Signatures of vibration frequency tuning in human neocortex

Humans can perceive and discriminate vibration frequency, yet the central representation of this fundamental feature is unknown. Using fMRI, we discovered that cortical responses are tuned for vibration frequency. Voxel tuning was biased in a manner that reflects perceptual sensitivity and the response profile of the Pacinian afferent system. These results imply the existence of tuned populations that may encode naturalistic vibrations according to their constituent spectra.

Human motor cortical gamma activity relates to GABAergic signalling and to behaviour

Gamma activity (γ, >30 Hz) is universally demonstrated across brain regions and species. However, the physiological basis and functional role of γ sub-bands (slow-γ, mid-γ, fast-γ) have been predominantly studied in rodent hippocampus; γ activity in the human neocortex is much less well understood. Here we combined neuroimaging and non-invasive brain stimulation to examine the properties of γ activity sub-bands in the primary motor cortex (M1), and their relationship to both local GABAergic activity and to motor learning. In 33 healthy individuals, we quantified movement-related γ activity in M1 using magnetoencephalography, assessed GABAergic signaling using transcranial magnetic stimulation (TMS), and estimated motor learning via a serial reaction time task. We characterised two distinct γ sub-bands (slow-γ, mid-γ) which show movement-related increase in activity during unilateral index finger movements and are characterised by distinct temporal-spectral-spatial profiles. Bayesian correlation analysis revealed strong evidence for a positive relationship between slow-γ (~30-60Hz) peak frequency and endogenous GABA signalling during movement preparation (as assessed using the TMS-metric short interval intracortical inhibition). There was also moderate evidence for a relationship between power of the movement-related mid-γ activity (60-90Hz) and motor learning. These relationships were neurochemically- and frequency-specific. These data provide new insights into the neurophysiological basis and functional roles of γ activity in human M1 and allow the development of a new theoretical framework for γ activity in the human neocortex.

Transcriptome-wide spatial RNA profiling maps the cellular architecture of the developing human neocortex

Spatial genomic technologies can map gene expression in tissues, but provide limited potential for transcriptome-wide discovery approaches and application to fixed tissue samples. Here, we introduce the GeoMX Whole Transcriptome Atlas (WTA), a new technology for transcriptome-wide spatial profiling of tissues with cellular resolution. WTA significantly expands the Digital Spatial Profiling approach to enable in situ hybridisation against 18,190 genes at high-throughput using a sequencing readout. We applied WTA to generate the first spatial transcriptomic map of the fetal human neocortex, validating transcriptome-wide spatial profiling on formalin-fixed tissue material and demonstrating the spatial enrichment of autism gene expression in deep cortical layers. To demonstrate the value of WTA for cell atlasing, we integrated single-cell RNA-sequencing (scRNA-seq) and WTA data to spatially map dozens of neural cell types and showed that WTA can be used to directly measure cell type specific transcriptomes in situ. Moreover, we developed computational tools for background correction of WTA data and accurate integration with scRNA-seq. Our results present WTA as a versatile transcriptome-wide discovery tool for cell atlasing and fixed tissue spatial transcriptomics.

The Amyloid Precursor Protein regulates human cortical neurogenesis

The human neocortex has undergone significant expansion during evolution partially underlying increased human cognitive capacities. The 16 billion neurons of the human neocortex are derived from a limited number of cortical neural progenitor cells (NPCs). Human cortical NPCs initially generate neurons at a slow rate while preserving their progenitor state for a prolonged period, partly contributing to increased human cortical size. How the balance between the progenitor state and neurogenic state is regulated, and whether it contributes to species-specific brain patterning, is poorly understood. We find that the human Amyloid Precursor Protein (APP), whose mutations cause Alzheimer’s disease, specifically regulates this fine balance. Mechanistically, APP regulates these two aspects via two pathways: the AP1 transcription factor and the canonical Wnt pathway. We propose that APP is a homeostatic regulator of the neurogenic potential of cortical NPCs thus potentially contributing to human-specific patterns of neurogenesis.

A Protocol for Cortical Type Analysis of the Human Neocortex Applied on Histological Samples, the Atlas of Von Economo and Koskinas, and Magnetic Resonance Imaging

The human cerebral cortex is parcellated in hundreds of areas using neuroanatomy and imaging methods. Alternatively, cortical areas can be classified into few cortical types according to their degree of laminar differentiation. Cortical type analysis is based on the gradual and systematic variation of laminar features observed across the entire cerebral cortex in Nissl stained sections and has profound implications for understanding fundamental aspects of evolution, development, connections, function, and pathology of the cerebral cortex. In this protocol paper, we explain the general principles of cortical type analysis and provide tables with the fundamental features of laminar structure that are studied for this analysis. We apply cortical type analysis to the micrographs of the Atlas of the human cerebral cortex of von Economo and Koskinas and provide tables and maps with the areas of this Atlas and their corresponding cortical type. Finally, we correlate the cortical type maps with the T1w/T2w ratio from widely used reference magnetic resonance imaging scans. The analysis, tables and maps of the human cerebral cortex shown in this protocol paper can be used to predict patterns of connections between areas according to the principles of the Structural Model and determine their level in cortical hierarchies. Cortical types can also predict the spreading of abnormal proteins in neurodegenerative diseases to the level of cortical layers. In summary, cortical type analysis provides a theoretical and practical framework for directed studies of connectivity, synaptic plasticity, and selective vulnerability to neurologic and psychiatric diseases in the human neocortex.

Developmental dynamics of voltage-gated sodium channel isoform expression in the human and mouse neocortex

ObjectiveGenetic variants in the voltage-gated sodium channels SCN1A, SCN2A, SCN3A, and SCN8A are leading causes of epilepsy, developmental delay, and autism spectrum disorder. The mRNA splicing patterns of all four genes vary across development in the rodent brain, including mutually exclusive copies of the fifth protein-coding exon detected in the neonate (5N) and adult (5A). A second pair of mutually exclusive exons is reported in SCN8A only (18N and 18A). We aimed to quantify the expression of individual exons in the developing human neocortex.MethodsRNA-seq data from 176 human dorsolateral prefrontal cortex samples across development were analyzed to estimate exon-level expression. Developmental changes in exon utilization were validated by assessing intron splicing. Exon expression was also estimated in RNA-seq data from 58 developing mouse neocortical samples.ResultsIn the mature human neocortex, exon 5A is consistently expressed at least 4-fold higher than exon 5N in all four genes. For SCN2A, SCN3A, and SCN8A a synchronized 5N/5A transition occurs between 24 post-conceptual weeks (2nd trimester) and six years of age. In mice, the equivalent 5N/5A transition begins at or before embryonic day 15.5. In SCN8A, over 90% of transcripts in the mature human cortex include exon 18A. Early in fetal development, most transcripts include 18N or skip both 18N and 18A, with a transition to 18A inclusion occurring from 13 post-conceptual weeks to 6 months of age. No other protein-coding exons showed comparably dynamic developmental trajectories.SignificanceSplice isoforms, which alter the biophysical properties of the encoded channels, may account for some of the observed phenotypic differences across development and between specific variants. Manipulation of the proportion of splicing isoforms at appropriate stages of development may act as a therapeutic strategy for specific mutations or even epilepsy in general.