Perspectives on a virtual student-led research conference in ophthalmology.

We share our experience of organizing a one-day virtual educational event, the first Canadian national student ophthalmology conference, in response to the need for ophthalmology career exploration. The conference included mentorship with residents, research presentations, keynote speakers, and more. Following the event, students expressed some improvement in accessing ophthalmology mentorship and research opportunities, along with a modest enhancement in their understanding of the specialty. We provide insights into the organizational framework and quality improvement results, aiming to assist students in adapting similar events for various specialities.

Nous partageons notre expérience portant sur l'organisation d'un événement éducatif virtuel d'une journée: la première conférence nationale canadienne des étudiants en ophtalmologie. Cette initiative a été prise en réponse au besoin d'exploration des carrières en ophtalmologie. La conférence comprenait des séances de mentorat avec des résidents, des présentations de recherche, des conférenciers d'honneur, entre autres. Suite à cet événement, les étudiants ont exprimé une amélioration dans l'accès au mentorat et aux opportunités de recherche en ophtalmologie, ainsi qu'une modeste amélioration de leur compréhension de la spécialité. Nous offrons un aperçu du cadre organisationnel et des résultats de l'amélioration de la qualité, dans le but d'aider d'autres étudiants à organiser des événements similaires pour diverses spécialités.

Inhibitory neurons: VIP neurons expect rewards.

Inhibitory neurons which express vasoactive intestinal polypeptide, VIPs, are a small subset of the mammalian cortex but in importance live up to their acronym. New research shows that these critical control knobs of cortical activity are specifically activated by actions taken when rewards are anticipated rather than consummated.

The influence of recovery period following a pre-load stimulus on physical performance measures in handball players.

The purpose of this research was to establish the optimal recovery duration following a pre-load stimulus on performance measures related to handball players. Seventeen senior male University handball players (mean ± SD: age 23.6 ± 2.3 yrs., height 1.79 ± 0.06 m and body mass 72.5 ± 10.7 kg) performed three experimental sessions. All sessions consisted of a standardised warm-up followed by a pre-load stimulus (HSR) back squats followed by a passive rest for either 4-min (PAP4), 8-min (PAP8), or 12-min (PAP12). Following the completion of the passive recovery, players then performed a countermovement jump (CMJ), a 20-m linear sprint and a modified agility t-test. The significance level was set at P < 0.05. There was a significant main effect of passive rest duration after the pre-load stimulus. The PAP12 condition improved CMJ scores (2.3-2.6%; effect size = small), 20-m linear sprint times (3.3-3.7%; effect size = small to moderate) and agility times (1.6-1.9%; effect size = trivial) compared to PAP4 and PAP8 conditions (P < 0.0005). Values of heart rate and rating of perceived exertion were also significantly lower during the PAP12 condition compared to the PAP4 and PAP8 conditions (P < 0.0005). A positive Pearson correlation was established between agility and CMJ for all conditions (P < 0.001). The findings provide novel data observing that a pre-load stimulus, followed by 12-min of recovery, results in greater maximal jump, sprint and agility measures when compared with a 4-min or 8-min recovery in male handball players.

Race, ethnicity, poverty and the social determinants of the coronavirus divide: U.S. county-level disparities and risk factors.

BACKGROUND: Communities with more Black or Hispanic residents have higher coronavirus rates than communities with more White residents, but relevant community characteristics are underexplored. The purpose of this study was to investigate poverty-, race- and ethnic-based disparities and associated economic, housing, transit, population health and health care characteristics. METHODS: Six-month cumulative coronavirus incidence and mortality were examined using adjusted negative binomial models among all U.S. counties (n = 3142). County-level independent variables included percentages in poverty and within racial/ethnic groups (Black, Hispanic, Native American, Asian), and rates of unemployment, lacking a high school diploma, housing cost burden, single parent households, limited English proficiency, diabetes, obesity, smoking, uninsured, preventable hospitalizations, primary care physicians, hospitals, ICU beds and households that were crowded, in multi-unit buildings or without a vehicle. RESULTS: Counties with higher percentages of Black (IRR = 1.03, 95% CI: 1.02-1.03) or Hispanic (IRR = 1.02, 95% CI: 1.01-1.03) residents had more coronavirus cases. Counties with higher percentages of Black (IRR = 1.02, 95% CI: 1.02-1.03) or Native American (IRR = 1.02, 95% CI: 1.01-1.04) residents had more deaths. Higher rates of lacking a high school diploma was associated with higher counts of cases (IRR = 1.03, 95% CI: 1.01-1.05) and deaths (IRR = 1.04, 95% CI: 1.01-1.07). Higher percentages of multi-unit households were associated with higher (IRR = 1.02, 95% CI: 1.01-1.04) and unemployment with lower (IRR = 0.96, 95% CI: 0.94-0.98) incidence. Higher percentages of individuals with limited English proficiency (IRR = 1.09, 95% CI: 1.04-1.14) and households without a vehicle (IRR = 1.04, 95% CI: 1.01-1.07) were associated with more deaths. CONCLUSIONS: These results document differential pandemic impact in counties with more residents who are Black, Hispanic or Native American, highlighting the roles of residential racial segregation and other forms of discrimination. Factors including economic opportunities, occupational risk, public transit and housing conditions should be addressed in pandemic-related public health strategies to mitigate disparities across counties for the current pandemic and future population health events.

