Biology subjects

Mierau, S. B.

Publications and source records attributed to Mierau, S. B..

4 recordsLinked to original sources

bioRxiv2025

Mecp2 deficiency impairs microscale cortical network topology and dynamics in a Rett syndrome mouse model

Rett syndrome is a debilitating neurodevelopmental disorder with cerebral processing impairments caused by MECP2 loss-of-function mutations. Mecp2-deficient mouse models reveal disruptions of microscale cortical circuits. Yet how cellular-scale information processing is altered in Mecp2-deficient microscale functional networks is unknown. We investigated the development of functional connectivity, network topology, and dynamics in microelectrode array (MEA) recordings of primary cortical cultures from Mecp2-deficient and wild-type mice. Mecp2-deficient cortical networks developed more slowly and showed decreased functional connectivity compared to wild-type, leading to smaller network size, density, and strength of connectivity. Altered network topological features in Mecp2-deficient microscale circuits predicted decreased efficiency and information-sharing capacity. This reveals developmental deficits in microscale functional networks, which may in turn underlie the cortical decline and severe cognitive disability in Rett syndrome. These findings also offer circuit-level targets and an in-vitro approach for evaluating new therapeutic products for restoring microscale network function.

neuroscience↗

bioRxiv2024

MEA-NAP compares microscale functional connectivity, topology, and network dynamics in organoid or monolayer neuronal cultures

Microelectrode array (MEA) recordings are commonly used to compare firing and burst rates in neuronal cultures. MEA recordings can also reveal microscale functional connectivity, topology, and network dynamics--patterns seen in brain networks across spatial scales. Network topology is frequently characterized in neuroimaging with graph theoretical metrics. However, few computational tools exist for analyzing microscale functional brain networks from MEA recordings. Here, we present a MATLAB MEA network analysis pipeline (MEA-NAP) for raw voltage time-series acquired from single- or multi-well MEAs. Applications to 3D human cerebral organoids or 2D human-derived or murine cultures reveal differences in network development, including topology, node cartography, and dimensionality. MEA-NAP incorporates multi-unit template-based spike detection, probabilistic thresholding for determining significant functional connections, and normalization techniques for comparing networks. MEA-NAP can identify network-level effects of pharmacologic perturbation and/or disease-causing mutations and, thus, can provide a translational platform for revealing mechanistic insights and screening new therapeutic approaches.

neuroscience↗

bioRxiv2022

Homophilic wiring principles underpin neuronal network topology in vitro

Economic efficiency has been a popular explanation for how networks self-organize within the developing nervous system. However, the precise nature of the economic negotiations governing this putative organizational principle remains unclear. Here, we address this question further by combining large-scale electrophysiological recordings, to characterize the functional connectivity of developing neuronal networks in vitro, with a generative modeling approach capable of simulating network formation. We find that the best fitting model uses a homophilic generative wiring principle in which neurons form connections to other neurons which are spatially proximal and have similar connectivity patterns to themselves. Homophilic generative models outperform more canonical models in which neurons wire depending upon their spatial proximity either alone or in combination with the extent of their local connectivity. This homophily-based mechanism for neuronal network emergence accounts for a wide range of observations that are described, but not sufficiently explained, by traditional analyses of network topology. Using rodent and human monolayer and organoid cultures, we show that homophilic generative mechanisms can accurately recapitulate the topology of emerging cellular functional connectivity, representing an important wiring principle and determining factor of neuronal network formation in vitro.

neuroscience↗

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↗