The du2J mouse model of ataxia and absence epilepsy has deficient cannabinoid CB1 receptor-mediated signalling

Key point summary • Cerebellar ataxias are progressive debilitating diseases with no known treatment and are associated with defective motor function and, in particular, abnormalities to Purkinje cells. • Mutant mice with deficits in Ca2+ channel auxiliary α2δ-2 subunits are used as models of cerebellar ataxia. • Our data in the du2J mouse model shows an association between the ataxic phenotype exhibited by homozygous du2J/du2J mice and increased irregularity of Purkinje cell firing. • We show that both heterozygous +/du2J and homozygous du2J/du2J mice completely lack the strong presynaptic modulation of neuronal firing by cannabinoid CB1 receptors which is exhibited by litter-matched control mice. • These results show that the du2J ataxia model is associated with deficits in CB1 receptor signalling in the cerebellar cortex, putatively linked with compromised Ca2+ channel activity due to reduced α2δ-2 subunit expression. Knowledge of such deficits may help design therapeutic agents to combat ataxias. Abstract Cerebellar ataxias are a group of progressive, debilitating diseases often associated with abnormal Purkinje cell (PC) firing and/or degeneration. Many animal models of cerebellar ataxia display abnormalities in Ca2+ channel function. The ‘ducky’ du2J mouse model of ataxia and absence epilepsy represents a clean knock-out of the auxiliary Ca2+ channel subunit, α2δ-2, and has been associated with deficient Ca2+ channel function in the cerebellar cortex. Here, we investigate effects of du2J mutation on PC layer (PCL) and granule cell (GC) layer (GCL) neuronal spiking activity and, also, inhibitory neurotransmission at interneurone-Purkinje cell(IN-PC) synapses. Increased neuronal firing irregularity was seen in the PCL and, to a less marked extent, in the GCL in du2J/du2J, but not +/du2J, mice; these data suggest that the ataxic phenotype is associated with lack of precision of PC firing, that may also impinge on GC activity and requires expression of two du2J alleles to manifest fully. du2J mutation had no clear effect on spontaneous inhibitory postsynaptic current (sIPSC) frequency at IN-PC synapses, but was associated with increased sIPSC amplitudes. du2J mutation ablated cannabinoid CB1 receptor (CB1R)-mediated modulation of spontaneous neuronal spike firing and CB1Rmediated presynaptic inhibition of synaptic transmission at IN-PC synapses in both +/du2J and du2J/du2J mutants; effects that occurred in the absence of changes in CB1R expression. These results demonstrate that the du2J ataxia model is associated with deficient CB1R signalling in the cerebellar cortex, putatively linked with compromised Ca2+ channel activity and the ataxic phenotype.

Neural processing of reward and punishment in young people at increased familial risk of depression

Background Abnormalities in the neural representation of rewarding and aversive stimuli have been well-described in patients with acute depression, and we previously found abnormal neural responses to rewarding and aversive sight and taste stimuli in recovered depressed patients. The aim of the present study was to determine whether similar abnormalities might be present in young people at increased familial risk of depression but with no personal history of mood disorder. Methods We therefore used functional magnetic resonance imaging to examine the neural responses to pleasant and aversive sights and tastes in 25 young people (16–21 years of age) with a biological parent with depression and 25 age- and gender-matched control subjects. Results We found that, relative to the control subjects, participants with a parental history of depression showed diminished responses in the orbitofrontal cortex to rewarding stimuli, whereas activations to aversive stimuli were increased in the lateral orbitofrontal cortex and insula. In anterior cingulate cortex the at-risk group showed blunted neural responses to both rewarding and aversive stimuli. Conclusions Our findings suggest that young people at increased familial risk of depression have altered neural representation of reward and punishment, particularly in cortical regions linked to the use of positive and negative feedback to guide adaptive behavior.

Older people's perceptions of assistive technology — An exploratory pan-European study

This paper describes a study undertaken to explore how assistive technology in the form of a wrist-worn device is perceived by older people for whom it has been devised.

