Biology subjects

Lancaster, M.

Publications and source records attributed to Lancaster, M..

4 recordsLinked to original sources

bioRxiv2025

NeuroSuite for Long-term Functional and Structural Studies of Air-Liquid Interface Cerebral Organoids

Over the past decade, air-liquid interface cerebral organoids (ALI-COs) have emerged as powerful in vitro models that capture essential structural and functional traits of the human brain, offering an exciting alternative to traditional animal models in neuroscience. Yet, the full potential of these systems has remained untapped due to the lack of non-invasive, long-term electrophysiological tools capable of preserving organoid integrity. Existing techniques, ranging from patch clamping to rigid and 3D microelectrode arrays, often compromise organoid growth and disrupt delicate cytoarchitecture. Here, we present NeuroSuite, an innovative bioelectronic platform designed to overcome these challenges. At its core is Neuroweb, a perforated, ultra-thin, and conformable organic microelectrode array engineered for minimal disruption of nutrient and oxygen exchange. Neuroweb is reusable and supports stable recordings for over six months, making it uniquely suited for longitudinal studies. Coated with poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS), a high-performance mixed ionic-electronic conductor, Neuroweb delivers exceptional signal-to-noise ratio recordings with high spatial precision. By pairing Neuroweb with NeuroMaps, an intuitive software for interactive analysis and visualisation, NeuroSuite enables long-term, non-invasive tracking and spatial mapping of electrical activity from brain organoids and ex vivo brain slices at the air-liquid interface. Following rigorous validation, we demonstrate that NeuroSuite can capture both high- and low-frequency throughout maturation. Our pipeline reveals evolving network connectivity, including the development of GABA-ergic interneurons, and concurrent shifts in high-frequency spiking and low-frequency oscillations indicative of a refinement in the excitatory-inhibitory balance. Finally, automated data acquisition and spatial spike mapping highlight local activity changes in response to media composition, a factor often overlooked in conventional recordings. NeuroSuite thus opens a new frontier in organoid neuroscience, enabling precise, long-term monitoring essential for modelling neurological diseases, understanding human brain development, and accelerating drug discovery. TeaserConformal organic bioelectronic arrays, combined with an open-access toolbox for analysis and visualisation, reveal real-time and long-term neural dynamics in brain organoid slices at the air-liquid interface.

neuroscience↗

bioRxiv2022

The genetics of cortical organisation and development: a study of 2,347 neuroimaging phenotypes

Our understanding of the genetic architecture of the human cerebral cortex is limited both in terms of the diversity of brain structural phenotypes and the anatomical granularity of their associations with genetic variants. Here, we conducted genome-wide association meta-analysis of 13 structural and diffusion magnetic resonance imaging derived cortical phenotypes, measured globally and at 180 bilaterally averaged regions in 36,843 individuals from the UK Biobank and the ABCD cohorts. These phenotypes include cortical thickness, surface area, grey matter volume, and measures of folding, neurite density, and water diffusion. We identified 4,349 experiment-wide significant loci associated with global and regional phenotypes. Multiple lines of analyses identified four genetic latent structures and causal relationships between surface area and some measures of cortical folding. These latent structures partly relate to different underlying gene expression trajectories during development and are enriched for different cell types. We also identified differential enrichment for neurodevelopmental and constrained genes and demonstrate that common genetic variants associated with surface area and volume specifically are associated with cephalic disorders. Finally, we identified complex inter-phenotype and inter-regional genetic relationships among the 13 phenotypes which reflect developmental differences among them. These analyses help refine the role of common genetic variants in human cortical development and organisation. One sentence summaryGWAS of 2,347 neuroimaging phenotypes shed light on the global and regional genetic organisation of the cortex, underlying cellular and developmental processes, and links to neurodevelopmental and cephalic disorders.

neuroscience↗

bioRxiv2018

CBP/EP300-dependent acetylation and stabilization of HSF2 are compromised in the rare disorder, Rubinstein-Taybi syndrome

Cells respond to protein-damaging insults by activating heat shock factors (HSFs), key transcription factors of proteostasis. Abnormal HSF protein levels occur in cancer and neurodegenerative disorders, highlighting the importance of the tight control of HSF expression. HSF2 is a short-lived protein, but it is abundant in the prenatal brain cortex and required for brain development. Here, we reveal that HSF2 is acetylated and co-localized with the lysine-acetyl transferases CBP and EP300 in human brain organoids. Using unbiased, biochemical, cell-imaging, and in silico approaches, we show that CBP/EP300 acetylates HSF2 at specific lysine residues, which promotes HSF2 stabilization, whereas the lysine deacetylase HDAC1 catalyzes its proteasomal degradation. The CBP KIX domain and KlX-recognizing motifs in HSF2 are critical for its interaction with acetylating enzymes. The functional importance of acetylated HSF2 is evidenced in Rubinstein-Taybi syndrome (RSTS), characterized by mutated CBP or EP300. We show that RSTS patient cells exhibit decreased HSF2 levels and impaired heat shock response. The dysregulated HSF pathway in RSTS opens new avenues for understanding the molecular basis of this multifaceted pathology.

developmental biology↗

bioRxiv2018

Cerebral organoids at the air-liquid interface generate diverse nerve tracts with functional output

Three-dimensional neural organoids are emerging tools with the potential for improving our understanding of human brain development and neurological disorders. Recent advances in this field have demonstrated their capacity to model neurogenesis1,2, neuronal migration and positioning3,4, and even response to sensory input5. However, it remains to be seen whether these tissues can model axon guidance dynamics and the formation of complex connectivity with functional neuronal output. Here, we have established a longterm air-liquid interface culture paradigm that leads to improved neuronal survival and allows for imaging of axon guidance. Over time, these cultures spontaneously form thick axon tracts capable of projecting over long distances. Axon bundles display various morphological behaviors including intracortical projection within and across the organoid, growth cone turning, decussation, and projection away from the organoid. Single-cell RNA-sequencing reveals the full repertoire of cortical neuronal identities, and retrograde labelling demonstrates these tract morphologies match the appropriate molecular identities, namely callosal and corticofugal neuron types. We show that these neurons are functionally mature, generate active networks within the organoid, and that extracortical projecting tracts innervate and activate mouse spinal cord-muscle explants. Muscle contractions can be evoked by stimulation of the organoid, while axotomy of the innervating tracts abolishes the muscle contraction response, demonstrating dependence on connection with the organoid. Overall, these results reveal a remarkable selforganization of corticofugal and callosal tracts with a functional output, providing new opportunities to examine relevant aspects of human CNS development and response to injury.

neuroscience↗