Heterozygous mutations in CNTNAP2 have been identified in patients with a range of complex phenotypes including intellectual disability, autism and schizophrenia. However heterozygous CNTNAP2 mutations are also found in the normal population. Conversely, homozygous mutations are rare in patient populations and have not been found in any unaffected individuals.

Copy number variants (CNVs) at the Breakpoint 1 to Breakpoint 2 region at 15q11.2 (BP1-2) are associated with language-related difficulties and increased risk for developmental disorders in which language is compromised. Towards underlying mechanisms, we investigated relationships between single nucleotide polymorphisms (SNPs) across the region and quantitative measures of human brain structure obtained by magnetic resonance imaging of healthy subjects. We report an association between rs4778298, a common variant at CYFIP1, and inter-individual variation in surface area across the left supramarginal gyrus (lh.SMG), a cortical structure implicated in speech and language in independent discovery (n = 100) and validation cohorts (n = 2621). In silico analyses determined that this same variant, and others nearby, is also associated with differences in levels of CYFIP1 mRNA in human brain. One of these nearby polymorphisms is predicted to disrupt a consensus binding site for FOXP2, a transcription factor implicated in speech and language. Consistent with a model where FOXP2 regulates CYFIP1 levels and in turn influences lh.SMG surface area, analysis of publically available expression data identified a relationship between expression of FOXP2 and CYFIP1 mRNA in human brain. We propose that altered CYFIP1 dosage, through aberrant patterning of the lh.SMG, may contribute to language-related difficulties associated with BP1-2 CNVs. More generally, this approach may be useful in clarifying the contribution of individual genes at CNV risk loci.

The many subcomponents of the human cortex are known to follow an anatomical pattern and functional relationship that appears to be highly conserved between individuals. This suggests that this pattern and the relationship among cortical regions are important for cortical function and likely shaped by genetic factors, although the degree to which genetic factors contribute to this pattern is unknown. We assessed the genetic relationships among 12 cortical surface areas using brain images and genotype information on 2,364 unrelated individuals, brain images on 466 twin pairs, and transcriptome data on 6 postmortem brains in order to determine whether a consistent and biologically meaningful pattern could be identified from these very different data sets. We find that the patterns revealed by each data set are highly consistent (p<10-3), and are biologically meaningful on several fronts. For example, close genetic relationships are seen in cortical regions within the same lobes and, the frontal lobe, a region showing great evolutionary expansion and functional complexity, has the most distant genetic relationship with other lobes. The frontal lobe also exhibits the most distinct expression pattern relative to the other regions, implicating a number of genes with known functions mediating immune and related processes. Our analyses reflect one of the first attempts to provide an assessment of the biological consistency of a genetic phenomenon involving the brain that leverages very different types of data, and therefore is not just statistical replication which purposefully use very similar data sets.

A fundamental condition for any work with free-ranging animals is correct species identification. However, in case of bats, information on local species assemblies is frequently limited especially in regions with high biodiversity such as the Neotropics. The bat genus Molossus is a typical example of this, with morphologically similar species often occurring in sympatry. We used a multi-method approach based on molecular, morphometric and acoustic information collected from 962 individuals of Molossus bondae, M. coibensis, and M. molossus captured in Panama. We distinguished M. bondae based on size and pelage coloration. We identified two robust species clusters composed of M. molossus and M. coibensis based on 18 microsatellite markers but also on a more stringently determined set of four markers. Phylogenetic reconstructions using the mitochondrial gene co1 (DNA barcode) were used to diagnose these microsatellite clusters as M. molossus and M. coibensis. To differentiate species, morphological information was only reliable when forearm length and body mass were combined in a linear discriminant function (95.9% correctly identified individuals). When looking in more detail at M. molossus and M. coibensis, only four out of 13 wing parameters were informative for species differentiation, with M. coibensis showing lower values for hand wing area and hand wing length and higher values for wing loading. Acoustic recordings after release required categorization of calls into types, yielding only two informative subsets: approach calls and two-toned search calls. Our data emphasizes the importance of combining morphological traits and independent genetic data to inform the best choice and combination of discriminatory information used in the field. Because parameters can vary geographically, the multi-method approach may need to be adjusted to local species assemblies and populations to be entirely informative.