Wearable device to assist independent living

Older people increasingly want to remain living independently in their own homes. The aim of the ENABLE project is to develop a wearable device that can be used to support older people in their daily lives and which can monitor their health status, detect potential problems, provide activity reminders and offer communication and alarm services. In order to determine the specifications and functionality required for the development of the device, user surveys and focus groups were undertaken, use case analysis and scenario modeling carried out. The project has resulted in the development of a wrist-worn device and mobile phone combination that can support and assist older and vulnerable wearers with a range of activities and services both inside their home and as they move around their local environment. The device is currently undergoing pilot trials in five European countries. The aim of this paper is to describe the ENABLE device, its features and services, and the infrastructure within which it operates.

The role of REST in transcriptional and epigenetic dysregulation in Huntington's disease

Huntington's disease (HD) is a devastating disorder that affects approximately 1 in 10,000 people and is accompanied by neuronal dysfunction and neurodegeneration. HD manifests as a progressive chorea, a decline in mental abilities accompanied by behavioural, emotional and psychiatric problems followed by, dementia, and ultimately, death. The molecular pathology of HD is complex but includes widespread transcriptional dysregulation. Although many transcriptional regulatory molecules have been implicated in the pathogenesis of HD, a growing body of evidence points to the pivotal role of RE1 Silencing Transcription Factor (REST). In HD, REST, translocates from the cytoplasm to the nucleus in neurons resulting in repression of key target genes such as BDNF. Since these original observations, several thousand direct target genes of REST have been identified, including numerous non-coding RNAs including both microRNAs and long non-coding RNAs, several of which are dysregulated in HD. More recently, evidence is emerging that hints at epigenetic abnormalities in HD brain. This in turn, promotes the notion that targeting the epigenetic machinery may be a useful strategy for treatment of some aspects of HD. REST also recruits a host of histone and chromatin modifying activities that can regulate the local epigenetic signature at REST target genes. Collectively, these observations present REST as a hub that coordinates transcriptional, posttranscriptional and epigenetic programmes, many of which are disrupted in HD. We identify several spokes emanating from this REST hub that may represent useful sites to redress REST dysfunction in HD.

Antidepressant medications reduce subcortical-cortical resting-state functional connectivity in healthy volunteers

Studies have revealed abnormalities in resting-state functional connectivity in those with major depressive disorder specifically in areas such as the dorsal anterior cingulate, thalamus, amygdala, the pallidostriatum and subgenual cingulate. However, the effect of antidepressant medications on human brain function is less clear and the effect of these drugs on resting-state functional connectivity is unknown. Forty volunteers matched for age and gender with no previous psychiatric history received either citalopram (SSRI; selective serotonergic reuptake inhibitor), reboxetine (SNRI; selective noradrenergic reuptake inhibitor) or placebo for 7 days in a double-blind design. Using resting-state functional magnetic resonance imaging and seed based connectivity analysis we selected the right nucleus accumbens, the right amygdala, the subgenual cingulate and the dorsal medial prefrontal cortex as seed regions. Mood and subjective experience were also measured before and after drug administration using self-report scales. Despite no differences in mood across the three groups, we found reduced connectivity between the amygdala and the ventral medial prefrontal cortex in the citalopram group and the amygdala and the orbitofrontal cortex for the reboxetine group. We also found reduced striatal-orbitofrontal cortex connectivity in the reboxetine group. These data suggest that antidepressant medications can decrease resting-state functional connectivity independent of mood change and in areas known to mediate reward and emotional processing in the brain. We conclude that hypothesis-driven seed based analysis of resting-state fMRI supports the proposition that antidepressant medications might work by normalising the elevated resting-state functional connectivity seen in depressed patients.

Abnormal functional activation and maturation of fronto-striato-temporal and cerebellar regions during sustained attention in autism spectrum disorder