Ophthalmology training in sub-Saharan Africa: a scoping review.

Sub-Saharan Africa is home to 12% of the global population, and 4.3 million are blind and over 15 million are visually impaired. There are only 2.5 ophthalmologists per million people in SSA. Training of ophthalmologists is critical. We designed a systematic literature review protocol, searched MEDLINE Ovid and Embase OVID on 1 August 2019 and limited these searches to the year 2000 onwards. We also searched Google Scholar and websites of ophthalmic institutions for additional information. We include a total of 49 references in this review and used a narrative approach to synthesise the results. There are 56 training institutions for ophthalmologists in eleven Anglophone, eleven Francophone, and two Lusophone SSA countries. The median duration of ophthalmology training programmes was 4 years. Most curricula have been regionally standardised. National, regional and international collaborations are a key feature to ophthalmology training in more than half of ophthalmology training programmes. There is a drive, although perhaps not always evidence-based, for sub-specialisation in the region. Available published scientific data on ophthalmic medical and surgical training in SSA is sparse, especially for Francophone and Lusophone countries. However, through a broad scoping review strategy it has been possible to obtain a valuable and detailed view of ophthalmology training in SSA. Training of ophthalmologists is a complex and multi-faceted task. There are challenges in appropriate selection, capacity, and funding of available training institutions. Numerous learning outcomes demand curriculum, time, faculty, support, and appropriate assessment. There are opportunities provided by modern training approaches. Partnership is key.

Independent representations of self-motion and object location in barrel cortex output.

During active tactile exploration, the dynamic patterns of touch are transduced to electrical signals and transformed by the brain into a mental representation of the object under investigation. This transformation from sensation to perception is thought to be a major function of the mammalian cortex. In primary somatosensory cortex (S1) of mice, layer 5 (L5) pyramidal neurons are major outputs to downstream areas that influence perception, decision-making, and motor control. We investigated self-motion and touch representations in L5 of S1 with juxtacellular loose-seal patch recordings of optogenetically identified excitatory neurons. We found that during rhythmic whisker movement, 54 of 115 active neurons (47%) represented self-motion. This population was significantly more modulated by whisker angle than by phase. Upon active touch, a distinct pattern of activity was evoked across L5, which represented the whisker angle at the time of touch. Object location was decodable with submillimeter precision from the touch-evoked spike counts of a randomly sampled handful of these neurons. These representations of whisker angle during self-motion and touch were independent, both in the selection of which neurons were active and in the angle-tuning preference of coactive neurons. Thus, the output of S1 transiently shifts from a representation of self-motion to an independent representation of explored object location during active touch.

Behavioral and Neural Bases of Tactile Shape Discrimination Learning in Head-Fixed Mice.

Tactile shape recognition requires the perception of object surface angles. We investigate how neural representations of object angles are constructed from sensory input and how they reorganize across learning. Head-fixed mice learned to discriminate object angles by active exploration with one whisker. Calcium imaging of layers 2-4 of the barrel cortex revealed maps of object-angle tuning before and after learning. Three-dimensional whisker tracking demonstrated that the sensory input components that best discriminate angles (vertical bending and slide distance) also have the greatest influence on object-angle tuning. Despite the high turnover in active ensemble membership across learning, the population distribution of object-angle tuning preferences remained stable. Angle tuning sharpened, but only in neurons that preferred trained angles. This was correlated with a selective increase in the influence of the most task-relevant sensory component on object-angle tuning. These results show how discrimination training enhances stimulus selectivity in the primary somatosensory cortex while maintaining perceptual stability.

