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Haussler, D.

Publications and source records attributed to Haussler, D..

At least 19 recordsLinked to original sources

A foundation model for brain organoid network dynamics uncovers intrinsic computation and convergent disease phenotypes

Brain organoids develop self-organizing neural networks that can be used to model neurodevelopment and disease. Here we introduce PULSE, a foundation model developed using over 900 hours of high-density microelectrode array recordings of in vitro and ex vivo neural tissue. We show that this single model can address two open questions: how disease-associated variants alter network development, and how naive circuits encode information. PULSE revealed accelerated network maturation in held-out human 16p11.2-deletion organoids. It also revealed a change in network coordination shared with SHANK3 deficiency. Because organoids develop without sensory input, they let us ask how circuits encode information before any representation is learned. Closed-loop control of a virtual inverted pendulum engaged existing spontaneous activity patterns rather than creating new ones. PULSE provides a common reference frame for neural circuits across genotypes, protocols and tasks.

neuroscience↗

Decoding brain anatomy from neuronal neighborhoods with MYCEL

Extracellular recordings carry information about neuronal location, and pooling per-unit predictions across neighboring electrodes improves its readout, but whether this local pooling should be learned is untested. We present MYCEL (Message-passing Yields Cellular Embeddings of Location), a graph neural network whose nodes are spike-sorted units carrying waveform and spike-timing features selected on cell-type ground truth, and whose edges encode recording geometry. On the Allen Brain Observatory Visual Coding Neuropixels dataset, learned message passing outperforms fixed aggregation, with the largest gains where single units are least informative. On the International Brain Laboratory Brain Wide Map, MYCEL matches the strongest population model at one-tenth the pairwise interactions. On held-out animals, the embeddings recover laminar depth within visual cortex. Retrained with only the edge geometry changed, the same framework decodes anatomy in macaque visual cortex and human medial temporal lobe. Thus, how neighboring neurons are combined matters as much as the features that describe them.

neuroscience↗

Servo-Actuated 3D-Printed Disposable Microvalves for Automated, Scalable Organoid Culture in Standard Incubators

Automation of organoid and cell culture processes is essential for achieving scalable and standardized experimentation in regenerative medicine and stem cell research. However, existing microfluidic platforms often rely on complex setups, limiting their integration within standard incubator environments. To address these challenges, we developed a compact, scalable multi-well platform featuring 3D-printed, servo-actuated disposable microvalves for fully automated media and drug exchange. This design eliminates the need for external pressure sources and control channels, providing a simplified and cost-effective solution for organoid culture. The platform integrates an internet-connected microscopy module with a motorized XYZ stage, allowing continuous, real-time imaging of individual wells directly within the incubator. It supports precise and reliable fluid handling under physiological conditions, improving throughput, reproducibility, and accessibility. We validate the platform through bench-top testing and in both mouse and human organoid models. Morphological analysis, immunohistochemistry (IHC), and qPCR demonstrate comparable viability, growth, and gene expression profiles between automated and manual culture conditions. These results establish a robust and scalable framework for fully automated organoid culture, offering a simplified and accessible alternative to conventional microfluidic systems with broad applications in regenerative medicine, drug discovery, and scalable biological screening. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=101 SRC="FIGDIR/small/732526v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@10297f1org.highwire.dtl.DTLVardef@1458d48org.highwire.dtl.DTLVardef@13e7eeeorg.highwire.dtl.DTLVardef@1ff4e5c_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

SpikeLab: Agentic tools for spike data analysis

Large language models have the potential to transform scientific research and analysis, but without domain-specific structure they produce silent methodological errors, unreported decisions, and irreproducible results. Here we present SpikeLab, a text-to-analysis framework for neural spike data that combines composable data structures with a skill-based agentic system enforcing bounded autonomy: mandatory use of expert-vetted methods, correctness over efficiency, and clarification-seeking on ambiguous requests. In a controlled benchmark on electrophysiology data, Sonnet 4.6 with SpikeLab produced correct and reproducible results across all tasks, outperforming both the unassisted Sonnet and the more capable Opus 4.6, which exhibited deterministic failures including ad hoc method invention, silent data reduction, and inconsistent experimental designs. We demonstrate versatility across in vivo mouse, human, and in vitro brain organoid recordings, and apply the framework to a pharmacological dose-response study spanning single-unit dynamics, pairwise network structure, burst-level temporal sequences, and latent population states, all through natural language prompts without writing analysis code.

neuroscience↗

Microfluidic Control of Dorsal-Ventral Patterning Within a Single Forebrain Organoid

How distinct regional identities emerge within a single developing brain remains poorly understood. Current in vitro models address this by fusing independently generated organoids, but this introduces variability in size, maturation state, and connectivity, confounding the study of regionalization itself. Here, we present a microfluidic platform that supports the co-development of different tissue identities within a single, continuous 3D culture domain. The device integrates controlled microfluidic flow with real-time fluorescence imaging, providing stable perfusion and high-resolution tracking of molecular transport without the need for embedded sensors or disruptive sampling. By delivering SAG, a Sonic hedgehog pathway agonist, to one surface of mouse forebrain organoids, we induced spatially segregated ventral (Nkx2.1+) and dorsal (Pax6+) domains within a unified tissue architecture. Controlled morphogen delivery is sufficient to drive region-specific fate specification without organoid fusion, offering a practical, scalable alternative for studying tissue regionalization in vitro.

