A human stem cell resource to decipher the biochemical and cellular basis of neurodevelopmental defects in Lowe Syndrome

Human brain development is a complex process where multiple cellular and developmental events are co-ordinated to generate normal structure and function. Alteration in any of these events can impact brain development, manifesting clinically as neurodevelopmental disorders. Human genetic disorders of lipid metabolism often present with features of altered brain function. Lowe syndrome (LS), is a X-linked recessive disease with features of altered brain function. LS results from mutations in OCRL1 that encodes a phosphoinositide 5-phosphatase enzyme. However, the cellular mechanisms by which loss of OCRL1 leads to brain defects remain unknown. Human brain development involves several cellular and developmental features not conserved in other species and understanding such mechanisms remains a challenge. Rodent models of LS have been generated, but failed to recapitulate features of the human disease. Here we describe the generation of human stem cell lines from LS patients. Further, we present biochemical characterization of lipid metabolism in patient cell lines and demonstrate their use as a “disease-in-a-dish” model for understanding the mechanism by which loss of OCRL1 leads to altered cellular and physiological brain development.

Low and high frequency intracranial neural signals match in the human associative cortex

In vivo intracranial recordings of neural activity offer a unique opportunity to understand human brain function. Intracranial electrophysiological (iEEG) activity related to sensory, cognitive or motor events manifests mostly in two types of signals: event-related local field potentials in lower frequency bands (<30 Hz, LF) and broadband activity in the higher end of the frequency spectrum (>30 Hz, High frequency, HF). While most current studies rely exclusively on HF, thought to be more focal and closely related to spiking activity, the relationship between HF and LF signals is unclear, especially in human associative cortex. Here we provide a large-scale in-depth investigation of the spatial and functional relationship between these 2 signals based on intracranial recordings from 121 individual brains (8000 recording sites). We measure selective responses to complex ecologically salient visual stimuli – human faces - across a wide cortical territory in the ventral occipito-temporal cortex (VOTC), with a frequency-tagging method providing high signal-to-noise ratio (SNR) and the same objective quantification of signal and noise for the two frequency ranges. While LF face-selective activity has higher SNR across the VOTC, leading to a larger number of significant electrode contacts especially in the anterior temporal lobe, LF and HF display highly similar spatial, functional, and timing properties. Specifically, and contrary to a widespread assumption, our results point to nearly identical spatial distribution and local spatial extent of LF and HF activity at equal SNR. These observations go a long way towards clarifying the relationship between the two main iEEG signals and reestablish the informative value of LF iEEG to understand human brain function.

Scene Context Impairs Perception of Semantically Congruent Objects

Visual scene context is well-known to facilitate the recognition of scene-congruent objects. Interestingly, however, according to predictive-processing accounts of brain function, scene congruency may lead to reduced (rather than enhanced) processing of congruent objects, compared with incongruent ones, because congruent objects elicit reduced prediction-error responses. We tested this counterintuitive hypothesis in two online behavioral experiments with human participants ( N = 300). We found clear evidence for impaired perception of congruent objects, both in a change-detection task measuring response times and in a bias-free object-discrimination task measuring accuracy. Congruency costs were related to independent subjective congruency ratings. Finally, we show that the reported effects cannot be explained by low-level stimulus confounds, response biases, or top-down strategy. These results provide convincing evidence for perceptual congruency costs during scene viewing, in line with predictive-processing theory.

Brain responses in aggression-prone individuals: A systematic review and meta-analysis of functional magnetic resonance imaging (fMRI) studies of anger- and aggression-eliciting tasks

Background: While reactive aggression (in response to a perceived threat or provocation) is part of humans' adaptive behavioral repertoire, it can violate social and legal norms. Understanding brain function in individuals with high levels of reactive aggression as they process anger- and aggression-eliciting stimuli is critical for refining interventions. Three neurobiological models of reactive aggression - the limbic hyperactivity, prefrontal hypoactivity, and dysregulated limbic-prefrontal connectivity models - have been proposed. However, these models are based on neuroimaging studies involving mainly healthy individuals, leaving it unclear which model best describes brain function in aggression-prone individuals. Methods: We conducted a systematic literature search (PubMed and Psycinfo) and Multilevel Kernel Density meta-analysis (MKDA) of nine functional magnetic resonance imaging (fMRI) studies of brain responses to tasks putatively eliciting anger and aggression in aggression-prone individuals alone, and relative to healthy controls. Results: Aggression-prone individuals exhibited greater activity during reactive aggression relative to baseline in the superior temporal gyrus and in regions comprising the cognitive control and default mode networks (right posterior cingulate cortex, precentral gyrus, precuneus, right inferior frontal gyrus). Compared to healthy controls, aggression-prone individuals exhibited increased activity in limbic regions (left hippocampus, left amygdala, left parahippocampal gyrus) and temporal regions (superior, middle, inferior temporal gyrus), and reduced activity in occipital regions (left occipital cortex, left calcarine cortex). Conclusions: These findings lend support to the limbic hyperactivity model and further indicate altered temporal and occipital activity in anger- and aggression-eliciting situations that involve face and speech processing.

