Molecular Psychiatry最新文献

Children's brains dynamically adapt to the stimuli from the internal state and the external environment, allowing for changes in cognitive and mental behavior. In this work, we performed a large-scale analysis of dynamic functional connectivity (DFC) in children aged 9~11 years, investigating how brain dynamics relate to cognitive performance and mental health at an early age. A hybrid independent component analysis framework was applied to the Adolescent Brain Cognitive Development (ABCD) data containing 10,988 children. We combined a sliding-window approach with k-means clustering to identify five brain states with distinct DFC patterns. Interestingly, the occurrence of a strongly connected state with the most within-network synchrony and the anticorrelations between networks, especially between the sensory networks and between the cerebellum and other networks, was negatively correlated with cognitive performance and positively correlated with dimensional psychopathology in children. Meanwhile, opposite relationships were observed for a DFC state showing integration of sensory networks and antagonism between default-mode and sensorimotor networks but weak segregation of the cerebellum. The mediation analysis further showed that attention problems mediated the effect of DFC states on cognitive performance. This investigation unveils the neurological underpinnings of DFC states, which suggests that tracking the transient dynamic connectivity may help to characterize cognitive and mental problems in children and guide people to provide early intervention to buffer adverse influences.

Specific cognitive abilities (SCA) correlate genetically about 0.50, which underpins general cognitive ability (g), but it also means that there is considerable genetic specificity. If g is not controlled, then genomic prediction of specific cognitive abilities is not truly specific because they are all perfused with g. Here, we investigated the heritability of mathematics, reading, and language ability independent of g (SCA.g) using twins and DNA, and the extent to which multiple genome-wide polygenic scores (multi-PGS) can jointly predict these SCA.g as compared to SCA uncorrected for g. We created SCA and SCA.g composites from a battery of 14 cognitive tests administered at age 12 to 5,000 twin pairs in the Twins Early Development Study (TEDS). Univariate twin analyses yielded an average heritability estimate of 40% for SCA.g, compared to 53% for uncorrected SCA. Using genome-wide SNP genotypes, average SNP-based heritabilities were 26% for SCA.g and 35% for SCA. We then created multi-PGS from at least 50 PGS to predict each SCA and SCA.g using elastic net penalised regression models. Multi-PGS predicted 4.4% of the variance of SCA.g on average, compared to 11.1% for SCA uncorrected for g. The twin, SNP and PGS heritability estimates for SCA.g provide further evidence that the heritabilities of SCA are not merely a reflection of g. Although the relative reduction in heritability from SCA to SCA.g was greater for PGS heritability than for twin or SNP heritability, this decrease is likely due to the paucity of PGS for SCA. We hope that these results encourage researchers to conduct genome-wide association studies of SCA, and especially SCA.g, that can be used to predict PGS profiles of SCA strengths and weaknesses independent of g.

We appreciate the opportunity to respond to Yde Ohki and colleagues’ commentary [1] on our recent publication [2]. We agree with the authors that sufficient and accurate information is critical for experimental reproducibility. Therefore, we added the following missing details and corrected typographical errors in our paper. First, regarding the YFP-STIM1/2 puncta formation assay that we present in Fig. 2I–K, it should have been mentioned in the Puncta Formation Assay section of the Supplementary Information that the pEX-CMV-SP-YFP-STIM1 (Plasmid #18857, initially described in ref. [3]) and pEX-CMV-SP-YFP-STIM2 (Plasmid #18862, initially described in ref. [4]) constructs were purchased from Addgene. Furthermore, 2.5 µg plasmid DNA and 12.5 µL of Lipofectamine 2000 reagent were used per dish for each transfection. Second, in the Neurosphere Assay section of the Supplementary Information, we incorrectly wrote that the …[iPSC/NPCs] were agitated at 75 rpm in NEM for 72 h. This should have been 48 h, as illustrated in Fig. 5A of our paper. And third, two typos concerning cell line ID were identified by Ohki and colleagues: in the legend and caption of Supplementary Fig. S8 we mistakenly wrote PSC-01-121 when this line was PSC-01-122, and we incorrectly wrote GM05440 when it should have been GM05224 in the NanoString miRNA Profiling method section and last row of the Reagent or Resource table in the Supplementary Information. One mention of GM05440 was also corrected to GM05224 in the main paper. Those corrections have been made to the available online documents. We would also like to highlight that p-values were always corrected in the case of multiple comparisons, such as the RNA-sequencing dataset. That information can be found in the Supplementary Methods. We thank the authors for bringing these oversights to our attention and regret any confusion they may have caused.