Attentive tracking requires sustained object-based attention, rather than passive vigilance or rapid attentional shifts to brief events. Several theories of tracking suggest a mechanism of indexing objects that allows for attentional resources to be directed toward the moving targets. Imaging studies have shown that cortical areas belonging to the dorsal frontoparietal attention network increase BOLD-signal during multiple object tracking (MOT). Among these areas, some studies have assigned IPS a particular role in object indexing, but the neuroimaging evidence has been sparse. In the present study, we tested participants on a continuous version of the MOT task in order to investigate how cortical areas engage in functional networks during attentional tracking. Specifically, we analyzed the data using eigenvector centrality mapping (ECM) analysis, which provides estimates of individual voxels' connectedness with hub-like parts of the functional network. The results obtained using permutation based voxel-wise statistics support the proposed role for the IPS in object indexing as this region displayed increased centrality during tracking as well as increased functional connectivity with both prefrontal and visual perceptual cortices. In contrast, the opposite pattern was observed for the SPL, with decreasing centrality, as well as reduced functional connectivity with the visual and frontal cortices, in agreement with a hypothesized role for SPL in attentional shifts. These findings provide novel evidence that IPS and SPL serve different functional roles during MOT, while at the same time being highly engaged during tracking as measured by BOLD-signal changes.

Oxytocin is a neuropeptide involved in animal and human reproductive and social behavior. Three oxytocin signaling genes have been frequently implicated in human social behavior: OXT (structural gene for oxytocin), OXTR (oxytocin receptor), and CD38 (oxytocin secretion). Here, we characterized the distribution of OXT, OXTR, and CD38 mRNA across the human brain by creating voxel-by-voxel volumetric expression maps, and identified putative gene pathway interactions by comparing gene expression patterns across 20,737 genes. Expression of the three selected oxytocin pathway genes was enriched in subcortical and olfactory regions and there was high co-expression with several dopaminergic and muscarinic acetylcholine genes, reflecting an anatomical basis for critical gene pathway interactions. fMRI meta-analysis revealed that the oxytocin pathway gene maps correspond with the processing of anticipatory, appetitive, and aversive cognitive states. The oxytocin signaling system may interact with dopaminergic and muscarinic acetylcholine signaling to modulate cognitive state processes involved in complex human behaviors.

Schizophrenia is a severe mental disorder characterized by numerous subtle changes in brain structure and function. Machine learning allows exploring the utility of combining structural and functional brain magnetic resonance imaging (MRI) measures for diagnostic application, but this approach has been hampered by sample size limitations and lack of differential diagnostic data. Here, we performed a multi-site machine learning analysis to explore brain structural patterns of T1 MRI data in 2668 individuals with schizophrenia, bipolar disorder or attention-deficit/ hyperactivity disorder, and healthy controls. We found reproducible changes of structural parameters in schizophrenia that yielded a classification accuracy of up to 76% and provided discrimination from ADHD, through it lacked specificity against bipolar disorder. The observed changes largely indexed distributed grey matter alterations that could be represented through a combination of several global brain-structural parameters. This multi-site machine learning study identified a brain-structural signature that could reproducibly differentiate schizophrenia patients from controls, but lacked specificity against bipolar disorder. While this currently limits the clinical utility of the identified signature, the present study highlights that the underlying alterations index substantial global grey matter changes in psychotic disorders, reflecting the biological similarity of these conditions, and provide a roadmap for future exploration of brain structural alterations in psychiatric patients.

Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.

Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.

Fatigue and depression are frequent and often co-occurring symptoms in multiple sclerosis (MS). Resting-state functional magnetic resonance imaging (rs-fMRI) represents a promising tool for disentangling differential associations between depression and fatigue and brain network function and connectivity. In this study we tested for associations between symptoms of fatigue and depression and DMN connectivity in patients with MS.

The growth of the vertebrate skull and brain is usually unidirectional and more or less stops when animals are adult. Red-toothed shrews break this rule. They seasonally shrink and regrow brain and skull size by 20% or more, presumably to save energy when conditions are harsh. The size change is anticipatory of environmental change and occurs in all individuals, but it is unknown whether its extent can be modulated by environmental conditions. We kept shrews under different conditions, monitored seasonal changes in skull size with series of X-rays, and compared them with free ranging animals. We found extensive differences in the pattern of skull size change between experimental groups. Skull size of shrews kept at constant temperature showed a steady decline, while the skull size changes of free ranging shrews and captive individuals exposed to natural temperature regimes were identical. In contrast, body mass never reached the spring values of free ranging shrews in either captive regime. The extent of this adaptive seasonal pattern can thus be flexibly adapted to current environmental conditions. Combining reversible size changes with such strong phenotypic plasticity may allow these small, non-hibernating predators with high metabolic rates to continue being successful in today's changing environments.