Touch: Fluctuating Waves of Perception.

Does sensory input flow into the brain as a stream, or does it come in waves? New research shows that tactile information in the cortex rises and falls in phase with the forward and back motion of whiskers during surface exploration.

High-content fluorescence imaging with the metabolic flux assay reveals insights into mitochondrial properties and functions.

Metabolic flux technology with the Seahorse bioanalyzer has emerged as a standard technique in cellular metabolism studies, allowing for simultaneous kinetic measurements of respiration and glycolysis. Methods to extend the utility and versatility of the metabolic flux assay would undoubtedly have immediate and wide-reaching impacts. Herein, we describe a platform that couples the metabolic flux assay with high-content fluorescence imaging to simultaneously provide means for normalization of respiration data with cell number; analyze cell cycle distribution; and quantify mitochondrial content, fragmentation state, membrane potential, and mitochondrial reactive oxygen species. Integration of fluorescent dyes directly into the metabolic flux assay generates a more complete data set of mitochondrial features in a single assay. Moreover, application of this integrated strategy revealed insights into mitochondrial function following PGC1a and PRC1 inhibition in pancreatic cancer and demonstrated how the Rho-GTPases impact mitochondrial dynamics in breast cancer.

The Sensorimotor Basis of Whisker-Guided Anteroposterior Object Localization in Head-Fixed Mice.

Active tactile perception combines directed motion with sensory signals to generate mental representations of objects in space. Competing models exist for how mice use these signals to determine the precise location of objects along their face. We tested six of these models using behavioral manipulations and statistical learning in head-fixed mice. Trained mice used a whisker to locate a pole in a continuous range of locations along the anteroposterior axis. Mice discriminated locations to ≤0.5 mm (<2°) resolution. Their motor program was noisy, adaptive to touch, and directed to the rewarded range. This exploration produced several sets of sensorimotor features that could discriminate location. Integration of two features, touch count and whisking midpoint at touch, was the simplest model that explained behavior best. These results show how mice locate objects at hyperacute resolution using a learned motor strategy and minimal set of mentally accessible sensorimotor features.

Central nicotine induces browning through hypothalamic κ opioid receptor.

Increased body weight is a major factor that interferes with smoking cessation. Nicotine, the main bioactive compound in tobacco, has been demonstrated to have an impact on energy balance, since it affects both feeding and energy expenditure at the central level. Among the central actions of nicotine on body weight, much attention has been focused on its effect on brown adipose tissue (BAT) thermogenesis, though its effect on browning of white adipose tissue (WAT) is unclear. Here, we show that nicotine induces the browning of WAT through a central mechanism and that this effect is dependent on the κ opioid receptor (KOR), specifically in the lateral hypothalamic area (LHA). Consistent with these findings, smokers show higher levels of uncoupling protein 1 (UCP1) expression in WAT, which correlates with smoking status. These data demonstrate that central nicotine-induced modulation of WAT browning may be a target against human obesity.

Defective AMH signaling disrupts GnRH neuron development and function and contributes to hypogonadotropic hypogonadism.

Congenital hypogonadotropic hypogonadism (CHH) is a condition characterized by absent puberty and infertility due to gonadotropin releasing hormone (GnRH) deficiency, which is often associated with anosmia (Kallmann syndrome, KS). We identified loss-of-function heterozygous mutations in anti-Müllerian hormone (AMH) and its receptor, AMHR2, in 3% of CHH probands using whole-exome sequencing. We showed that during embryonic development, AMH is expressed in migratory GnRH neurons in both mouse and human fetuses and unconvered a novel function of AMH as a pro-motility factor for GnRH neurons. Pathohistological analysis of Amhr2-deficient mice showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in reduced fertility in adults. Our findings highlight a novel role for AMH in the development and function of GnRH neurons and indicate that AMH signaling insufficiency contributes to the pathogenesis of CHH in humans.

Emerging Roles of Anti-Müllerian Hormone in Hypothalamic-Pituitary Function.