The six cell lines (3 bipolar disorder patients and 3 healthy controls) that we characterized in our study (PSC-01-024, PSC-01-223, PSC-01-185, PSC-01-003, PSC-01-009, PSC-01-122) were generated as part of NIMH Project Number 5P50MH106933-02 (NIH RePORTER, Neuropsychiatric Genome-Scale and RDOC Individualized Domains, https://reporter.nih.gov/project-details/8929310) and are available through the NIMH Repository & Genomics Resource (Study 163, https://studyreg.nimhgenetics.org/ListOfStudies.jsp). Those cell lines were used in a previous study [5]. Further, two additional cell lines from the Coriell Cell Repository (one healthy control GM8330 and one bipolar disorder GM05224) were included in our NanoString miRNA Profiling experiment. These two lines have been extensively published (for examples, see refs. [6,7,8,9,10,11]). Finally, the use of neural induction supplement to produce neural progenitor cells (NPCs) from human pluripotent stem cells has been used by many other studies (for examples, see refs. [12,13,14,15,16]). This approach, which does not require th

The plasma proteome can mediate associations between periodontal disease (Pd) and brain white matter integrity (WMI). We screened 5089 UK Biobank participants aged 40-70 years for poor oral health problems (POHP). We examined the association between POHP and WMI (fractional anisotropy (FA), mean diffusivity (MD), Intracellular Volume Fraction (ICVF), Isotropic Volume Fraction (ISOVF) and Orientation Diffusion (OD)), decomposing the total effect through the plasma proteome of 1463 proteins into pure mediation, pure interaction, neither, while adjusting for socio-demographic and cardiovascular health factors. Similarly, structural equations modeling (SEM) was conducted. POHP was more prevalent among men (12.3% vs. 9.6%), and was associated with lower WMI on most metrics, in a sex-specific manner. Of 15 proteins strongly associated with POHP, growth differentiation factor 15 (GDF15) and WAP four-disulfide core domain 2 (WFDC2; also known as human epididymis protein 4; HE4) were consistent mediators. Both proteins mediated 7-8% of total POHP effect on FA_mean. SEM yielded significant total effects for FA_mean, MD_mean and ISOVF_mean in full models, with %mediated by common latent factor (GDF15 and WFDC2) ranging between 13% (FA_mean) and 19% (ISOVF_mean). For FA, mediation by this common factor was found for 16 of 49 tract-specific and global mean metrics. Protein metabolism, immune system, and signal transduction were the most common pathways for mediational effects. POHP was associated with poorer WMI, which was partially mediated by GDF15 and WFDC2.

Neurovascular defects are one of the most common alterations in Alzheimer's disease (AD) pathogenesis, but whether these deficits develop before the onset of amyloid beta (Aβ) accumulation remains to be determined. Using in vivo optical imaging in freely moving mice, we explored activity-induced hippocampal microvascular blood flow dynamics in App^SAA knock-in and J20 mouse models of AD at early stages of disease progression. We found that prior to the onset of Aβ accumulation, there was a pathologically elevated blood flow response to context exploration, termed functional hyperemia. After the onset of Aβ accumulation, this context exploration-induced hyperemia declined rapidly relative to that in control mice. Using in vivo electrophysiology recordings to explore the neural circuit mechanism underlying this blood flow alteration, we found that hippocampal interneurons before the onset of Aβ accumulation were hyperactive during context exploration. Chemogenetic tests suggest that hyperactive activation of inhibitory neurons accounted for the elevated functional hyperemia. The suppression of nitric oxide (NO) produced from hippocampal interneurons in young AD mice decreased the accumulation of Aβ. Together, these findings reveal that neurovascular coupling is aberrantly elevated before Aβ deposition, and this hyperactive functional hyperemia declines rapidly upon Aβ accumulation.

