Sound-driven modulation of sub- and suprathreshold activity in mouse primary visual cortex

Integration of multimodal information is essential for the integrative response of the brain and is thought to be accomplished mostly in sensory association areas. However, available evidences in humans and monkeys indicate that this process begins already in primary sensory cortices. However, how cross-modal synaptic integration occurs in vivo along cortical microcircuitries remains to be investigated. Primary sensory cortices of rodents are well-suited to address this issue as they have a well-known anatomy and synaptic physiology. Here we quantified how acoustic stimulation (white noise, 50 ms duration) affects spontaneous and sensory-driven activity of pyramidal neurons in different layers of primary visual cortex by intrinsic signal imaging-targeted in vivo whole-cell recordings in lightly anesthetized and awake, head-fixed mice. Acoustic stimuli reliably evoked hyperpolarizations -lasting about 200-300 ms- in layer 2-3 and 6 neurons, but not in the main thalamorecipient lamina, layer 4. We found depolarizing responses to sound only in layer 5 (about 1/4 of recorded neurons), whereas the remaining cells exhibited no response or hyperpolarizations. To explore the synaptic nature of sound-driven hyperpolarizations in supragranular pyramids, we measured the inhibitory and excitatory conductances elicited by sound. Hyperpolarizations were due to the combined effect of activation of inhibitory conductances along with a withdrawal of excitatory ones. In agreement with this, sound-driven hyperpolarizations were significantly reduced by intracellular perfusion with a cesium-based solution containing 1 mM picrotoxin to block GABA-B and GABA-A receptors, respectively (-3,3 ± 0,4 mV vs -1,1 ± 0,3 mV, t-test, p<0,001). We next quantified the impact of sound-driven inhibition on visual responsiveness by coupling flashed or moving light bars with white noise. Sub- and suprathreshold responses were significantly reduced in the case of bimodal stimulation compared to the pure visual modality (of about 30 and 50%, respectively, paired statistics, p<0.05). Finally, transection experiments guided by intrinsic signal imaging indicated that auditory-driven synaptic inputs onto visual cortical neurons persisted despite inactivation of horizontal connections between primary visual and auditory cortices. Taken together, our findings illustrate a simple scheme by which spontaneous and evoked activity in a retinotopic column of the mouse primary visual cortex can be shaped by the acoustic external environment in a layer-specific manner

Novel mutations in human and mouse SCN4A implicate AMPK in myotonia and periodic paralysis

Mutations in the skeletal muscle channel (SCN4A), encoding the Nav1.4 voltage-gated sodium channel, are causative of a variety of muscle channelopathies, including non-dystrophic myotonias and periodic paralysis. The effects of many of these mutations on channel function have been characterized both in vitro and in vivo. However, little is known about the consequences of SCN4A mutations downstream from their impact on the electrophysiology of the Nav1.4 channel. Here we report the discovery of a novel SCN4A mutation (c.1762A>G; p.I588V) in a patient with myotonia and periodic paralysis, located within the S1 segment of the second domain of the Nav1.4 channel. Using N-ethyl-N-nitrosourea mutagenesis, we generated and characterized a mouse model (named draggen), carrying the equivalent point mutation (c.1744A>G; p.I582V) to that found in the patient with periodic paralysis and myotonia. Draggen mice have myotonia and suffer from intermittent hind-limb immobility attacks. In-depth characterization of draggen mice uncovered novel systemic metabolic abnormalities in Scn4a mouse models and provided novel insights into disease mechanisms. We discovered metabolic alterations leading to lean mice, as well as abnormal AMP-activated protein kinase activation, which were associated with the immobility attacks and may provide a novel potential therapeutic target

Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features

The recent identification of multiple dominant mutations in the gene encoding β-catenin in both humans and mice has enabled exploration of the molecular and cellular basis of β-catenin function in cognitive impairment. In humans, β-catenin mutations that cause a spectrum of neurodevelopmental disorders have been identified. We identified de novo β-catenin mutations in patients with intellectual disability, carefully characterized their phenotypes, and were able to define a recognizable intellectual disability syndrome. In parallel, characterization of a chemically mutagenized mouse line that displays features similar to those of human patients with β-catenin mutations enabled us to investigate the consequences of β-catenin dysfunction through development and into adulthood. The mouse mutant, designated batface (Bfc), carries a Thr653Lys substitution in the C-terminal armadillo repeat of β-catenin and displayed a reduced affinity for membrane-associated cadherins. In association with this decreased cadherin interaction, we found that the mutation results in decreased intrahemispheric connections, with deficits in dendritic branching, long-term potentiation, and cognitive function. Our study provides in vivo evidence that dominant mutations in β-catenin underlie losses in its adhesion-related functions, which leads to severe consequences, including intellectual disability, childhood hypotonia, progressive spasticity of lower limbs, and abnormal craniofacial features in adult

LTA4H rs2660845 association with montelukast response in early and late-onset asthma

