Dopamine and memory dedifferentiation in aging.

The dedifferentiation theory of aging proposes that a reduction in the specificity of neural representations causes declines in complex cognition as people get older, and may reflect a reduction in dopaminergic signaling. The present pharmacological fMRI study investigated episodic memory-related dedifferentiation in young and older adults, and its relation to dopaminergic function, using a randomized placebo-controlled double-blind crossover design with the agonist Bromocriptine (1.25mg) and the antagonist Sulpiride (400mg). We used multi-voxel pattern analysis to measure memory specificity: the degree to which distributed patterns of activity distinguishing two different task contexts during an encoding phase are reinstated during memory retrieval. As predicted, memory specificity was reduced in older adults in prefrontal cortex and in hippocampus, consistent with an impact of neural dedifferentiation on episodic memory representations. There was also a linear age-dependent dopaminergic modulation of memory specificity in hippocampus reflecting a relative boost to memory specificity on Bromocriptine in older adults whose memory was poorer at baseline, and a relative boost on Sulpiride in older better performers, compared to the young. This differed from generalized effects of both agents on task specificity in the encoding phase. The results demonstrate a link between aging, dopaminergic function and dedifferentiation in the hippocampus.This research was funded mainly by a Fellowship to AMM from Research into Ageing, UK, and by an RCUK Academic Fellowship at the University of Edinburgh. Some of the research was conducted by Hunar Abdulrahman as part of a dissertation for the MSc in Neurosciences at the University of Edinburgh. The research was also supported by a Human Brain Project grant from the National Institute of Mental Health and the National Institute of Biomedical Imaging & Bioengineering. PCF was supported by a Wellcome Trust Senior Fellowship in Clinical Science, and by the Bernard Wolfe Health Neuroscience Fund. ETB is a part-time (50%) employee and shareholder of GSK. AMM is a member of the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross-council Lifelong Health and Wellbeing Initiative, Grant number G0700704/84698.This is the accepted manuscript. The final version is available at http://dx.doi.org/10.1016/j.neuroimage.2015.03.03

Does Sleep Improve Your Grammar? : Preferential Consolidation of Arbitrary Components of New Linguistic Knowledge

We examined the role of sleep-related memory consolidation processes in learning new form-meaning mappings. Specifically, we examined a Complementary Learning Systems account, which implies that sleep-related consolidation should be more beneficial for new hippocampally dependent arbitrary mappings (e.g. new vocabulary items) relative to new systematic mappings (e.g. grammatical regularities), which can be better encoded neocortically. The hypothesis was tested using a novel language with an artificial grammatical gender system. Stem-referent mappings implemented arbitrary aspects of the new language, and determiner/suffix+natural gender mappings implemented systematic aspects (e.g. tib scoiffesh + ballerina, tib mofeem + bride; ked jorool + cowboy, ked heefaff + priest). Importantly, the determiner-gender and the suffix-gender mappings varied in complexity and salience, thus providing a range of opportunities to detect beneficial effects of sleep for this type of mapping. Participants were trained on the new language using a word-picture matching task, and were tested after a 2-hour delay which included sleep or wakefulness. Participants in the sleep group outperformed participants in the wake group on tests assessing memory for the arbitrary aspects of the new mappings (individual vocabulary items), whereas we saw no evidence of a sleep benefit in any of the tests assessing memory for the systematic aspects of the new mappings: Participants in both groups extracted the salient determiner-natural gender mapping, but not the more complex suffix-natural gender mapping. The data support the predictions of the complementary systems account and highlight the importance of the arbitrariness/systematicity dimension in the consolidation process for declarative memories

A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data

A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-011-1094-6) contains supplementary material, which is available to authorized users

Multidimensional approach to the study of olfactory fear conditioning in individuals with low and high trait anxiety vulnerability

Introduction: Fear conditioning is a fundamental learning mechanism often used to model anxiety reactions across species. Threat-processing anomalies dependent on anxiety vulnerability have been mostly identified in cognition. However, recent evidence stresses the impact of anxiety on even the earlier stages of stimulus perception (sensory processing) and on the physiological and neurophysiological reactions. To experimentally test the effects of fear conditioning, most studies have used audio-visual material even though emotionally salient odors have been proven to produce stronger emotional reactions than visual stimuli, possibly in virtue of their direct access to amygdala and hippocampus. Here we aim to test, with a multidimensional approach, the impact of anxiety vulnerability on perception, physiological arousal, mean neural activations and activation atterns in an odor-based fear conditioning paradigm. Methods: Twenty-one healthy participants were divided in two subgroups on the basis of their low (LAV) or high (HAV) trait anxiety vulnerability. Event-related perceptual ratings of odor intensity (visual analogous scales, VAS), psychophysiological arousal (skin conductance responses, SCR) and functional magnetic resonance imaging were co-registered within participants over a 20-min period in which odor-threat associations were repeatedly induced. Results: Subjective odor intensity increased post-conditioning for both groups, suggesting experience -dependent sensory evaluation processing. Skin conductance responses were heightened for the HAV as compared to the LAV group, favoring the appearance of differential learning (CS+ vs. CS-) post conditioning. Anxiety vulnerability selectively impacted neural processing in areas of the fear network such as amygdala, insula and cingulate cortex. Multivariate pattern analyses of fMRI activity reveal learning-dependent effects on odor representations within both primary (piriform cortex) and secondary olfactory areas (orbitofrontal cortex) over time. Conclusions: These results indicate that anxiety vulnerability differentially and dynamically modulates perceptual, physiological and neural responses to emotionally salient odors. Taken together, these results contribute to the implication of sensory stimuli in the development and maintenance of anxiety disorders