The estrous cycle modulates early-life adversity effects on mouse avoidance behavior through progesterone signaling.

Early-life adversity (ELA) increases the likelihood of neuropsychiatric diagnoses, which are more prevalent in women than men. Since changes in reproductive hormone levels can also increase the probability of anxiety disorders in women, we examined the effects of ELA on adult female mice across the estrous cycle. We found that during diestrus, when progesterone levels are relatively high, ELA mice exhibit increased avoidance behavior and increased theta oscillation power in the ventral hippocampus (vHIP). We also found that diestrus ELA mice had higher levels of progesterone and lower levels of allopregnanolone, a neurosteroid metabolite of progesterone, in the vHIP compared with control-reared mice. Progesterone receptor antagonism normalized avoidance behavior in ELA mice, while treatment with a negative allosteric modulator of allopregnanolone promoted avoidance behavior in control mice. These results suggest that altered vHIP progesterone and allopregnanolone signaling during diestrus increases avoidance behavior in ELA mice.

PlexinA4-Semaphorin3A-mediated crosstalk between main cortical interneuron classes is required for superficial interneuron lamination.

In the mammalian cerebral cortex, the developmental events governing allocation of different classes of inhibitory interneurons (INs) to distinct cortical layers are poorly understood. Here we report that the guidance receptor PlexinA4 (PLXNA4) is upregulated in serotonin receptor 3a-expressing (HTR3A+) cortical INs (hINs) as they invade the cortical plate, and that it regulates their laminar allocation to superficial cortical layers. We find that the PLXNA4 ligand Semaphorin3A (SEMA3A) acts as a chemorepulsive factor on hINs migrating into the nascent cortex and demonstrate that SEMA3A specifically controls their laminar positioning through PLXNA4. We identify deep-layer INs as a major source of SEMA3A in the developing cortex and demonstrate that targeted genetic deletion of Sema3a in these INs specifically affects laminar allocation of hINs. These data show that, in the neocortex, deep-layer INs control laminar allocation of hINs into superficial layers.

How Early Life Adversity Influences Defensive Circuitry.

Childhood maltreatment increases the likelihood of developing anxiety disorders in humans. Early life adversity (ELA) paradigms in rodents produce lasting increases in avoidant and inhibitory responses to both immediate and nonspecific threats, collectively referred to as defensive behaviors. This approach provides an opportunity to thoroughly investigate the underlying mechanisms, an effort that is currently under way. In this review, we consider the growing literature indicating that ELA alters the rhythmic firing of neurons in brain regions associated with defensive behavior, as well as potential neuronal, glial, and extracellular matrix contributions to functional changes in this circuitry. We also consider how ELA studies in rodents may inform us about both susceptible and resilient outcomes in humans.

Perineuronal Nets, Inhibitory Interneurons, and Anxiety-Related Ventral Hippocampal Neuronal Oscillations Are Altered by Early Life Adversity.

BACKGROUND: In humans, accumulated adverse experiences during childhood increase the risk of anxiety disorders and attention-deficit/hyperactivity disorder. In rodents, the ventral hippocampus (vHIP) is associated with anxiety regulation, and lesions in this region alter both anxiety-like behavior and activity levels. Neuronal oscillations in the vHIP of the theta frequency range (4-12 Hz) have been implicated in anxious states and derive in part from the activity of inhibitory interneurons in the hippocampus, some of which are enwrapped with perineuronal nets (PNNs), extracellular matrix structures known to regulate plasticity. We sought to investigate the associations among early life stress-induced anxiety and hyperactivity with vHIP neuronal oscillations, inhibitory interneurons, and PNNs in mice. METHODS: We used repeated maternal separation with early weaning (MSEW) to model accumulated early life adversity in mouse offspring and studied the underlying cellular and electrophysiological changes in the vHIP that are associated with excessive anxiety and hyperactivity. RESULTS: We found increased anxiety-like behavior and activity levels in MSEW adult males, along with increased theta power and enhanced theta-gamma coupling in the vHIP. MSEW mice showed reduced intensity of parvalbumin as well as increased PNN intensity around parvalbumin-positive interneurons in the vHIP. We further observed that MSEW increased orthodenticle homeobox protein 2, a transcription factor promoting PNN development, in the choroid plexus, where it is produced, as well as in parvalbumin-positive interneurons, where it is sequestered. CONCLUSIONS: These findings raise the possibility of causal links among parvalbumin-positive interneurons, PNNs, orthodenticle homeobox protein 2, and MSEW-induced anxiety and hyperactivity.

The effects of living in an outdoor enclosure on hippocampal plasticity and anxiety-like behavior in response to nematode infection.