Objective Sustained attention problems are common in people with autism spectrum disorder (ASD) and may have significant implications for the diagnosis and management of ASD and associated comorbidities. Furthermore, ASD has been associated with atypical structural brain development. The authors used functional MRI to investigate the functional brain maturation of attention between childhood and adulthood in people with ASD. Method Using a parametrically modulated sustained attention/vigilance task, the authors examined brain activation and its linear correlation with age between childhood and adulthood in 46 healthy male adolescents and adults (ages 11–35 years) with ASD and 44 age- and IQ-matched typically developing comparison subjects. Results Relative to the comparison group, the ASD group had significantly poorer task performance and significantly lower activation in inferior prefrontal cortical, medial prefrontal cortical, striato-thalamic, and lateral cerebellar regions. A conjunction analysis of this analysis with group differences in brain-age correlations showed that the comparison group, but not the ASD group, had significantly progressively increased activation with age in these regions between childhood and adulthood, suggesting abnormal functional brain maturation in ASD. Several regions that showed both abnormal activation and functional maturation were associated with poorer task performance and clinical measures of ASD and inattention. Conclusions The results provide first evidence that abnormalities in sustained attention networks in individuals with ASD are associated with underlying abnormalities in the functional brain maturation of these networks between late childhood and adulthood.

A low glycaemic load breakfast can attenuate cognitive impairments observed in middle aged obese females with impaired glucose tolerance.

Increased central adiposity and abnormalities in glucose tolerance preceding type 2 diabetes can have demonstrable negative effects on cognitive function, even in ostensibly healthy, middle-aged females. The potential for GL manipulations to modulate glycaemic response and cognitive function in type 2 diabetes and obesity merits further investigation..

Type 2 diabetes and impaired glucose tolerance are associated with word memory source monitoring recollection deficits but not simple recognition familiarity deficits following water, low glycaemic load, and high glycaemic load breakfasts.

Isolated source monitoring recollection deficits indicate that abnormalities in glucose metabolism are not detrimental for global episodic memory processes. This enhances our understanding of how metabolic disorders are associated with memory impairments.

Acute glycaemic load breakfast manipulations do not attenuate cognitive impairments in adults with type 2 diabetes

Abnormalities in glucose tolerance such as type 2 diabetes can have demonstrable negative effects on a range of cognitive functions. However, there was no evidence that low GL breakfasts administered acutely could confer benefits for cognitive function (ClincalTrials.gov identifier, NCT01047813).

Impairments in glucose tolerance can have a negative impact on cognitive function: a systematic research review

There is an increasing body of research investigating whether abnormal glucose tolerance is associated with cognitive impairments, the evidence from which is equivocal. A systematic search of the literature identified twenty-three studies which assessed either clinically defined impaired glucose tolerance (IGT) or variance in glucose tolerance within the clinically defined normal range (NGT). The findings suggest that poor glucose tolerance is associated with cognitive impairments, with decrements in verbal memory being most prevalent. However, the evidence for decrements in other domains was weak. The NGT studies report a stronger glucose tolerance-cognition association than the IGT studies, which is likely to be due to the greater number of glucose tolerance parameters and the more sensitive cognitive tests in the NGT studies compared to the IGT studies. It is also speculated that the negative cognitive impact of abnormalities in glucose tolerance increases with age, and that glucose consumption is most beneficial to individuals with poor glucose tolerance compared to individuals with normal glucose tolerance. The role of potential mechanisms are discussed.

Deficits in agency in schizophrenia, and additional deficits in body image, body schema, and internal timing, in passivity symptoms

Individuals with schizophrenia, particularly those with passivity symptoms, may not feel in control of their actions, believing them to be controlled by external agents. Cognitive operations that contribute to these symptoms may include abnormal processing in agency as well as body representations that deal with body schema and body image. However, these operations in schizophrenia are not fully understood, and the questions of general versus specific deficits in individuals with different symptom profiles remain unanswered. Using the projected-hand illusion (a digital video version of the rubber-hand illusion) with synchronous and asynchronous stroking (500 ms delay), and a hand laterality judgment task, we assessed sense of agency, body image, and body schema in 53 people with clinically stable schizophrenia (with a current, past, and no history of passivity symptoms) and 48 healthy controls. The results revealed a stable trait in schizophrenia with no difference between clinical subgroups (sense of agency) and some quantitative (specific) differences depending on the passivity symptom profile (body image and body schema). Specifically, a reduced sense of self-agency was a common feature of all clinical subgroups. However, subgroup comparisons showed that individuals with passivity symptoms (both current and past) had significantly greater deficits on tasks assessing body image and body schema, relative to the other groups. In addition, patients with current passivity symptoms failed to demonstrate the normal reduction in body illusion typically seen with a 500 ms delay in visual feedback (asynchronous condition), suggesting internal timing problems. Altogether, the results underscore self-abnormalities in schizophrenia, provide evidence for both trait abnormalities and state changes specific to passivity symptoms, and point to a role for internal timing deficits as a mechanistic explanation for external cues becoming a possible source of self-body input.