The intercalated cells (ITCs) of the amygdala have been shown to be critical regulatory components of amygdalar circuits, which control appropriate fear responses. Despite this, the molecular processes guiding ITC development remain poorly understood. Here we establish the zinc finger transcription factor Tshz1 as a marker of ITCs during their migration from the dorsal lateral ganglionic eminence through maturity. Using germline and conditional knock-out (cKO) mouse models, we show that Tshz1 is required for the proper migration and differentiation of ITCs. In the absence of Tshz1, migrating ITC precursors fail to settle in their stereotypical locations encapsulating the lateral amygdala and BLA. Furthermore, they display reductions in the ITC marker Foxp2 and ectopic persistence of the dorsal lateral ganglionic eminence marker Sp8. Tshz1 mutant ITCs show increased cell death at postnatal time points, leading to a dramatic reduction by 3 weeks of age. In line with this, Foxp2-null mutants also show a loss of ITCs at postnatal time points, suggesting that Foxp2 may function downstream of Tshz1 in the maintenance of ITCs. Behavioral analysis of male Tshz1 cKOs revealed defects in fear extinction as well as an increase in floating during the forced swim test, indicative of a depression-like phenotype. Moreover, Tshz1 cKOs display significantly impaired social interaction (i.e., increased passivity) regardless of partner genetics. Together, these results suggest that Tshz1 plays a critical role in the development of ITCs and that fear, depression-like and social behavioral deficits arise in their absence.SIGNIFICANCE STATEMENT We show here that the zinc finger transcription factor Tshz1 is expressed during development of the intercalated cells (ITCs) within the mouse amygdala. These neurons have previously been shown to play a crucial role in fear extinction. Tshz1 mouse mutants exhibit severely reduced numbers of ITCs as a result of abnormal migration, differentiation, and survival of these neurons. Furthermore, the loss of ITCs in mouse Tshz1 mutants correlates well with defects in fear extinction as well as the appearance of depression-like and abnormal social interaction behaviors reminiscent of depressive disorders observed in human patients with distal 18q deletions, including the Tshz1 locus.

Cognitive aging is accompanied by a range of structural and functional differences in the brain, even in the absence of neurodegenerative disease. Functional magnetic resonance imaging (fMRI) studies have reported increased bilateral activation during task performance in elderly participants compared to their younger counterparts, particularly in frontal regions. Alterations have also been observed in the functional architecture of the resting brain, suggesting that aging is associated with changes in the organization of the networks of the brain. However, previous studies have largely focused on the default mode network, and little is known about the effects of age on other resting state-networks (RSNs). The aim of the present study was to investigate age-differences in resting state functional connectivity (RSFC) using fMRI data obtained during rest from 238 healthy participants aged 21-80 years. Using independent component analysis (ICA) and dual-regression, the results revealed age-related increases in RSFC across a range of RSNs, including task-positive networks in frontal and parietal regions. In contrast, age-related reductions in the default mode network and occipital visual networks were observed. Furthermore, whereas the effects of age on the various RSNs were found independent of age-related decreases in gray matter volume, sex and subject motion, we report strong positive and widespread effects of estimated subject motion on the RSFC across RSNs. The results provide support for the notion of network-specific effects in aging, manifested as increased tonic activation of task-positive networks, supporting higher-order cognitive functions and cognitive control, along with reduced task-negative default mode network and sensory visual networks during rest. The present results also corroborate recent evidence of strong influence of subject motion on estimated functional connectivity measures and strongly suggest that studies using RSFC measures as imaging phenotypes should adjust for individual differences in in-scanner subject motion.

