The cognitive impact of light: illuminating ipRGC circuit mechanisms.

Ever-present in our environments, light entrains circadian rhythms over long timescales, influencing daily activity patterns, health and performance. Increasing evidence indicates that light also acts independently of the circadian system to directly impact physiology and behaviour, including cognition. Exposure to light stimulates brain areas involved in cognition and appears to improve a broad range of cognitive functions. However, the extent of these effects and their mechanisms are unknown. Intrinsically photosensitive retinal ganglion cells (ipRGCs) have emerged as the primary conduit through which light impacts non-image-forming behaviours and are a prime candidate for mediating the direct effects of light on cognition. Here, we review the current state of understanding of these effects in humans and mice, and the tools available to uncover circuit-level and photoreceptor-specific mechanisms. We also address current barriers to progress in this area. Current and future efforts to unravel the circuits through which light influences cognitive functions may inform the tailoring of lighting landscapes to optimize health and cognitive function.

Dab1 is required for synaptic plasticity and associative learning.

Disabled-1 (Dab1) is an adaptor protein that is an obligate effector of the Reelin signaling pathway, and is critical for neuronal migration and dendrite outgrowth during development. Components of the Reelin pathway are highly expressed during development, but also continue to be expressed in the adult brain. Here we investigated in detail the expression pattern of Dab1 in the postnatal and adult forebrain, and determined that it is expressed in excitatory as well as inhibitory neurons. Dab1 was found to be localized in different cellular compartments, including the soma, dendrites, presynaptic and postsynaptic structures. Mice that are deficient in Dab1, Reelin, or the Reelin receptors ApoER2 and VLDLR exhibit severely perturbed brain cytoarchitecture, limiting the utility of these mice for investigating the role of this signaling pathway in the adult brain. In this study, we developed an adult forebrain-specific and excitatory neuron-specific conditional knock-out mouse line, and demonstrated that Dab1 is a critical regulator of synaptic function and hippocampal-dependent associative and spatial learning. These dramatic abnormalities were accompanied by a reduction in dendritic spine size, and defects in basal and plasticity-induced Akt and ERK1/2 signaling. Deletion of Dab1 led to no obvious changes in neuronal positioning, dendrite morphology, spine density, or synaptic composition. Collectively, these data conclusively demonstrate an important role for Reelin-Dab1 signaling in the adult forebrain, and underscore the importance of this pathway in learning and memory.

Circadian rhythm shifts and alcohol access in adolescence synergistically increase alcohol preference and intake in adulthood in male C57BL/6 mice.

BACKGROUND: Adolescents have a natural tendency to be night owls, maintaining delayed circadian rhythms, and this rhythm is in direct conflict with the early wake times required during the school year. This leads to 'social jetlag', chronic circadian stress or desynchrony (CD) in which the rhythm of the intrinsic body clock is out of sync with behavior. CD increases alcohol intake in adolescents and adults, yet it is unknown whether adolescent CD also increases long-term addiction risk. The goal of this study was to determine whether adolescent alcohol intake in CD would increase adult alcohol preference and intake in male C57BL/6 J mice. METHODS: We measured free access alcohol intake, water intake, and wheel-running activity during a normal 12 h (h) baseline photoperiod and then during shifting lighting schedules (Experiment 1) or a shortened circadian day (Experiment 2). RESULTS: In Experiment 1, altered lighting produced a persistent increase in adolescent alcohol intake and in binge-like drinking (drinking at least 5 licks per minute, with no more than a 1 min break in drinking) in adulthood, but only a transient increase in total alcohol intake for the first week after alcohol was reintroduced in adulthood. In Experiment 2, the circadian shift produced a significant increase in alcohol intake in both adolescence and adulthood. Molecular analysis demonstrated changes in plasma corticosterone and neuronal markers of stress and addiction at the conclusion of these experiments in the CD and alcohol-exposed groups. CONCLUSIONS: Thus, we conclude that circadian stress during adolescence is sufficient to produce a long-lasting susceptibility to alcohol use.

DISC1 and reelin interact to alter cognition, inhibition, and neurogenesis in a novel mouse model of schizophrenia.

The etiology of schizophrenia (SCZ) is multifactorial, and depending on a host of genetic and environmental factors. Two putative SCZ susceptibility genes, Disrupted-in-Schizophrenia-1 (DISC1) and reelin (RELN), interact at a molecular level, suggesting that combined disruption of both may lead to an intensified SCZ phenotype. To examine this gene-gene interaction, we produced a double mutant mouse line. Mice with heterozygous RELN haploinsufficiency were crossed with mice expressing dominant-negative c-terminal truncated human DISC1 to produce offspring with both mutations (HRM/DISC1 mice). We used an array of behavioral tests to generate a behavioral phenotype for these mice, then examined the prefrontal cortex and hippocampus using western blotting and immunohistochemistry to probe for SCZ-relevant molecular and cellular alterations. Compared to wild-type controls, HRM/DISC1 mice demonstrated impaired pre-pulse inhibition, altered cognition, and decreased activity. Diazepam failed to rescue anxiety-like behaviors, paradoxically increasing activity in HRM/DISC1 mice. At a cellular level, we found increased α1-subunit containing GABA receptors in the prefrontal cortex, and a reduction in fast-spiking parvalbumin positive neurons. Maturation of adult-born neurons in the hippocampus was also altered in HRM/DISC1 mice. While there was no difference in the total number proliferating cells, more of these cells were in immature stages of development. Homozygous DISC1 mutation combined with RELN haploinsufficiency produces a complex phenotype with neuropsychiatric characteristics relevant to SCZ and related disorders, expanding our understanding of how multiple genetic susceptibility factors might interact to influence the variable presentation of these disorders.

