Grid cells on steeply sloping terrain: evidence for planar rather than volumetric encoding

Neural encoding of navigable space involves a network of structures centred on the hippocampus, whose neurons –place cells – encode current location. Input to the place cells includes afferents from the entorhinal cortex, which contains grid cells. These are neurons expressing spatially localised activity patches, or firing fields, that are evenly spaced across the floor in a hexagonal close-packed array called a grid. It is thought that grid cell grids function to enable the calculation of distances. The question arises as to whether this odometry process operates in three dimensions, and so we queried whether grids permeate three-dimensional space – that is, form a lattice – or whether they simply follow the environment surface. If grids form a three-dimensional lattice then a tilted floor should transect several layers of this lattice, resulting in interruption of the hexagonal pattern. We model this prediction with simulated grid lattices and show that on a 40-degree slope the firing of a grid cell should cover proportionally less of the surface, with smaller field size and fewer fields and reduced hexagonal symmetry. However, recording of grid cells as animals foraged on a 40-degree-tilted surface found that firing of grid cells was almost indistinguishable, in pattern or rate, from that on the horizontal surface, with if anything increased coverage and field number, and preserved field size. It thus appears unlikely that the sloping surface transected a lattice. However, grid cells on the slope displayed slightly degraded firing patterns, with reduced coherence and slightly reduced symmetry. These findings collectively suggest that the grid cell component of the metric representation of space is not fixed in absolute three-dimensional space but is influenced both by the surface the animal is on and by the relationship of this surface to the horizontal, supporting the hypothesis that the neural map of space is multi-planar rather than fully volumetric

Neural encoding of large-scale three-dimensional space-properties and constraints

How the brain represents represent large-scale, navigable space has been the topic of intensive investigation for several decades, resulting in the discovery that neurons in a complex network of cortical and subcortical brain regions co-operatively encode distance, direction, place, movement etc. using a variety of different sensory inputs. However, such studies have mainly been conducted in simple laboratory settings in which animals explore small, two-dimensional (i.e., flat) arenas. The real world, by contrast, is complex and three dimensional with hills, valleys, tunnels, branches, and—for species that can swim or fly—large volumetric spaces. Adding an additional dimension to space adds coding challenges, a primary reason for which is that several basic geometric properties are different in three dimensions. This article will explore the consequences of these challenges for the establishment of a functional three-dimensional metric map of space, one of which is that the brains of some species might have evolved to reduce the dimensionality of the representational space and thus sidestep some of these problems

Short screening tools for risky drinking in Aboriginal and Torres Strait Islander Australians : Modified AUDIT-C and a new approach

Background Alcohol consumption among Indigenous Australians can involve a stop-start pattern of drinking, with consumption well above recommended guidelines on each occasion. Such intermittent drinking patterns can make screening for risky drinking difficult. This study evaluates the ability of several short alcohol screening tools, contained in the Grog Survey Application, to detect short- or long-term risky drinking as defined by Australian guidelines. Tested tools include a modification of Alcohol Use Disorders Identification Test-Consumption (AUDIT-Cm). Methods Alcohol consumption was assessed in current drinkers in the past year (n = 184) using AUDIT-Cm and using the last four drinking occasions (Finnish method). Sensitivity and specificity were assessed relative to the Finnish method, for how AUDIT-Cm score (3 + for women, 4 + for men), and how subsets of AUDIT-Cm questions (AUDIT-1m and AUDIT-2m; and AUDIT-3mV alone) were able to determine short- or long-term risk from drinking. Responses to AUDIT-Cm were used to calculate the average standard drinks consumed per day, and the frequency at which more than four standard drinks were consumed on single occasions. Finally, shorter versions of the Finnish method (1, 2, or 3 occasions of drinking) were compared to the full Finnish method, by examining the percentage of variance retained by shorter versions. Results AUDIT-Cm has a high sensitivity in detecting at-risk drinking compared with the Finnish method (sensitivity = 99%, specificity = 67%). The combination of AUDIT-1m and AUDIT-2m was able to classify the drinking risk status for all but four individuals in the same way as the Finnish method did. For the Finnish method, two drinking sessions to calculate drinks per drinking occasion, and four to calculate frequency resulted in nearly identical estimates to data on all four of the most recent drinking occasions (r2 = 0.997). Conclusions The combination of AUDIT-1m and AUDIT-2m may offer advantages as a short screening tool, over AUDIT-3mV, in groups where intermittent and high per occasion drinking is common. As an alternative to the full Finnish method, the quantity consumed on the last two occasions and timing of the last four occasions may provide a practical short screening tool