Retinoic acid-related orphan receptor alpha gene (RORa) and the microRNA MIR137 have both recently been identified as novel candidate genes for neuropsychiatric disorders. RORa encodes a ligand-dependent orphan nuclear receptor that acts as a transcriptional regulator and miR-137 is a brain enriched small non-coding RNA that interacts with gene transcripts to control protein levels. Given the mounting evidence for RORa in autism spectrum disorders (ASD) and MIR137 in schizophrenia and ASD, we investigated if there was a functional biological relationship between these two genes. Herein, we demonstrate that miR-137 targets the 3'UTR of RORa in a site specific manner. We also provide further support for MIR137 as an autism candidate by showing that a large number of previously implicated autism genes are also putatively targeted by miR-137. This work supports the role of MIR137 as an ASD candidate and demonstrates a direct biological link between these previously unrelated autism candidate genes.

We hypothesized that higher levels of omega-3 fatty acids, vitamin D, and physical activity relate to cortical sparing, whereas higher levels of cholesterol, systolic blood pressure, and body mass index (BMI) relate to increased atrophy in the adult lifespan. Longitudinal measures of cortical thickness were derived from magnetic resonance imaging scans acquired (mean interval 3.6 years) from 203 healthy persons aged 23-87 years. At follow-up, measures of BMI, blood pressure, and physical activity were obtained. Blood levels of docosahexaenoic acid, eicosapentaenoic acid, vitamin D, and cholesterol were measured in a subsample (n = 92). Effects were tested in cortical surface-based analyses, with sex, age, follow-up interval, and the interactions between each included as covariates. Higher levels of docosahexaenoic acid, vitamin D, and physical activity related to cortical sparing. Higher cholesterol and BMI related to increased cortical thinning. Effects were independent, did not interact with age, and the cholesterol effect was restricted to males. Eicosapentaenoic acid and blood pressure showed no effects. The observed effects show promise for potential factors to reduce cortical atrophy in normal aging.

Single nucleotide polymorphisms (SNPs) within the MIR137, TCF4, and ZNF804A genes show genome-wide association to schizophrenia. However, the biological basis for the associations is unknown. Here, we tested the effects of these genes on brain structure in 1300 healthy adults. Using volumetry and voxel-based morphometry, neither gene-wide effects--including the combined effect of the genes--nor single SNP effects--including specific psychosis risk SNPs--were found on total brain volume, grey matter, white matter, or hippocampal volume. These results suggest that the associations between these risk genes and schizophrenia are unlikely to be mediated via effects on macroscopic brain structure.

The genetic determinants of cerebral asymmetries are unknown. Sex differences in asymmetry of the planum temporale (PT), that overlaps Wernicke's classical language area, have been inconsistently reported. Meta-analysis of previous studies has suggested that publication bias established this sex difference in the literature. Using probabilistic definitions of cortical regions we screened over the cerebral cortex for sexual dimorphisms of asymmetry in 2337 healthy subjects, and found the PT to show the strongest sex-linked asymmetry of all regions, which was supported by two further datasets, and also by analysis with the FreeSurfer package that performs automated parcellation of cerebral cortical regions. We performed a genome-wide association scan (GWAS) meta-analysis of PT asymmetry in a pooled sample of 3095 subjects, followed by a candidate-driven approach which measured a significant enrichment of association in genes of the 'steroid hormone receptor activity' and 'steroid metabolic process' pathways. Variants in the genes and pathways identified may affect the role of the PT in language cognition.

Oxytocin has been proposed to mediate amygdala dysfunction associated with altered emotion processing in schizophrenia, but the contribution of oxytocin pathway genes is yet to be investigated.

Converging evidence demonstrates the important role of the neuropeptide hormone oxytocin (OT) in human behaviour and cognition. Intranasal OT administration has been shown to improve several aspects of social communication, such as the theory of mind performance and gaze to the eye region, and reduce anxiety and related negative cognitive appraisals. While this early research has demonstrated the potential for intranasal OT to treat psychiatric illnesses characterized by social impairments, the neurobiological mechanisms are not well known. Researchers have used functional magnetic resonance imaging (fMRI) to examine the neural correlates of OT response; however, results have been variable and moderating factors are poorly understood. The aim of this meta-analysis is to synthesize data examining the impact of intranasal OT administration on neural activity.

An abundance of experimental studies have motivated a range of models concerning the cognitive underpinnings of severe mental disorders, yet the conception that cognitive and brain dysfunction is confined to specific cognitive domains and contexts has limited ecological validity. Schizophrenia and bipolar spectrum disorders have been conceptualized as disorders of brain connectivity; yet little is known about the pervasiveness across cognitive tasks.