indicated mild physical letter distortions and a significant spelling deficit characterised by letter substitutions, insertions, omissions, and transpositions that was systematically sensitive to word length while insensitive to real word versus nonword category, word frequency, regularity, imagery, grammatical class and ambiguity. Our findings suggest a primary graphemic buffer disorder underlies LM's spelling errors, possibly originating from disruption to the operation of a fronto-parietal network implicated in verbal working memory.