Since its initial discovery in the 1940s, research into the physiological actions of anti-Müllerian hormone (AMH), from its eponymous role in male developmental biology to its routine clinical use in female reproductive health, has undergone a paradigm shifting change. With several exciting studies recently reporting hitherto unforeseen AMH actions at all levels in the hypogonadal-pituitary-gonadal axis, the importance of this hormone for both hypothalamic and pituitary reproductive control is finding increasing support and significance. In this review, we will briefly summarize what is known about the traditional roles and biology of AMH and how this could be integrated with new findings of AMH actions at the level of the hypothalamic-pituitary axis. We also synthesize the important findings from these new studies and discuss their potential impact and significance to our understanding of one of the most common reproductive disorders currently affecting women, polycystic ovary syndrome.

Dynamic cues for whisker-based object localization: An analytical solution to vibration during active whisker touch.

Vibrations are important cues for tactile perception across species. Whisker-based sensation in mice is a powerful model system for investigating mechanisms of tactile perception. However, the role vibration plays in whisker-based sensation remains unsettled, in part due to difficulties in modeling the vibration of whiskers. Here, we develop an analytical approach to calculate the vibrations of whiskers striking objects. We use this approach to quantify vibration forces during active whisker touch at a range of locations along the whisker. The frequency and amplitude of vibrations evoked by contact are strongly dependent on the position of contact along the whisker. The magnitude of vibrational shear force and bending moment is comparable to quasi-static forces. The fundamental vibration frequencies are in a detectable range for mechanoreceptor properties and below the maximum spike rates of primary sensory afferents. These results suggest two dynamic cues exist that rodents can use for object localization: vibration frequency and comparison of vibrational to quasi-static force magnitude. These complement the use of quasi-static force angle as a distance cue, particularly for touches close to the follicle, where whiskers are stiff and force angles hardly change during touch. Our approach also provides a general solution to calculation of whisker vibrations in other sensing tasks.

Mechanisms underlying a thalamocortical transformation during active tactile sensation.

During active somatosensation, neural signals expected from movement of the sensors are suppressed in the cortex, whereas information related to touch is enhanced. This tactile suppression underlies low-noise encoding of relevant tactile features and the brain's ability to make fine tactile discriminations. Layer (L) 4 excitatory neurons in the barrel cortex, the major target of the somatosensory thalamus (VPM), respond to touch, but have low spike rates and low sensitivity to the movement of whiskers. Most neurons in VPM respond to touch and also show an increase in spike rate with whisker movement. Therefore, signals related to self-movement are suppressed in L4. Fast-spiking (FS) interneurons in L4 show similar dynamics to VPM neurons. Stimulation of halorhodopsin in FS interneurons causes a reduction in FS neuron activity and an increase in L4 excitatory neuron activity. This decrease of activity of L4 FS neurons contradicts the "paradoxical effect" predicted in networks stabilized by inhibition and in strongly-coupled networks. To explain these observations, we constructed a model of the L4 circuit, with connectivity constrained by in vitro measurements. The model explores the various synaptic conductance strengths for which L4 FS neurons actively suppress baseline and movement-related activity in layer 4 excitatory neurons. Feedforward inhibition, in concert with recurrent intracortical circuitry, produces tactile suppression. Synaptic delays in feedforward inhibition allow transmission of temporally brief volleys of activity associated with touch. Our model provides a mechanistic explanation of a behavior-related computation implemented by the thalamocortical circuit.

Beyond cones: an improved model of whisker bending based on measured mechanics and tapering.

The sense of touch is represented by neural activity patterns evoked by mechanosensory input forces. The rodent whisker system is exceptional for studying the neurophysiology of touch in part because these forces can be precisely computed from video of whisker deformation. We evaluate the accuracy of a standard model of whisker bending, which assumes quasi-static dynamics and a linearly tapered conical profile, using controlled whisker deflections. We find significant discrepancies between model and experiment: real whiskers bend more than predicted upon contact at locations in the middle of the whisker and less at distal locations. Thus whiskers behave as if their stiffness near the base and near the tip is larger than expected for a homogeneous cone. We assess whether contact direction, friction, inhomogeneous elasticity, whisker orientation, or nonconical shape could explain these deviations. We show that a thin-middle taper of mouse whisker shape accounts for the majority of this behavior. This taper is conserved across rows and columns of the whisker array. The taper has a large effect on the touch-evoked forces and the ease with which whiskers slip past objects, which are key drivers of neural activity in tactile object localization and identification. This holds for orientations with intrinsic whisker curvature pointed toward, away from, or down from objects, validating two-dimensional models of simple whisker-object interactions. The precision of computational models relating sensory input forces to neural activity patterns can be quantitatively enhanced by taking thin-middle taper into account with a simple corrective function that we provide.

