Excitable neurons, firing threshold manifolds and canards

We investigate firing threshold manifolds in a mathematical model of an excitable neuron. The model analyzed investigates the phenomenon of post-inhibitory rebound spiking due to propofol anesthesia and is adapted from McCarthy et al. (SIAM J. Appl. Dyn. Syst. 11(4):1674-1697, 2012). Propofol modulates the decay time-scale of an inhibitory GABAa synaptic current. Interestingly, this system gives rise to rebound spiking within a specific range of propofol doses. Using techniques from geometric singular perturbation theory, we identify geometric structures, known as canards of folded saddle-type, which form the firing threshold manifolds. We find that the position and orientation of the canard separatrix is propofol dependent. Thus, the speeds of relevant slow synaptic processes are encoded within this geometric structure. We show that this behavior cannot be understood using a static, inhibitory current step protocol, which can provide a single threshold for rebound spiking but cannot explain the observed cessation of spiking for higher propofol doses. We then compare the analyses of dynamic and static synaptic inhibition, showing how the firing threshold manifolds of each relate, and why a current step approach is unable to fully capture the behavior of this model

Striatal cholinergic interneurons generate beta and gamma oscillations in the corticostriatal circuit and produce motor deficits

Cortico-basal ganglia-thalamic (CBT) neural circuits are critical modulators of cognitive and motor function. When compromised, these circuits contribute to neurological and psychiatric disorders, such as Parkinson's disease (PD). In PD, motor deficits correlate with the emergence of exaggerated beta frequency (15-30 Hz) oscillations throughout the CBT network. However, little is known about how specific cell types within individual CBT brain regions support the generation, propagation, and interaction of oscillatory dynamics throughout the CBT circuit or how specific oscillatory dynamics are related to motor function. Here, we investigated the role of striatal cholinergic interneurons (SChIs) in generating beta and gamma oscillations in cortical-striatal circuits and in influencing movement behavior. We found that selective stimulation of SChIs via optogenetics in normal mice robustly and reversibly amplified beta and gamma oscillations that are supported by distinct mechanisms within striatal-cortical circuits. Whereas beta oscillations are supported robustly in the striatum and all layers of primary motor cortex (M1) through a muscarinic-receptor mediated mechanism, gamma oscillations are largely restricted to the striatum and the deeper layers of M1. Finally, SChI activation led to parkinsonian-like motor deficits in otherwise normal mice. These results highlight the important role of striatal cholinergic interneurons in supporting oscillations in the CBT network that are closely related to movement and parkinsonian motor symptoms.DP2 NS082126 - NINDS NIH HHS; R01 NS081716 - NINDS NIH HHS; R21 NS078660 - NINDS NIH HHShttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896681/Published versio

Neurosystems: brain rhythms and cognitive processing

Neuronal rhythms are ubiquitous features of brain dynamics, and are highly correlated with cognitive processing. However, the relationship between the physiological mechanisms producing these rhythms and the functions associated with the rhythms remains mysterious. This article investigates the contributions of rhythms to basic cognitive computations (such as filtering signals by coherence and/or frequency) and to major cognitive functions (such as attention and multi-modal coordination). We offer support to the premise that the physiology underlying brain rhythms plays an essential role in how these rhythms facilitate some cognitive operations.098352 - Wellcome Trust; 5R01NS067199 - NINDS NIH HH

The path to fracture in granular flows: dynamics of contact networks

Capturing the dynamics of granular flows at intermediate length scales can often be difficult. We propose studying the dynamics of contact networks as a new tool to study fracture at intermediate scales. Using experimental three-dimensional flow fields with particle-scale resolution, we calculate the time evolving broken-links network and find that a giant component of this network is formed as shear is applied to this system. We implement a model of link breakages where the probability of a link breaking is proportional to the average rate of longitudinal strain (elongation) in the direction of the edge and find that the model demonstrates qualitative agreement with the data when studying the onset of the giant component. We note, however, that the broken-links network formed in the model is less clustered than our experimental observations, indicating that the model reflects less localized breakage events and does not fully capture the dynamics of the granular flow.Comment: 15 pages, 6 figures, accepted for publication in Phys. Rev.