Inhibition of casein kinase 1 δ/ε improves cognitive performance in adult C57BL/6J mice.

Time-of-day effects have been noted in a wide variety of cognitive behavioral tests, and perturbation of the circadian system, either at the level of the master clock in the SCN or downstream, impairs hippocampus-dependent learning and memory. A number of kinases, including the serine-threonine casein kinase 1 (CK1) isoforms CK1δ/ε, regulate the timing of the circadian period through post-translational modification of clock proteins. Modulation of these circadian kinases presents a novel treatment direction for cognitive deficits through circadian modulation. Here, we tested the potential for PF-670462, a small molecule inhibitor of CK1δ/ε, to improve cognitive performance in C57BL/6J mice in an array of behavioral tests. Compared to vehicle-treated mice tested at the same time of the circadian day, mice treated with PF-670462 displayed better recall of contextual fear conditioning, made fewer working memory errors in the radial arm water maze, and trained more efficiently in the Morris Water Maze. These benefits were accompanied by increased expression of activity-regulated cytoskeleton-associated protein (Arc) in the amygdala in response to an acute learning paradigm. Our results suggest the potential utility of CK1δ/ε inhibition in improving time-of-day cognitive performance.

Updating the UK competence framework for orthopaedic and trauma nurses 2019.

The updated RCN Competence Framework for orthopaedic and trauma practitioners was published in 2019 following completion of a 2 year project undertaken by a working group of representatives from England, Northern Ireland, Scotland and Wales. Expert musculoskeletal practitioners, including an allied health professional and working across the lifespan in varying domains of orthopaedic and trauma practice, collaborated to produce a working document applicable to trauma and orthopaedic (T&O) practitioners from all NHS (UK) pay bands. The 2019 document builds on the original and subsequent versions (2005 and 2012), importing new evidence and reformatting it so that it is contemporary and easily cross referenced with the NMC Code (2018). The restructure includes an example of a learning contract demonstrating how the framework can be applied in practice, whether for self-learning, or in conjunction with the revalidation process. This paper reflects on and describes the process undertaken by the working group in the development and restructuring of the 2019 framework, including its evaluation to date and planned in the future.

Making an "Attitude Adjustment": Using a Simulation-Enhanced Interprofessional Education Strategy to Improve Attitudes Toward Teamwork and Communication.

INTRODUCTION: Health care providers must effectively function in highly skilled teams in a collaborative manner, but there are few interprofessional training strategies in place. Interprofessional education (IPE) using simulation technology has gained popularity to address this need because of its inherent ability to impact learners' cognitive frames and promote peer-to-peer dialog. Provider attitudes toward teamwork have been directly linked to the quality of patient care. Investigators implemented a simulation-enhanced IPE intervention to improve staff attitudes toward teamwork and interprofessional communication in the emergency department setting. METHODS: The 3-hour course consisted of a didactic session highlighting teamwork and communication strategies, 2 simulation scenarios on septic shock and cardiac arrest, and structured debriefing directed at impacting participant attitudes to teamwork and communication. This was a survey-based observational study. We used the TeamSTEPPS Teamwork Attitudes Questionnaire immediately before and after the session as a measurement of attitude change as well as the Hospital Survey on Patient Safety Culture before the session and 1 year after the intervention for program impact at the behavior level. RESULTS: Seventy-two emergency department nurses and resident physicians participated in the course from July to September 2012. Of the 5 constructs in TeamSTEPPS Teamwork Attitudes Questionnaire, 4 had a significant improvement in scores-6.4%, 2.8%, 4.0%, and 4.0% for team structure, leadership, situation monitoring, and mutual support, respectively (P < 0.0001, P = 0.029, P = 0.014, and P = 0.003, respectively). For Hospital Survey on Patient Safety Culture, 3 of 6 composites directly related to teamwork and communication showed a significant improvement-20.6%, 20.5%, and 23.9%, for frequency of event reporting, teamwork within hospital units, and hospital handoffs and transitions, respectively (P = 0.028, P = 0.035, and P = 0.024, respectively). CONCLUSIONS: A simulation-enhanced IPE curriculum was successful in improving participant attitudes toward teamwork and components of patient safety culture related to teamwork and communication.

Deciphering peripheral nerve myelination by using Schwann cell expression profiling.

Although mutations in multiple genes are associated with inherited demyelinating neuropathies, the molecular components and pathways crucial for myelination remain largely unknown. To approach this question, we performed genome-wide expression analysis in several paradigms where the status of peripheral nerve myelination is dynamically changing. Anchor gene correlation analysis, a form of microarray analysis that integrates functional information, using correlation-based clustering, with a statistically rigorous test, the Westfall and Young step-down algorithm, was applied to this data set. Biological pathways active in myelination, genes encoding proteins involved in myelin synthesis, and genes whose mutation results in myelination defects were identified. Many known genes and previously uncharacterized ESTs not heretofore associated with myelination were also identified. One of these ESTs, MASR (myelin-associated SUR4 protein), encodes a member of the SUR4 family of fatty acid desaturases, enzymes involved in elongation of very long chain fatty acids. Its specific localization in myelinating Schwann cells indicates a crucial role for MASR in normal myelin lipid synthesis.