The hippocampus of rodents undergoes structural remodeling throughout adulthood, including the addition of new neurons. Adult neurogenesis is sensitive to environmental enrichment and stress. Microglia, the brain's resident immune cells, are involved in adult neurogenesis by engulfing dying new neurons. While previous studies using laboratory environmental enrichment have investigated alterations in brain structure and function, they do not provide an adequate reflection of living in the wild, in which stress and environmental instability are common. Here, we compared mice living in standard laboratory settings to mice living in outdoor enclosures to assess the complex interactions among environment, gut infection, and hippocampal plasticity. We infected mice with parasitic worms and studied their effects on adult neurogenesis, microglia, and functions associated with the hippocampus, including cognition and anxiety regulation. We found an increase in immature neuron numbers of mice living in outdoor enclosures regardless of infection. While outdoor living prevented increases in microglial reactivity induced by infection in both the dorsal and ventral hippocampus, outdoor mice with infection had fewer microglia and microglial processes in the ventral hippocampus. We observed no differences in cognitive performance on the hippocampus-dependent object location task between infected and uninfected mice living in either setting. However, we found that infection caused an increase in anxiety-like behavior in the open field test but only in outdoor mice. These findings suggest that living conditions, as well as gut infection, interact to produce complex effects on brain structure and function.

MEttLE: a modelling-based learning environment for undergraduate engineering estimation problem solving.

Estimation is an important class of problems that engineering undergraduates must be able to solve. However teaching-learning of estimation is under emphasized in the current engineering curriculum. In this paper, we report on the first cycle of a design-based research project to design a technology-enhanced learning environment (TELE) to help students learn estimation. The TELE includes features such as a progressive higher-order modelling-based structuring of the estimation process, a problem system simulator and metacognitive scaffolds. We performed a lab study and found that learners were able to use the features in the TELE to solve the estimation problem and obtain an order-of-magnitude estimate. Further, learners learned some of the reasoning processes involved in performing estimation and recognized the role of evaluation and the need for practical considerations in estimation. We identified the roles of various features in the TELE for learning these estimation reasoning processes. These results have implications for the redesign of our TELE to improve student learning of estimation.

MIC-O-MAP: a technology-enhanced learning environment for developing micro-macro thinking skills.

MIC-O-MAP (MICroscopic-Observations-Macroscopic-Predictions) is a technology-enhanced learning (TEL) environment designed for developing micro-macro thinking skills among science and engineering undergraduate students. Micro-macro thinking involves being able to analyze dynamic processes and interactions on a microscopic level and establish co-relations to the outcomes which we can see and measure in the macroscopic world. In this paper, we report 2 cycles of iterative design, development, and evaluation of MIC-O-MAP, based on a design-based research approach. We first identify the pedagogical design features and learning activities of MIC-O-MAP based on a literature review of the development of micro-macro thinking. We then report an experimental study, which showed positive results that the design features and learning activities of MIC-O-MAP helped students develop micro-macro thinking. This was followed by a detailed interaction analysis, which provided insights into the redesign of MIC-O-MAP. An evaluation of the revised version of MIC-O-MAP showed that the shortcomings of the original version were addressed. The interaction analysis also led us to identify effective actions and learning paths as students learn in interactive TEL environments.

Designing Reciprocative Dynamic Linking to improve learners' Representational Competence in interactive learning environments.

Learning from interactive learning environments enriched with multiple external representations (MERs) is often beneficial. The learning benefits of MERs highly rely on the development of Representational Competence. Representational Competence refers to an ability to translate and see relations between MERs. The relevant research findings have consistently reported learners' difficulty in relating and translating in MERs due to insufficient development of Representational Competence. Although dynamic linking is one of the strategies recommended to address this issue, it offers mixed results. This paper reports design of a new interaction feature that overcomes some of the limitations of traditional dynamically linked representations. We designed an additional interaction in dynamically linked MERs to support learners' cognitive demands; we refer to this as Reciprocative Dynamic Linking. The goal of this additional affordance was to strengthen learners' cross-representation cognitive linkage by promoting Representational Competence. The paper reports the study conducted to investigate effects of Reciprocative Dynamic Linking on students' Representational Competence. The said study was conducted in a course on Signals and Systems from Electrical Engineering program (N = 24). The subjects were assigned to two conditions: a Simulation and a Simulation with Reciprocative Dynamic Linking. The representation competence was assessed with an instrument for measuring Representational Competence within Signals and Systems domain. The effect of Reciprocative Dynamic Linking on learners' cognitive load was also investigated. The results confirmed that Reciprocative Dynamic Linking could lead to improvement in Representational Competence and thus, higher learning for "Apply and Analyze Procedural knowledge" categories of tasks. Reciprocative Dynamic Linking also promoted germane cognitive load of learners, as it could offer the required cognitive support to improve learners' Representational Competence. The findings from semi-structured interviews and screen capture analysis corroborated the results. This paper provides details of how to design Reciprocative Dynamic Linking in interactive learning environments and its effect on learners' Representational Competence. Apart from establishing learning effectiveness of Reciprocative Dynamic Linking, the study further contributes by confirming the role of cognitive processing of learners while learning from interactive learning environments. The findings from the study suggest designing strategies not for just creating highly interactive learning environments but equipping a given learning environment with conducive interaction features that foster learning.