#MeToo in EM: A Multicenter Survey of Academic Emergency Medicine Faculty on Their Experiences with Gender Discrimination and Sexual Harassment

Introduction: Gender-based discrimination and sexual harassment of female physicians are well documented. The #MeToo movement has brought renewed attention to these problems. This study examined academic emergency physicians’ experiences with workplace gender discrimination and sexual harassment.Methods: We conducted a cross-sectional survey of a convenience sample of emergency medicine (EM) faculty across six programs. Survey items included the following: the Overt Gender Discrimination at Work (OGDW) Scale; the frequency and source of experienced and observed discrimination; and whether subjects had encountered unwanted sexual behaviors by a work superior or colleague in their careers. For the latter question, we asked subjects to characterize the behaviors and whether those experiences had a negative effect on their self-confidence and career advancement. We made group comparisons using t-tests or chi-square analyses, and evaluated relationships between gender and physicians’ experiences using correlation analyses.Results: A total of 141 out of 352 (40.1%) subjects completed at least a portion of the survey. Women reported higher mean OGDW scores than men (15.4 vs 10.2; 95% confidence interval [CI], 3.6–6.8). Female faculty were also more likely to report having experienced gender-based discriminatory treatment than male faculty (62.7% vs 12.5%; 95% CI, 35.1%-65.4%), although male and female faculty were equally likely to report having observed gender-based discriminatory treatment of another physician (64.7% vs 56.3%; 95% CI, 8.6%-25.5%). The three most frequent sources of experienced or observed gender-based discriminatory treatment were patients, consulting or admitting physicians, and nursing staff. The majority of women reported having encountered unwanted sexual behaviors in their careers, with a significantly greater proportion of women reporting them compared to men (52.9% vs 26.2%, 95% CI, 9.9%-43.4%). The majority of unwanted behaviors were sexist remarks and sexual advances. Of those respondents who encountered these unwanted behaviors, 22.9% and 12.5% reported at least somewhat negative effects on their self-confidence and career advancement.Conclusion: Female EM faculty perceived more gender-based discrimination in their workplaces than their male counterparts. The majority of female and approximately a quarter of male EM faculty encountered unwanted sexual behaviors in their careers.

“All I wanted was a happy life”: the struggles of women with learning disabilities to raise their children whilst also experiencing domestic violence

Women with learning disabilities are especially vulnerable to domestic violence from partners. The lives of mothers with learning disabilities who experience domestic violence are very challenging. This in-depth qualitative study of 6 mothers with learning disabilities in the UK uses interpretative phenomenological analysis to explore the impact of domestic violence on the women and children. The women reported violent conceptions and violent pregnancies, perpetrators sabotaging the mother-child bond, living with a broad spectrum of abuse and their feelings about having their children removed from their care. Recommendations are made for professional and informal support of these women

An Allosteric Inhibitor of KRas Identified Using a Barcoded Rapid Assay Microchip Platform

Protein catalyzed capture agents (PCCs) are synthetic antibody surrogates that can target a wide variety of biologically relevant proteins. As a step toward developing a high-throughput PCC pipeline, we report on the preparation of a barcoded rapid assay platform for the analysis of hits from PCC library screens. The platform is constructed by first surface patterning a micrometer scale barcode composed of orthogonal ssDNA strands onto a glass slide. The slide is then partitioned into microwells, each of which contains multiple copies of the full barcode. Biotinylated candidate PCCs from a click screen are assembled onto the barcode stripes using a complementary ssDNA-encoded cysteine-modified streptavidin library. This platform was employed to evaluate candidate PCC ligands identified from an epitope targeted in situ click screen against the two conserved allosteric switch regions of the Kirsten rat sarcoma (KRas) protein. A single microchip was utilized for the simultaneous evaluation of 15 PCC candidate fractions under more than a dozen different assay conditions. The platform also permitted more than a 10-fold savings in time and a more than 100-fold reduction in biological and chemical reagents relative to traditional multiwell plate assays. The best ligand was shown to exhibit an in vitro inhibition constant (IC_(50)) of ∼24 μM

The teacher as double agent: performative compliance, allegiance and survival in the contemporary classroom

In a context of increasing complexity and with serious challenges facing contemporary schooling, teachers regularly make strategic decisions about how they engage with policy reforms and system mandates. In this paper, we deploy the notion of the teacher as a ‘double agent’. The double agent is required to performatively demonstrate allegiance to education policies and practices, which sometimes sit at odds with the teacher’s professional commitment and responsibility to students. The teacher as double agent is produced through the contradictions of subjectivity, which are always present in the enactment of teacher agency. The reflective accounts from Australian teachers shared in this paper illustrate how their enactment of double agency can be deployed as an important survival strategy, which enables them to meet the policy demands of schooling systems, while also meaningfully engaging in curriculum and relational work with the students in their care. However, the tactics of compliance, allegiance and survival used by teachers also comes at a professional and personal cost, which need to be countered by more responsive and supportive education policy reforms