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation

Phenotypic Characterization of <i>EIF2AK4</i> Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension

Background: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 ( BMPR2 ) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene ( EIF2AK4 ) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. Methods: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource–Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of &lt;1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. Results: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (K co ; 33% [interquartile range, 30%–35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23–38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. Conclusions: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low K co and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation. </jats:sec

GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility

How heterogeneous place cell responding arises from homogeneous grids—a contextual gating hypothesis

How entorhinal grids generate hippocampal place fields remains unknown. The simplest hypothesis—that grids of different scales are added together—cannot explain a number of place field phenomena, such as (1) Summed grids form a repeating, dispersed activation pattern whereas place fields are focal and nonrepeating; (2) Grid cells are active in all environments but place cells only in some, and (3) Partial environmental changes cause either heterogeneous (“partial”) remapping in place cells whereas they result in all-or-nothing “realignment” remapping in grid cells. We propose that this dissociation between grid cell and place cell behavior arises in the entorhinal-dentate projection. By our view, the grid-cell/place-cell projection is modulated by context, both organizationally and activationally. Organizationally, we propose that when the animal first enters a new environment, the relatively homogeneous input from the grid cells becomes spatially clustered by Hebbian processes in the dendritic tree so that inputs active in the same context and having overlapping fields come to terminate on the same sub-branches of the tree. Activationally, when the animal re-enters the now-familiar environment, active contextual inputs select (by virtue of their clustered terminations) which parts of the dendritic tree, and therefore which grid cells, drive the granule cell. Assuming this pattern of projections, our model successfully produces focal hippocampal place fields that remap appropriately to contextual changes

Prevalence and correlates of alcohol dependence in an Australian Aboriginal and Torres Strait Islander representative sample : Using the Grog Survey App

Introduction Little is known about the prevalence of current alcohol dependence in Indigenous Australian communities. Here we identify the frequency of reported symptoms, estimate the prevalence and describe the correlates of current alcohol dependence. Methods A representative sample of Indigenous Australians (16+ years) was recruited from an urban and remote community in South Australia. Data were collected between July and October 2019 via a tablet computer-based application. Participants were likely dependent if they reported two or more dependence symptoms (ICD-11; in the last 12 -months), weekly or more frequently. Chi-square tests described the relationship between demographics, remoteness and alcohol dependence. Spearman correlations estimated the relationship between symptoms of dependence, consumption characteristics and demographics. Results A total of 775 Indigenous Australians participated. The most frequently reported symptoms were prioritising alcohol over other things and loss of control. Overall, 2.2% were likely dependent on alcohol (n = 17/775). Prevalence did not vary by remoteness. Participants who drank more and more frequently tended to report more frequent symptoms of dependence. In the urban site, men tended to report more frequent symptoms of dependence than women. Age, income and schooling were not linked to dependence. Discussion and Conclusions The prevalence of current alcohol dependence in this representative sample was similar to that of the general Australian and international estimates. Understanding risk factors for current alcohol dependence will be useful to inform the allocation of funding and support. Accurate estimates of the prevalence of current alcohol dependence are important to better identify specialist treatment needs

Erratum: Correction to: Developing a tablet computer-based application ('App') to measure self-reported alcohol consumption in Indigenous Australians

After publication of the original article [1] it was noted that the name of author, Peter Jack, was erroneously typeset in both the PDF and online formats of the manuscript as Peter Jack GradDipIndigH. This inclusion of his qualification as part of his surname was introduced during typesetting, thus the publisher apologises for this error. The original article has also been updated to reflect this correction