Neural coding in barrel cortex during whisker-guided locomotion.

Animals seek out relevant information by moving through a dynamic world, but sensory systems are usually studied under highly constrained and passive conditions that may not probe important dimensions of the neural code. Here, we explored neural coding in the barrel cortex of head-fixed mice that tracked walls with their whiskers in tactile virtual reality. Optogenetic manipulations revealed that barrel cortex plays a role in wall-tracking. Closed-loop optogenetic control of layer 4 neurons can substitute for whisker-object contact to guide behavior resembling wall tracking. We measured neural activity using two-photon calcium imaging and extracellular recordings. Neurons were tuned to the distance between the animal snout and the contralateral wall, with monotonic, unimodal, and multimodal tuning curves. This rich representation of object location in the barrel cortex could not be predicted based on simple stimulus-response relationships involving individual whiskers and likely emerges within cortical circuits.

Low-noise encoding of active touch by layer 4 in the somatosensory cortex.

Cortical spike trains often appear noisy, with the timing and number of spikes varying across repetitions of stimuli. Spiking variability can arise from internal (behavioral state, unreliable neurons, or chaotic dynamics in neural circuits) and external (uncontrolled behavior or sensory stimuli) sources. The amount of irreducible internal noise in spike trains, an important constraint on models of cortical networks, has been difficult to estimate, since behavior and brain state must be precisely controlled or tracked. We recorded from excitatory barrel cortex neurons in layer 4 during active behavior, where mice control tactile input through learned whisker movements. Touch was the dominant sensorimotor feature, with >70% spikes occurring in millisecond timescale epochs after touch onset. The variance of touch responses was smaller than expected from Poisson processes, often reaching the theoretical minimum. Layer 4 spike trains thus reflect the millisecond-timescale structure of tactile input with little noise.

Tapered whiskers are required for active tactile sensation.

Many mammals forage and burrow in dark constrained spaces. Touch through facial whiskers is important during these activities, but the close quarters makes whisker deployment challenging. The diverse shapes of facial whiskers reflect distinct ecological niches. Rodent whiskers are conical, often with a remarkably linear taper. Here we use theoretical and experimental methods to analyze interactions of mouse whiskers with objects. When pushed into objects, conical whiskers suddenly slip at a critical angle. In contrast, cylindrical whiskers do not slip for biologically plausible movements. Conical whiskers sweep across objects and textures in characteristic sequences of brief sticks and slips, which provide information about the tactile world. In contrast, cylindrical whiskers stick and remain stuck, even when sweeping across fine textures. Thus the conical whisker structure is adaptive for sensor mobility in constrained environments and in feature extraction during active haptic exploration of objects and surfaces. DOI: http://dx.doi.org/10.7554/eLife.01350.001.

Aß induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss.

Synaptic loss is the cardinal feature linking neuropathology to cognitive decline in Alzheimer's disease (AD). However, the mechanism of synaptic damage remains incompletely understood. Here, using FRET-based glutamate sensor imaging, we show that amyloid-ß peptide (Aß) engages α7 nicotinic acetylcholine receptors to induce release of astrocytic glutamate, which in turn activates extrasynaptic NMDA receptors (eNMDARs) on neurons. In hippocampal autapses, this eNMDAR activity is followed by reduction in evoked and miniature excitatory postsynaptic currents (mEPSCs). Decreased mEPSC frequency may reflect early synaptic injury because of concurrent eNMDAR-mediated NO production, tau phosphorylation, and caspase-3 activation, each of which is implicated in spine loss. In hippocampal slices, oligomeric Aß induces eNMDAR-mediated synaptic depression. In AD-transgenic mice compared with wild type, whole-cell recordings revealed excessive tonic eNMDAR activity accompanied by eNMDAR-sensitive loss of mEPSCs. Importantly, the improved NMDAR antagonist NitroMemantine, which selectively inhibits extrasynaptic over physiological synaptic NMDAR activity, protects synapses from Aß-induced damage both in vitro and in vivo.