Friday, June 21st, 2024

Time	Event
9:20a	Sex Differences in Human Brain Structure at Birth Sex differences in human brain anatomy have been well-documented; however, their underlying causes remain controversial. Neonatal research offers a pivotal opportunity to address this long-standing debate. Given that postnatal environmental influences (e.g., gender socialisation) are minimal at birth, any sex differences observed at this stage can be more readily attributed to prenatal influences. Here, we assessed on-average sex differences in global and regional brain volumes in 514 newborns (236 birth-assigned females and 278 birth-assigned males) using data from the developing Human Connectome Project. On average, males had significantly larger intracranial and total brain volumes, even after controlling for birth weight. After controlling for total brain volume, females showed higher total cortical gray matter volumes, whilst males showed higher total white matter volumes. After controlling for total brain volume in regional comparisons, females had increased white matter volumes in the corpus callosum and increased gray matter volumes in the bilateral parahippocampal gyri (posterior parts), left anterior cingulate gyrus, bilateral parietal lobes, and right caudate nucleus. Males had increased gray matter volumes in the right medial and inferior temporal gyrus (posterior part) and right subthalamic nucleus. Effect sizes ranged from small for regional comparisons to large for global comparisons. While postnatal experiences likely amplify sex differences in the brain, our findings demonstrate that several global and regional on-average sex differences are already present at birth. (Comment on this)
9:20a	The transcriptomic architecture of the human cerebral cortex For over a century, scientists have been attempting to map the human cerebral cortex, however, they have not taken into account the complex molecular structure of the cortex, which is only beginning to be understood. Here, we parcellate the human cerebral cortex using a machine learning (ML) approach to define its transcriptomic architecture, revealing a multi-resolution organization across individuals. The transcriptomically-derived spatial patterns of gene expression separate the cortex into three major regions, frontal, temporal and parietooccipital, with smaller subregions appearing at lower levels of the transcriptomic hierarchy. The core regions, which remain stable across different hierarchical levels, are physiologically associated with language, emotion regulation, social cognition, motor and visuospatial processing and planning. Importantly, some core regions cross structural and anatomical boundaries identified in previous parcellations of the cortex, revealing that the transcriptomic architecture of the cortex is closely linked to human-specific higher cognitive function. (Comment on this)
9:20a	Privileged representational axes in biological and artificial neural networks How do neurons code information? Recent work emphasizes properties of population codes, such as their geometry and decodable information, using measures that are blind to the native tunings (or axes) of neural responses. But might these representational axes matter, with some privileged systematically over others? To find out, we developed methods to test for alignment of neural tuning across brains and deep convolutional neural networks (DCNNs). Across both vision and audition, both brains and DCNNs consistently favored certain axes for representing the natural world. Moreover, the representational axes of DCNNs trained on natural inputs were aligned to those in perceptual cortices, such that axis-sensitive model-brain similarity metrics better differentiated competing models of biological sensory systems. We further show that coding schemes that privilege certain axes can reduce downstream wiring costs and improve generalization. These results motivate a new framework for understanding neural tuning in biological and artificial networks and its computational benefits. (Comment on this)
9:20a	Connectivity profile and function of uniquely human cortical areas Quantitative comparison of the white matter organization of the human neocortex with that of the chimpanzee and macaque shows a wide distribution of areas with a uniquely human connectivity profile, including the frontal-parietal fiber systems and the temporal visual pathway. Functional decoding of these areas shows their involvement in language, abstract reasoning, and social information processing. Overall, these results counter models that assign primacy to prefrontal cortex for human uniqueness. (Comment on this)
9:20a	Theta-phase locking of single neurons during human spatial memory The precise timing of single-neuron activity in relation to local field potentials may support various cognitive functions. Extensive research in rodents, along with some evidence in humans, suggests that single-neuron activity at specific phases of theta oscillations plays a crucial role in memory processes. Our fundamental understanding of such theta-phase locking in humans and its dependency on basic electrophysiological properties of the local field potential is still limited, however. Here, using single-neuron recordings in epilepsy patients performing a spatial memory task, we thus aimed at improving our understanding of factors modulating theta-phase locking in the human brain. Combining a generalized-phase approach for frequency-adaptive theta-phase estimation with time-resolved spectral parameterization, our