Technical Challenges and Opportunities when Implementing Pharmacogenomics Decision Support Integrated in the Electronic Health Record.

Clinical use of pharmacogenomic (PGx) knowledge at the bedside is new and complex. Our program has implemented multiple PGx-CDS interventions in different clinical settings and in multiple commercial EHRs. Herein, we discuss lessons learned and propose general technical guidelines related to PGx implementation.

Effect of active learning using program visualization in technology-constrained college classrooms.

Multiple studies report that Computer Science (CS) instructors face problems on how to integrate visualizations in their teaching. This problem gets compounded for instructors in technology-constrained classrooms that are common in developing countries. In these classrooms, students are not able to interact with visualization directly; instead, their interaction is mediated by the instructor who alone may have access to the visualization. In the current study, we contrasted learning outcome from integrating program visualization at two different engagement levels in instructor-mediated classroom setting. The two levels were "Responding" (prediction activity with visualization) and "Viewing" (watching visualization with instructor commentary) as per Naps' taxonomy. The study was conducted for a programming topic of medium complexity. We found the strategy of prediction with visualization ("Responding") led to statistically significant higher active behavioral engagement and higher perception of learning among students than the strategy of watching the visualization with instructor commentary ("Viewing"). We also found statistically significant higher cognitive achievement in terms of the rate of problem solving for the "Responding" group, if the students had prior training in active learning. This study can serve as a reference guide to design effective integration of visualizations in instructor-mediated classrooms.

Serotonin receptor 3A controls interneuron migration into the neocortex.

Neuronal excitability has been shown to control the migration and cortical integration of reelin-expressing cortical interneurons (INs) arising from the caudal ganglionic eminence (CGE), supporting the possibility that neurotransmitters could regulate this process. Here we show that the ionotropic serotonin receptor 3A (5-HT(3A)R) is specifically expressed in CGE-derived migrating interneurons and upregulated while they invade the developing cortex. Functional investigations using calcium imaging, electrophysiological recordings and migration assays indicate that CGE-derived INs increase their response to 5-HT(3A)R activation during the late phase of cortical plate invasion. Using genetic loss-of-function approaches and in vivo grafts, we further demonstrate that the 5-HT(3A)R is cell autonomously required for the migration and proper positioning of reelin-expressing CGE-derived INs in the neocortex. Our findings reveal a requirement for a serotonin receptor in controlling the migration and laminar positioning of a specific subtype of cortical IN.

Retinal input directs the recruitment of inhibitory interneurons into thalamic visual circuits.

Inhibitory interneurons (INs) critically control the excitability and plasticity of neuronal networks, but whether activity can direct INs into specific circuits during development is unknown. Here, we report that in the dorsal lateral geniculate nucleus (dLGN), which relays retinal input to the cortex, circuit activity is required for the migration, molecular differentiation, and functional integration of INs. We first characterize the prenatal origin and molecular identity of dLGN INs, revealing their recruitment from an Otx2(+) neuronal pool located in the adjacent ventral LGN. Using time-lapse and electrophysiological recordings, together with genetic and pharmacological perturbation of retinal waves, we show that retinal activity directs the navigation and circuit incorporation of dLGN INs during the first postnatal week, thereby regulating the inhibition of thalamocortical circuits. These findings identify an input-dependent mechanism regulating IN migration and circuit inhibition, which may account for the progressive recruitment of INs into expanding excitatory circuits during evolution.

Alpha2-adrenergic receptor activation regulates cortical interneuron migration.