Functional interdependence of the actin regulators CAP1 and cofilin1 in control of dendritic spine morphology

The vast majority of excitatory synapses are formed on small dendritic protrusions termed dendritic spines. Dendritic spines vary in size and density that are both crucial determinants of excitatory synaptic transmission. Aberrations in spine morphogenesis can compromise brain function and have been associated with neuropsychiatric disorders. Because actin filaments (F-actin) are the major structural component in spines, actin-binding proteins (ABP) that control F-actin dis-/assembly moved into the focus as critical regulators of brain function. Indeed, mouse studies identified the ABP cofilin1 as a key regulator of spine morphology, synaptic transmission and behavior. These studies emphasized the necessity for a tight control of cofilin1 to ensure proper brain function. We report spine enrichment of cyclase-associated protein 1 (CAP1), a conserved multidomain protein with largely unknown physiological functions. Super-resolution microscopy and live cell imaging of CAP1-deficient hippocampal neurons revealed impaired synaptic F-actin organization and dynamics associated with alterations in spine morphology. Mechanistically, we found that CAP1 cooperated with cofilin1 in spines and that its helical folded domain mediated this interaction. Moreover, our data proved functional interdependence of CAP1 and cofilin1 in control of spine morphology. In summary, we identified CAP1 as a novel regulator of the postsynaptic actin cytoskeleton that was essential for synaptic cofilin1 activity.

Effects of the DRD4 −521 C/T SNP on Local Neural Activity and Functional Connectivity in Children With ADHD

Objective: The present study aimed to investigate the effects of the dopamine receptor D4 (DRD4) −521 C/T single-nucleotide polymorphism on brain function among children with attention deficit hyperactivity disorder (ADHD) and to evaluate whether brain function is associated with behavioral performance among this demographic.Methods: Using regional homogeneity, fractional amplitude low-frequency fluctuation, and functional connectivity as measurement indices, we compared differences in resting-state brain function between 34 boys with ADHD in the TT homozygous group and 37 boys with ADHD in the C-allele carrier group. The Conners' Parent Rating Scale, the SNAP-IV Rating Scale, the Stroop Color Word Test, the go/no-go task, the n-back task, and the working memory index within the Wechsler Intelligence Scale for Children-Fourth Edition were selected as comparative indicators in order to test effects on behavioral performance.Results: We found that TT homozygotes had low behavioral performance as compared with C-allele carriers. The regional homogeneity for TT homozygotes decreased in the right middle occipital gyrus and increased in the right superior frontal gyrus as compared with C-allele carriers. In addition, the right middle occipital gyrus and the right superior frontal gyrus were used as the seeds of functional connectivity, and we found that the functional connectivity between the right middle occipital gyrus and the right cerebellum decreased, as did the functional connectivity between the right superior frontal gyrus and the angular gyrus. No statistically significant differences were observed in the respective brain regions when comparing the fractional amplitudes for low-frequency fluctuation between the two groups. Correlation analyses demonstrated that the fractional amplitude low-frequency fluctuation in the precentral gyrus for TT homozygotes were statistically significantly correlated with working memory.Conclusions: We found differing effects of DRD4 −521 C/T polymorphisms on brain function among boys with ADHD. These findings promote our understanding of the genetic basis for neurobiological differences observed among children with ADHD, but they must be confirmed in larger samples.

Toward the Decipherment of Molecular Interactions in the Diabetic Brain

Diabetes mellitus (DM) has been associated with cognitive complications in the brain resulting from acute and chronic metabolic disturbances happening peripherally and centrally. Numerous studies have reported on the morphological, electrophysiological, biochemical, and cognitive changes in the brains of diabetic individuals. The detailed pathophysiological mechanisms implicated in the development of the diabetic cognitive phenotype remain unclear due to intricate molecular changes evolving over time and space. This review provides an insight into recent advances in understanding molecular events in the diabetic brain, focusing on cerebral glucose and insulin uptake, insulin action in the brain, and the role of the brain in the regulation of glucose homeostasis. Fully competent mitochondria are essential for energy metabolism and proper brain function; hence, the potential contribution of mitochondria to the DM-induced impairment of the brain is also discussed.