Language in genetic syndromes and cognitive modularity

In recent years, research into the impact of genetic abnormalities on cognitive development, including language, has become recognized for its potential to make valuable contributions to our understanding of the brain–behaviour relationships underlying language acquisition as well as to understanding the cognitive architecture of the human mind. The publication of Fodor’s ( 1983 ) book The Modularity of Mind has had a profound impact on the study of language and the cognitive architecture of the human mind. Its central claim is that many of the processes involved in comprehension are undertaken by special brain systems termed ‘modules’. This domain specificity of language or modularity has become a fundamental feature that differentiates competing theories and accounts of language acquisition (Fodor 1983 , 1985 ; Levy 1994 ; Karmiloff-Smith 1998 ). However, although the fact that the adult brain is modularized is hardly disputed, there are different views of how brain regions become specialized for specific functions. A question of some interest to theorists is whether the human brain is modularized from the outset (nativist view) or whether these distinct brain regions develop as a result of biological maturation and environmental input (neuroconstructivist view). One source of insight into these issues has been the study of developmental disorders, and in particular genetic syndromes, such as Williams syndrome (WS) and Down syndrome (DS). Because of their uneven profiles characterized by dissociations of different cognitive skills, these syndromes can help us address theoretically significant questions. Investigations into the linguistic and cognitive profiles of individuals with these genetic abnormalities have been used as evidence to advance theoretical views about innate modularity and the cognitive architecture of the human mind. The present chapter will be organized as follows. To begin, two different theoretical proposals in the modularity debate will be presented. Then studies of linguistic abilities in WS and in DS will be reviewed. Here, the emphasis will be mainly on WS due to the fact that theoretical debates have focused primarily on WS, there is a larger body of literature on WS, and DS subjects have typically been used for the purposes of comparison. Finally, the modularity debate will be revisited in light of the literature review of both WS and DS. Conclusions will be drawn regarding the contribution of these two genetic syndromes to the issue of cognitive modularity, and in particular innate modularity.

Smart-phone based electrocardiogram wavelet decomposition and neural network classification

This paper discusses ECG classification after parametrizing the ECG waveforms in the wavelet domain. The aim of the work is to develop an accurate classification algorithm that can be used to diagnose cardiac beat abnormalities detected using a mobile platform such as smart-phones. Continuous time recurrent neural network classifiers are considered for this task. Records from the European ST-T Database are decomposed in the wavelet domain using discrete wavelet transform (DWT) filter banks and the resulting DWT coefficients are filtered and used as inputs for training the neural network classifier. Advantages of the proposed methodology are the reduced memory requirement for the signals which is of relevance to mobile applications as well as an improvement in the ability of the neural network in its generalization ability due to the more parsimonious representation of the signal to its inputs.

Orexin restores aging-related brown adipose tissue dysfunction in male mice

The aging process causes an increase in percent body fat, but the mechanism remains unclear. In the present study we examined the impact of aging on brown adipose tissue (BAT) thermogenic activity as potential cause for the increase in adiposity. We show that aging is associated with interscapular BAT morphologic abnormalities and thermogenic dysfunction. In vitro experiments revealed that brown adipocyte differentiation is defective in aged mice. Interscapular brown tissue in aged mice is progressively populated by adipocytes bearing white morphologic characteristics. Aged mice fail to mobilize intracellular fuel reserves from brown adipocytes and exhibit deficiency in homeothermy. Our results suggest a role for orexin (OX) signaling in the regulation of thermogenesis during aging. Brown fat dysfunction and age-related assimilation of fat mass were accelerated in mice in which OX-producing neurons were ablated. Conversely, OX injections in old mice increased multilocular morphology, increased core body temperature, improved cold tolerance, and reduced adiposity. These results argue that BAT can be targeted for interventions to reverse age-associated increase in fat mass.