Monoamines such as serotonin and dopamine have been shown to regulate cortical interneuron migration but very little is known regarding noradrenaline. Similarly to other monoamines, noradrenaline is detected during embryonic cortical development and adrenergic receptors are expressed in transient embryonic zones of the pallium that contain migrating neurons. Evidence of a functional role for the adrenergic system in interneuron migration is lacking. In this study we first investigated the expression pattern of adrenergic receptors in mouse cortical interneuron subtypes preferentially derived from the caudal ganglionic eminences, and found that they expressed different subtypes of adrenergic receptors. To directly monitor the effects of adrenergic receptor stimulation on interneuron migration we used time-lapse recordings in cortical slices and observed that alpha2 adrenergic receptors (adra2) receptor activation inhibits the migration of cortical interneurons in a concentration-dependent and reversible manner. Furthermore, we observed that following adra2 activation the directionality of migrating interneurons was significantly modified, suggesting that adra2 stimulation could modulate their responsiveness to guidance cues. Finally the distribution of cortical interneurons was altered in vivo in adra2a/2c-knockout mice. These results support the general hypothesis that adrenergic dysregulation occurring during embryonic development alters cellular processes involved in the formation of cortical circuits.

Modeling and executing electronic health records driven phenotyping algorithms using the NQF Quality Data Model and JBoss® Drools Engine.

With increasing adoption of electronic health records (EHRs), the need for formal representations for EHR-driven phenotyping algorithms has been recognized for some time. The recently proposed Quality Data Model from the National Quality Forum (NQF) provides an information model and a grammar that is intended to represent data collected during routine clinical care in EHRs as well as the basic logic required to represent the algorithmic criteria for phenotype definitions. The QDM is further aligned with Meaningful Use standards to ensure that the clinical data and algorithmic criteria are represented in a consistent, unambiguous and reproducible manner. However, phenotype definitions represented in QDM, while structured, cannot be executed readily on existing EHRs. Rather, human interpretation, and subsequent implementation is a required step for this process. To address this need, the current study investigates open-source JBoss® Drools rules engine for automatic translation of QDM criteria into rules for execution over EHR data. In particular, using Apache Foundation's Unstructured Information Management Architecture (UIMA) platform, we developed a translator tool for converting QDM defined phenotyping algorithm criteria into executable Drools rules scripts, and demonstrated their execution on real patient data from Mayo Clinic to identify cases for Coronary Artery Disease and Diabetes. To the best of our knowledge, this is the first study illustrating a framework and an approach for executing phenotyping criteria modeled in QDM using the Drools business rules management system.

Molecular changes associated with hippocampal long-lasting depression induced by the serine protease subtilisin-A.

The serine protease subtilisin-A (SubA) induces a form of long-term depression (LTD) of synaptic transmission in the rat hippocampus, and molecular changes associated with SubA-induced LTD (SubA-LTD) were explored by using recordings of evoked postsynaptic potentials and immunoblotting. SubA-LTD was prevented by a selective inhibitor of SubA proteolysis, but the same inhibitor did not affect LTD induced by electrical stimulation or activation of metabotropic glutamate receptors. SubA-LTD was reduced by the protein kinase inhibitors genistein and lavendustin A, although not by inhibitors of p38 mitogen-activated protein kinase, glycogen synthase kinase-3, or protein phosphatases. It was also reduced by (RS)-α-methyl-4-carboxyphenylglycine, a broad-spectrum antagonist at metabotropic glutamate receptors. Inhibition of the Rho kinase enzyme Rho-associated coiled-coil kinase reduced SubA-LTD, although inhibitors of the RhoGTPase-activating enzymes farnesyl transferase and geranylgeranyl transferase did not. In addition, a late phase of SubA-LTD was dependent on new protein synthesis. There was a small, non-significant difference in SubA-LTD between wild-type and RhoB(-/-) mice. Marked decreases were seen in the levels of Unc-5H3, a protein that is intimately involved in the development and plasticity of glutamatergic synapses. Smaller changes were noted, at higher concentrations of SubA, in Unc-5H1, vesicle-associated membrane protein-1 (synaptobrevin), and actin, with no changes in the levels of synaptophysin, synaptotagmin, RhoA, or RhoB. None of these changes was associated with LTD induced electrically or by the metabotropic glutamate receptor agonist (RS)-3,5-dihydroxyphenylglycine. These results indicate that SubA induces molecular changes that overlap with other forms of LTD, but that the overall molecular profile of SubA-LTD is quite different.

Compressibility divergence and the finite temperature Mott transition.

In the context of the dynamical mean-field theory (DMFT) of the Hubbard model, we study the behavior of the compressibility near the density driven Mott transition at finite temperatures. We demonstrate this divergence using DMFT and quantum Monte Carlo simulations in the one-band and the two-band Hubbard model. We supplement this result with considerations based on the Landau theory framework, and discuss the relevance of our results to the alpha-gamma end point in cerium.