Neocortical Interneurons: From Diversity, Strength

Interneurons in the neocortex of the brain are small, locally projecting inhibitory GABAergic cells with a broad array of anatomical and physiological properties. The diversity of interneurons is believed to be crucial for regulating myriad operations in the neocortex. Here, we describe current theories about how interneuron diversity may support distinct neocortical processes that underlie perception

Dysfunction of cortical GABAergic neurons leads to sensory hyper-reactivity in a Shank3 mouse model of ASD.

Hyper-reactivity to sensory input is a common and debilitating symptom in individuals with autism spectrum disorders (ASD), but the neural basis underlying sensory abnormality is not completely understood. Here we examined the neural representations of sensory perception in the neocortex of a Shank3B-/- mouse model of ASD. Male and female Shank3B-/- mice were more sensitive to relatively weak tactile stimulation in a vibrissa motion detection task. In vivo population calcium imaging in vibrissa primary somatosensory cortex (vS1) revealed increased spontaneous and stimulus-evoked firing in pyramidal neurons but reduced activity in interneurons. Preferential deletion of Shank3 in vS1 inhibitory interneurons led to pyramidal neuron hyperactivity and increased stimulus sensitivity in the vibrissa motion detection task. These findings provide evidence that cortical GABAergic interneuron dysfunction plays a key role in sensory hyper-reactivity in a Shank3 mouse model of ASD and identify a potential cellular target for exploring therapeutic interventions

Determinants of physiological uptake of 18F-fluorodeoxyglucose in palatine tonsils

To determine the extent of physiological variation of uptake of 18F-flurodeoxyglucose (FDG) within palatine tonsils. To define normal limits for side-to-side variation and characterize factors affecting tonsillar uptake of FDG.Over a period of 16 weeks 299 adult patients at low risk for head and neck pathology, attending our center for FDG positron emission tomography/computed tomography (PET/CT) scans were identified. The maximum standardized uptake value (SUVmax) was recorded for each palatine tonsil. For each patient age, gender, smoking status, scan indication and prior tonsillectomy status as well as weather conditions were noted.There was a wide variation in palatine tonsil FDG uptake with SUVmax values between 1.3 and 11.4 recorded. There was a strong left to right correlation for tonsillar FDG uptake within each patient (P < .01). The right palatine tonsil showed increased FDG uptake (4.63) compared to the left (4.47) (P < .01). In multivariate analysis, gender, scan indication, and prevailing weather had no significant impact of tonsillar FDG uptake. Lower tonsillar uptake was seen in patients with a prior history of tonsillectomy (4.13) than those without this history (4.64) (P < .01). Decreasing tonsillar FDG uptake was seen with advancing age (P < .01). Significantly lower uptake was seen in current smokers (SUVmax 4.2) than nonsmokers (SUV 4.9) (P = .03).Uptake of FDG in palatine tonsils is variable but shows a strong side-to-side correlation. We suggest the left/ right SUVmax ratio as a guide to normality with a first to 99th percentiles of (0.70–1.36) for use in patients not suspected to have tonsillar pathology

Global estimates of mineral dust aerosol iron and aluminum solubility that account for particle size using diffusion-controlled and surface-area-controlled approximations

Mineral aerosol deposition is recognized as the dominant source of iron to the open ocean and the solubility of iron in the dust aerosol is highly variable, with measurements ranging from 0.01–80%. Global models have difficulty capturing the observed variations in solubility, and have ignored the solubility dependence on aerosol size. We introduce two idealized physical models to estimate the size dependence of mineral aerosol solubility: a diffusion‐controlled model and a surface‐area‐controlled model. These models produce differing time‐ and space‐varying solubility maps for aerosol Fe and Al given the dust age at deposition, size‐resolved dust entrainment fields, and the aerosol acidity. The resulting soluble iron deposition fluxes are substantially different, and more realistic, than a globally uniform solubility approximation. The surface‐area‐controlled solubility varies more than the diffusion‐controlled solubility and better captures the spatial pattern of observed solubility in the Atlantic. However, neither of these two models explains the large solubility variation observed in the Pacific. We then examine the impacts of spatially variable, size‐dependent solubility on marine biogeochemistry with the Biogeochemical Elemental Cycling (BEC) ocean model by comparing the modeled surface ocean dissolved Fe and Al with observations. The diffusion‐based variable solubility does not significantly improve the simulation of dissolved Fe relative to a 5% globally uniform solubility, while the surface‐area‐based variable solubility improves the simulation in the North Atlantic but worsens it in the Pacific and Indian Oceans

Targeted optogenetic stimulation and recording of neurons in vivo using cell-type-specific expression of Channelrhodopsin-2