Interaction of Gut Microbiota and Brain Function in Patients With Chronic Insomnia: A Regional Homogeneity Study

Recent studies have shown that the human gut microbiota (GM) plays a critical role in brain function and behavior via the complex microbiome–gut–brain axis. However, knowledge about the underlying relationship between the GM and changes in brain function in patients with chronic insomnia (CI) is still very limited. In this prospective study, 31 CI patients and 30 healthy controls were recruited. Resting-state functional magnetic resonance imaging scans were performed and brain functional alterations in CI patients were evaluated using the regional homogeneity (ReHo) method. We collected fecal samples of CI patients and used 16S rDNA amplicon sequencing to assess the relative abundance (RA) and alpha diversity of the GM. We also performed extensive sleep, mood, and cognitive assessments. Then, we tested for potential associations between the GM profile, ReHo alterations, and neuropsychological changes in CI patients. Our results showed associations between the RA of Lactobacilli, ReHo values in the left fusiform gyrus, and depression scores in CI patients. We also found some bacterial genera related to ReHo values of the right triangular inferior frontal gyrus. In addition, the RA of genus Coprobacter was correlated with ReHo values of the left angular gyrus and with specific cognitive performance. These findings revealed complex relationships between GM, brain function, and behavior in patients with CI.

Image Features of Resting-State Functional Magnetic Resonance Imaging in Evaluating Poor Emotion and Sleep Quality in Patients with Chronic Pain under Artificial Intelligence Algorithm

The balanced iterative reducing and clustering using hierarchies (BIRCH) method was adopted to optimize the results of the resting-state functional magnetic resonance imaging (RS-fMRI) to analyze the changes in the brain function of patients with chronic pain accompanied by poor emotion or abnormal sleep quality in this study, so as to provide data support for the prevention and treatment of clinical chronic pain with poor emotion or sleep quality. 159 patients with chronic pain who visited the hospital were selected as the research objects, and they were grouped according to the presence or absence of abnormalities in emotion and sleep. The patients without poor emotion and sleep quality were set as the control group (60 cases), and the patients with the above symptoms were defined in the observation group (90 cases). The brain function was detected by RS-fMRI technology based on the BIRCH algorithm. The results showed that the rand index (RI), adjustment of RI (ARI), and Fowlkes–Mallows index (FMI) results in the k-means, flow cytometry (FCM), and BIRCH algorithms were 0.82, 0.71, and 0.88, respectively. The scores of Hamilton Depression Scale (HAHD), Hamilton Anxiety Scale (HAMA), and Pittsburgh Sleep Quality Index (PSQI) were 7.26 ± 3.95, 7.94 ± 3.15, and 8.03 ± 4.67 in the observation group and 4.03 ± 1.95, 5.13 ± 2.35, and 4.43 ± 2.07 in the control group; the higher proportion of RS-fMRI was with abnormal brain signal connections. A score of 7 or more meant that the number of brain abnormalities was more than 90% and that of less than 7 was less than 40%, showing a statistically obvious difference in contrast P < 0.05 . Therefore, the BIRCH clustering algorithm showed reliable value in the optimization of RS-fMRI images, and RS-fMRI showed high application value in evaluating the emotion and sleep quality of patients with chronic pain.

Cavβ surface charged residues contribute to the regulation of neuronal calcium channels

Voltage-gated calcium channels are essential regulators of brain function where they support depolarization-induced calcium entry into neurons. They consist of a pore-forming subunit (Cavα1) that requires co-assembly with ancillary subunits to ensure proper functioning of the channel. Among these ancillary subunits, the Cavβ plays an essential role in regulating surface expression and gating of the channels. This regulation requires the direct binding of Cavβ onto Cavα1 and is mediated by the alpha interacting domain (AID) within the Cavα1 subunit and the α binding pocket (ABP) within the Cavβ subunit. However, additional interactions between Cavα1 and Cavβ have been proposed. In this study, we analyzed the importance of Cavβ3 surface charged residues in the regulation of Cav2.1 channels. Using alanine-scanning mutagenesis combined with electrophysiological recordings we identified several amino acids within the Cavβ3 subunit that contribute to the gating of the channel. These findings add to the notion that additional contacts besides the main AID/ABP interaction may occur to fine-tune the expression and properties of the channel.