Leukotrienes play a central pathophysiological role in both paediatric and adult asthma. However, 35% to 78% of asthmatics do not respond to leukotriene inhibitors. In this study we tested the role of the LTA4H regulatory variant rs2660845 and age of asthma onset in response to montelukast in ethnically diverse populations. We identified and genotyped 3,594 asthma patients treated with montelukast (2,514 late-onset and 1,080 early-onset) from seven cohorts (UKBiobank, GoSHARE, BREATHE, Tayside RCT, PAGES, GALA II and SAGE). Individuals under montelukast treatment experiencing at least one exacerbation in a 12-month period were compared against individuals with no exacerbation, using logistic regression for each cohort and meta-analysis. While no significant association was found with European late-onset subjects, a meta-analysis of 523 early-onset individuals from European ancestry demonstrated the odds of experiencing asthma exacerbations by carriers of at least one G allele, despite montelukast treatment, were increased (odds-ratio = 2.92, 95%confidence interval (CI): 1.04–8.18, I2 = 62%, p = 0.0412) compared to those in the AA group. When meta-analysing with other ethnic groups, no significant increased risk of asthma exacerbations was found (OR = 1.60, 95% CI: 0.61–4.19, I2 = 85%, p = 0.342). Our study demonstrates that genetic variation in LTA4H, together with timing of asthma onset, may contribute to variability in montelukast response. European individuals with early-onset (≤18y) carrying at least one copy of rs2660845 have increased odd of exacerbation under montelukast treatment, presumably due to the up-regulation of LTA4H activity. These findings support a precision medicine approach for the treatment of asthma with montelukast

Loss of Gnas Imprinting Differentially Affects REM/NREM Sleep and Cognition in Mice

It has been suggested that imprinted genes are important in the regulation of sleep. However, the fundamental question of whether genomic imprinting has a role in sleep has remained elusive up to now. In this work we show that REM and NREM sleep states are differentially modulated by the maternally expressed imprinted gene Gnas. In particular, in mice with loss of imprinting of Gnas, NREM and complex cognitive processes are enhanced while REM and REM–linked behaviors are inhibited. This is the first demonstration that a specific overexpression of an imprinted gene affects sleep states and related complex behavioral traits. Furthermore, in parallel to the Gnas overexpression, we have observed an overexpression of Ucp1 in interscapular brown adipose tissue (BAT) and a significant increase in thermoregulation that may account for the REM/NREM sleep phenotypes. We conclude that there must be significant evolutionary advantages in the monoallelic expression of Gnas for REM sleep and for the consolidation of REM–dependent memories. Conversely, biallelic expression of Gnas reinforces slow wave activity in NREM sleep, and this results in a reduction of uncertainty in temporal decision-making processes

Agreement and movement: A syntactic analysis of attraction

This paper links experimental psycholinguistics and theoretical syntax in the study of subject–verb agreement. Three experiments of elicited spoken production making use of specific characteristics of Italian and French are presented. They manipulate and examine its impact on the occurrence of ‘attraction' errors (i.e. incorrect agreement with a word that is not the subject of the sentence). Experiment 1 (in Italian) shows that subject modifiers do not trigger attraction errors in free inverted VS (Verb Subject) structures, although attraction was found in VS interrogatives in English (Vigliocco, G., & Nicol, J. (1998). Separating hierarchical relations and word order in language production. Is proximity concord syntactic or linear? Cognition, 13– 29) In Experiment 2 (in French), we report stronger attraction with preverbal clitic object pronouns than with subject modifiers. Experiment 3 (in French) shows that displaced direct objects in the cleft construction trigger attraction effects, in spite of the fact that the object does not intervene between the subject and the verb in the surface word order (OSV). Moreover, attraction is stronger in structures with subject–verb inversion (...). These observations are shown to be naturally interpretable through the tools of formal syntax, as elaborated within the Principles and Parameters/Minimalist tradition. Three important constructs are discussed: (1) the hierarchical representation of the sentence during syntactic construction, and the role of intermediate positions by which words transit when they move; (2) the role of specific hierarchical (c-command) but also linear (precedence) relations; and (3) the possibility that agreement involves two functionally distinct components. A gradient of computational complexity in agreement is presented which relates empirical evidence to these theoretical constructs

Sleep-stage scoring in mice:The influence of data pre-processing on a system's performance

Sleep-stage analysis in mice and rats has received growing attention in recent years, due to the fact that mice display electrical activity during sleep which has underlying similarities with that of human sleep. Both conventional manual and automatic sleep-wakefulness scoring are rule based tasks which use brain waves measured by Electroencephalogram (EEG) and activity detected by Electromyography (EMG) of skeletal muscles. Several works have been conducted trying to provide an automatic sleep-scoring system on the basis of machine learning methods. In this study we try to understand the reasons behind the complexity of this problem and we emphasize the importance of normalization procedure that leads to a better stage discrimination comparing different classification methods