A major long-term goal of systems neuroscience is to identify the different roles of neural subtypes in brain circuit function. The ability to causally manipulate selective cell types is critical to meeting this goal. This protocol describes techniques for optically stimulating specific populations of excitatory neurons and inhibitory interneurons in vivo in combination with electrophysiology. Cell type selectivity is obtained using Cre-dependent expression of the light-activated channel Channelrhodopsin-2. We also describe approaches for minimizing optical interference with simultaneous extracellular and intracellular recording. These optogenetic techniques provide a spatially and temporally precise means of studying neural activity in the intact brain and allow a detailed examination of the effect of evoked activity on the surrounding local neural network. Injection of viral vectors requires 30–45 min, and in vivo electrophysiology with optogenetic stimulation requires 1–4 h.National Institutes of Health (U.S.)National Science Foundation (U.S.)Simons FoundationNational Institutes of Health (U.S.). Pioneer AwardNational Eye Institue (K99 Award)Knut and Alice Wallenberg Foundation (Postdoctoral Fellowship)Brain & Behavior Research Foundation. Young Investigator AwardThomas F. Peterse

Using intervention mapping to develop and facilitate implementation of a multifaceted behavioural intervention targeting physical activity and sedentary behaviour in stroke survivors: Physical Activity Routines After Stroke (PARAS): intervention development study

Objectives: The benefits of increased physical activity for stroke survivors include improved function and mental health and wellbeing. However, less than 30% achieve recommended physical activity levels, and high levels of sedentary behaviour are reported. We developed a multifaceted behavioural intervention (and accompanying implementation plan) targeting physical activity and sedentary behaviour of stroke survivors. Design: Intervention Mapping facilitated intervention development. Step 1 involved a systematic review, focus group discussions and a review of care pathways. Step 2 identified social cognitive determinants of behavioural change and behavioural outcomes. Step 3 linked determinants of behavioural outcomes with specific behaviour change techniques (BCTs) to target behaviours of interest. Step 4 involved intervention development informed by steps 1–3. Subsequently, an implementation plan was developed (Step 5) followed by an evaluation plan (Step 6). Setting: Community and secondary care settings, North East England. Participants: Stroke survivors and healthcare professionals (HCPs) working in stroke services. Results: Systematic review findings informed selection of nine ‘promising’ BCTs (e.g. problem-solving). Focus groups with stroke survivors (n = 18) and HCPs (n= 24) identified the need for an intervention delivered throughout the rehabilitation pathway, tailored to individual needs with training for HCPs delivering the intervention. Intervention delivery was considered feasible within local stroke services. The target behaviours for the intervention were levels of physical activity and sedentary behaviour in adult stroke survivors. Assessment of acceptability and usability with 11 HCPs and 21 stroke survivors/relatives identified issues with self-monitoring tools and the need for a physical activity repository of local services’ and training for HCPs with feedback on intervention delivery. A feasibility study protocol was designed to evaluate the intervention. Conclusions: A systematic development process using intervention mapping resulted in a multi-faceted evidence- and theory-informed intervention (Physical Activity Routines After Stroke – PARAS) for delivery by community stroke rehabilitation teams

Meta-analysis of Complex Diseases at Gene Level with Generalized Functional Linear Models

We developed generalized functional linear models (GFLMs) to perform a meta-analysis of multiple case-control studies to evaluate the relationship of genetic data to dichotomous traits adjusting for covariates. Unlike the previously developed meta-analysis for sequence kernel association tests (MetaSKATs), which are based on mixed-effect models to make the contributions of major gene loci random, GFLMs are fixed models; i.e., genetic effects of multiple genetic variants are fixed. Based on GFLMs, we developed chi-squared-distributed Rao’s efficient score test and likelihood-ratio test (LRT) statistics to test for an association between a complex dichotomous trait and multiple genetic variants. We then performed extensive simulations to evaluate the empirical type I error rates and power performance of the proposed tests. The Rao’s efficient score test statistics of GFLMs are very conservative and have higher power than MetaSKATs when some causal variants are rare and some are common. When the causal variants are all rare [i.e., minor allele frequencies (MAF) < 0.03], the Rao’s efficient score test statistics have similar or slightly lower power than MetaSKATs. The LRT statistics generate accurate type I error rates for homogeneous genetic-effect models and may inflate type I error rates for heterogeneous genetic-effect models owing to the large numbers of degrees of freedom and have similar or slightly higher power than the Rao’s efficient score test statistics. GFLMs were applied to analyze genetic data of 22 gene regions of type 2 diabetes data from a meta-analysis of eight European studies and detected significant association for 18 genes (P < 3.10 × 10−6), tentative association for 2 genes (HHEX and HMGA2; P ≈ 10−5), and no association for 2 genes, while MetaSKATs detected none. In addition, the traditional additive-effect model detects association at gene HHEX. GFLMs and related tests can analyze rare or common variants or a combination of the two and can be useful in whole-genome and whole-exome association studies