Rare recurrent copy number variants (CNVs) at chromosomal loci 22q11.2 and 16p11.2 are genetic disorders with lifespan risk for neuropsychiatric disorders. Microdeletions and duplications are associated with neurocognitive deficits, yet few studies compared these groups using the same measures to address confounding measurement differences. We report a prospective international collaboration applying the same computerized neurocognitive assessment, the Penn Computerized Neurocognitive Battery (CNB), administered in a multi-site study on rare genomic disorders: 22q11.2 deletions (n = 492); 22q11.2 duplications (n = 106); 16p11.2 deletion (n = 117); and 16p11.2 duplications (n = 46). Domains examined include executive functions, episodic memory, complex cognition, social cognition, and psychomotor speed. Accuracy and speed for each domain were included as dependent measures in a mixed-model repeated measures analysis. Locus (22q11.2, 16p11.2) and Copy number (deletion/duplication) were grouping factors and Measure (accuracy, speed) and neurocognitive domain were repeated measures factors, with Sex and Site as covariates. We also examined correlation with IQ. We found a significant Locus × Copy number × Domain × Measure interaction (p = 0.0004). 22q11.2 deletions were associated with greater performance accuracy deficits than 22q11.2 duplications, while 16p11.2 duplications were associated with greater specific deficits than 16p11.2 deletions. Duplications at both loci were associated with reduced speed compared to deletions. Performance profiles differed among the groups with particularly poor memory performance of the 22q11.2 deletion group while the 16p11.2 duplication group had greatest deficits in complex cognition. Average accuracy on the CNB was moderately correlated with Full Scale IQ. Deletions and duplications of 22q11.2 and 16p11.2 have differential effects on accuracy and speed of neurocognition indicating locus specificity of performance profiles. These profile differences can help inform mechanistic substrates to heterogeneity in presentation and outcome, and can only be established in large-scale international consortia using the same neurocognitive assessment. Future studies could aim to link performance profiles to clinical features and brain function.

The amygdala is an established site for fear memory formation, and clinical studies suggest involvement of hormone signaling cascades in development of trauma-related disorders. While an association of thyroid hormone (TH) status and mood disorders is established, the related brain-based mechanisms and the role of TH in anxiety disorders are unknown. Here we examine the role that TH receptor (TR, a nuclear transcriptional repressor when unbound and a transcriptional activator when bound to TH) may have in mediating the initial formation of fear memories in the amygdala. We identified mRNA levels of TR and other TH pathway regulatory genes, including thyrotropin-releasing hormone (Trh), transthyretin (Ttr), thyrotropin-releasing hormone receptor (Trhr), type 2 iodothyronine deiodinase (Dio2), mediator complex subunit 12 (Med12/Trap230) and retinoid X receptor gamma (Rxrg) to be altered in the amygdala following Pavlovian fear conditioning. Using TH agonist and antagonist infusion into the amygdala, we demonstrated that this pathway is both necessary and sufficient for fear memory consolidation. Inhibition of TH signaling with the TR antagonist 1-850 decreased fear memory consolidation; while activation of TR with T3 (triiodothyronine) resulted in increased memory formation. Using a systemic hypothyroid mouse model, we found that intra-amygdala infusions of T3 were sufficient to rescue deficits in fear memory. Finally, we demonstrated that T3 was sufficient to activate TR-specific gene pathways in the amygdala. These findings on the role of activity-dependent TR modulation support a model in which local TH is a critical regulator of fear memory-related plasticity in the amygdala.

The subgenual anterior cingulate cortex (sgACC) has been identified as a key brain area involved in various cognitive and emotional processes. While the sgACC has been implicated in both emotional valuation and emotional conflict monitoring, it is still unclear how this area integrates multiple functions. We characterized both single neuron and local field oscillatory activity in 14 patients undergoing sgACC deep brain stimulation for treatment-resistant depression. During recording, patients were presented with a modified Stroop task containing emotional face images that varied in valence and congruence. We further analyzed spike-field interactions to understand how network dynamics influence single neuron activity in this area. Most single neurons responded to both valence and congruence, revealing that sgACC neuronal activity can encode multiple processes within the same task, indicative of multifunctionality. During peak neuronal response, we observed increased spectral power in low frequency oscillations, including theta-band synchronization (4-8 Hz), as well as desynchronization in beta-band frequencies (13-30 Hz). Theta activity was modulated by current trial congruency with greater increases in spectral power following non-congruent stimuli, while beta desynchronizations occurred regardless of emotional valence. Spike-field interactions revealed that local sgACC spiking was phase-locked most prominently to the beta band, whereas phase-locking to the theta band occurred in fewer neurons overall but was modulated more strongly for neurons that were responsive to task. Our findings provide the first direct evidence of spike-field interactions relating to emotional cognitive processing in the human sgACC. Furthermore, we directly related theta oscillatory dynamics in human sgACC to current trial congruency, demonstrating it as an important regulator during conflict detection. Our data endorse the sgACC as an integrative hub for cognitive emotional processing through modulation of beta and theta network activity.