results show that theta-phase locking is a strong and prevalent phenomenon across human medial temporal lobe regions, both during spatial memory encoding and retrieval. Neuronal theta-phase locking increased during periods of elevated theta power, when clear theta oscillations were present, and when aperiodic activity exhibited steeper slopes. Theta-phase locking was similarly strong during successful and unsuccessful memory, and most neurons activated at similar theta phases between encoding and retrieval. Some neurons changed their preferred theta phases between encoding and retrieval, in line with the idea that different memory processes are separated within the theta cycle. Together, these results help disentangle how different properties of local field potentials and memory states influence theta-phase locking of human single neurons. This contributes to a better understanding of how interactions between single neurons and local field potentials may support human spatial memory. (Comment on this)
9:20a	A low-activity cortical network selectively encodes syntax Syntax, the abstract structure of language, is a hallmark of human cognition. Despite its importance, its neural underpinnings remain obscured by inherent limitations of non-invasive brain measures and a near total focus on comprehension paradigms. Here, we address these limitations with high-resolution neurosurgical recordings (electrocorticography) and a controlled sentence production experiment. We uncover three syntactic networks that are broadly distributed across traditional language regions, but with focal concentrations in middle and inferior frontal gyri. In contrast to previous findings from comprehension studies, these networks process syntax mostly to the exclusion of words and meaning, supporting a cognitive architecture with a distinct syntactic system. Most strikingly, our data reveal an unexpected property of syntax: it is encoded independent of neural activity levels. We propose that this "low-activity coding" scheme represents a novel mechanism for encoding information, reserved for higher-order cognition more broadly. (Comment on this)
11:15a	Neurotransmitter release is triggered by a calcium-induced rearrangement in the Synaptotagmin-1/SNARE complex primary interface The Ca2+ sensor synaptotagmin-1 triggers neurotransmitter release together with the neuronal SNARE complex formed by syntaxin-1, SNAP25 and synaptobrevin. Moreover, synaptotagmin-1 increases synaptic vesicle priming and impairs spontaneous vesicle release. The synaptotagmin-1 C2B domain binds to the SNARE complex through a primary interface via two regions (I and II), but how exactly this interface mediates distinct functions of synaptotagmin-1, and the mechanism underlying Ca2+-triggering of release is unknown. Using mutagenesis and electrophysiological experiments, we show that region II is functionally and spatially subdivided: binding of C2B domain arginines to SNAP-25 acidic residues at one face of region II is crucial for Ca2+-evoked release but not for vesicle priming or clamping of spontaneous release, whereas other SNAP-25 and syntaxin-1 acidic residues at the other face mediate priming and clamping of spontaneous release but not evoked release. Mutations that disrupt region I impair the priming and clamping functions of synaptotagmin-1 while, strikingly, mutations that enhance binding through this region increase vesicle priming and clamping of spontaneous release, but strongly inhibit evoked release and vesicle fusogenicity. These results support previous findings that the primary interface mediates the functions of synaptotagmin-1 in vesicle priming and clamping of spontaneous release, and, importantly, show that Ca2+-triggering of release requires a rearrangement of the primary interface involving dissociation of region I, while region II remains bound. Together with modeling and biophysical studies presented in the accompanying paper, our data suggest a model whereby this rearrangement pulls the SNARE complex to facilitate fast synaptic vesicle fusion. Significance statementThe synaptic SNARE complex and synaptotagmin-1 are required for fast neurotransmitter release. The functions of synaptotagmin-1 in preparing synaptic vesicles for fusion and executing the triggering step have been proposed to be regulated through interactions with the SNARE complex via the so-called primary interface. Using site-directed mutagenesis and functional analysis in neurons, we now show that synaptotagmin-1 mediates its release preparatory functions via two contact sites with the SNARE complex at this interface. During Ca2+ triggering, synaptotagmin-1 continues to contact the SNAREs at one site but disconnects the other site. We propose that this switch generates a pulling force on the SNARE complex that in turn triggers release. Biochemical and modeling studies described in the accompanying paper support this hypothesis. (Comment on this)
12:35p	Cortical synaptic vulnerabilities revealed in a α-synuclein aggregation model of Parkinson's disease Cognitive impairment is a frequent non-motor symptom in Parkinson's disease, and cortical Lewy pathology is strongly associated with cognitive decline. Synaptic pathology has been observed in the PD cortex, but the extent of synaptic vulnerabilities and their temporal and spatial relationship to pathology remains unclear. We employed high-resolution imaging to analyze synaptic abnormalities in layer 5 of the secondary motor cortex. We used striatal injections of -synuclein pre-formed fibrils as a model to cause the progressive pathological aggregation of endogenous -synuclein. We find that cortical -synuclein pathology results in the progressive loss of excitatory synapses, followed by a reduction in inhibitory postsynaptic sites. Synapse loss is most pronounced in areas with high pathology. Additionally, we observed ultrastructural changes in the remaining excitatory synaptic loci, including smaller synaptic vesicles. Consistent with these results, gene ontology analysis of synaptic genes exhibiting altered expression in pathological neurons supported pre- and post-synaptic changes, including in synapse organizing pathways. Our results demonstrate that -synuclein aggregation in the cortex is linked to molecular and structural alterations that disrupt synaptic connectivity and provide insights into the progressive PD-relevant vulnerability of cortical synapses. (Comment on this)
6:18p	Movie reconstruction from mouse visual cortex activity The ability to reconstruct imagery represented by the brain has the potential to give us an intuitive understanding of what the brain sees. Reconstruction of visual input from human fMRI data has garnered significant attention in recent years. Comparatively less focus has been directed towards vision reconstruction from single-cell recordings, despite its potential to provide a more direct measure of the information represented by the brain. Here, we achieve high-quality reconstructions of videos presented to mice, from the activity of neurons in their visual cortex. Using our method of video optimization via gradient descent through a state-of-the-art dynamic neural encoding model we reliably reconstruct 10-second movies at 30 Hz from two-photon calcium imaging data. We achieve a {approx} 2-fold increase in pixel-by-pixel correlation compared to previous reconstructions of static images from mouse V1, while also capturing temporal dynamics. We find that critical for high-quality reconstructions are the number of neurons in the dataset and the use of model ensembling. (Comment on this)
6:18p	Childhood brain morphometry in children with persistent stunting and catch-up growth Background: Early childhood stunting affects around 150 million young children worldwide and leads to suboptimal human potential in later life. However, there is limited data on the effects of early childhood stunting and catch-up growth on brain morphometry. Methods: We evaluated childhood brain volumes at nine years of age in a community-based birth-cohort follow-up study in Vellore, south India among four groups based on anthropometric assessments at two, five, and nine years namely 'Never Stunted' (NS), 'Stunted at two years and caught up by five years' (S2N5), 'Stunted at two and five years and caught up by nine years' (S2N9), and 'Always Stunted' (AS). T1-weighted magnetic resonance imaging (MRI) images were acquired using a 3T MRI scanner, and brain volumes were quantified using FreeSurfer software. Findings: Amongst 251 children from the overall cohort, 178 children with a mean age of 9.54 were considered for further analysis. The total brain volume, subcortical volume, bilateral cerebellar white matter, and posterior corpus callosum showed a declining trend from NS to AS. Regional cortical brain analysis showed significant lower bilateral lateral occipital volumes, right pallidum, bilateral caudate, and right thalamus volumes between NS and AS. Interpretation: To the best of our knowledge, this first neuroimaging analysis to investigate the effects of persistent childhood stunting and catch-up growth on brain volumetry indicates impairment at different brain levels involving total brain and subcortical volumes, networking/connecting centres (thalamus, basal ganglia, callosum, cerebellum) and visual processing area of lateral occipital cortex. (Comment on this)
7:33p	Transcriptional pathobiology and multi-omics predictors for Parkinson's disease Early diagnosis and biomarker discovery to bolster the therapeutic pipeline for Parkinson's disease (PD) are urgently needed. In this study, we leverage the large-scale whole-blood total RNA-seq dataset from the Accelerating Medicine Partnership in Parkinson's Disease (AMP PD) program to identify PD-associated RNAs, including both known genes and novel circular RNAs (circRNA) and enhancer RNAs (eRNAs). There were 1,111 significant marker RNAs, including 491 genes, 599 eRNAs, and 21 circRNAs, that were first discovered in the PPMI cohort (FDR < 0.05) and confirmed in the PDBP/BioFIND cohorts (nominal p < 0.05). Functional enrichment analysis showed that the PD-associated genes are involved in neutrophil activation and degranulation, as well as the TNF-alpha signaling pathway. We further compare the PD-associated genes in blood with those in post-mortem brain dopamine neurons in our BRAINcode cohort. 44 genes show significant changes with the same direction in both PD brain neurons and PD blood, including neuroinflammation-associated genes IKBIP, CXCR2, and NFKBIB. Finally, we built a novel multi-omics machine learning model to predict PD diagnosis with high performance (AUC = 0.89), which was superior to previous studies and might aid the decision-making for PD diagnosis in clinical practice. In summary, this study delineates a wide spectrum of the known and novel RNAs linked to PD and are detectable in circulating blood cells in a harmonized, large-scale dataset. It provides a generally useful computational framework for further biomarker development and early disease prediction. (Comment on this)

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