bioengineering↗

CytoVerse: Single-Cell AI Foundation Models in the Browser

Mapping single-cell datasets to large atlases is often hindered by server constraints and privacy concerns. We present CytoVerse, a framework that runs scRNA-seq Foundation Models (scFM) entirely in the browser. Three key contributions enable this: (1) deploying models via ONNX without server side compute; (2) using compressed indexing (IVFPQ) to search a more then 20 million cell reference from the client; and (3) a lightweight protocol for sharing embeddings across consortia without exposing raw data. CytoVerse thereby provides a scalable, privacy preserving framework for distributed single-cell analysis.

bioinformatics↗

A Modular In-Incubator Microscope for Longitudinal Live Cell Microscopy

Longitudinal live cell imaging is valuable for characterizing dynamic morphological and phenotypic changes in biological systems. However, conventional approaches rely on manual microscope operation, which is labor-intensive, limits imaging frequency, and disrupts the cellular environment. These constraints reduce scalability, increase experimental variability, and restrict both the duration and temporal resolution of continuous imaging. Although automated imaging platforms partially address these limitations, existing solutions are often constrained by the cost, footprint, and inflexibility of in-incubator microscopes or stage-top incubators. Here, we present an automated in-incubator epifluorescence microscope designed for long-term operation. The system features a modular architecture with optional multi-fluorescence imaging, automated plate scanning, configurable light sources, and compatibility with multiple plate formats, including integration with fluidic automation devices. By positioning the light sources and control electronics outside the incubator, the platform improves thermal stability and long-term operational reliability. This approach enables continuous, high-frequency imaging over extended durations, providing a source of rich data for quantifying time-dependent tissue phenotypes, morphological remodeling, and transient biological processes.

bioengineering↗

Cloud-Connected Pluripotent Stem Cell Platform Enhances Scientific Identity in Underrepresented Students

Stem cell research offers unique opportunities for authentic scientific engagement, yet infrastructure requirements have confined participation to elite institutions, perpetuating workforce disparities. We developed an integrated framework combining engineered biology, cloud-connected microscopy, and validated psychometric assessment to make pluripotent stem cell (PSC) experimentation widely accessible. The framework comprises three components: a doxycycline-inducible NGN2 mouse embryonic stem cell line for rapid neuronal specification, low-cost cloud microscopy for remote observation, and the validated Stem Cell Research Identity Scale (SCRIS) for quantifying educational outcomes. Implementation across a Title I high school and urban community college demonstrated significant increases in scientific identity. Students using differentiating PSCs showed broader science identity development than those using neuroblastoma cells, particularly in competence, research readiness, and recognition. High school students showed enhanced research competence gains compared to community college students despite equivalent intervention duration. Demographic analyses revealed enhanced effectiveness for Hispanic and first-generation college students. This framework provides a scalable model for broadening participation in advanced biomedical research.

scientific communication and education↗

Scalable high-fidelity human vascularized cortical assembloids recapitulate neurovascular co-development and cell specialization

Human cortical development involves the coupling of neurogenesis and cerebrovascular growth. However, interactions between neural and vascular cells are largely missing in most brain organoids, which are crucial models for studying neurodevelopment and disease. Here, we establish vascularized cortical assembloids (vCAs) by fusing mesoderm-derived vascular organoids (VOs) with cortical organoids (COs). vCAs self-assemble lumenized networks of endothelial cells, pericytes, and perivascular fibroblasts that acquire blood-brain barrier (BBB) specialization and arteriovenous specification in vitro. Single-cell RNA-sequencing and immunofluorescence imaging revealed that vascularization improves neuroepithelial architecture, reduces hypoxia and apoptosis, expands cortical progenitor pools, and enhances neuronal maturation and connectivity compared with COs. Moreover, atlas-level integration with human neurodevelopmental tissue and cross-protocol benchmarking demonstrate superior transcriptional concordance, especially for vascular cell and glial populations, relative to existing approaches. This scalable and reproducible platform improves fidelity and throughput for modeling human neurovascular co-development and enables systematic studies across brain regions and diseases using engineered or patient-derived iPSCs.

developmental biology↗

Incubator-Free Organoid Culture in a Sealed Recirculatory System

Discovery in human biology is pivoting toward high-dimensional computational analysis of 3D in vitro models, but this progress is limited by reliance on conventional cell culture techniques. Realism and data collection are hindered by the environmental instabilities and accessibility constraints of standard incubators. We introduce an automated, sealed recirculatory system that eliminates these barriers, enabling unconstrained instrument integration and infrastructure-independent scalability. By employing gas-tight sealing, a liquid-phase gas buffer and a non-porous plastic gas exchanger, our technology maintains biological stability without the compromises of open-air vessels. This design eliminates the need for CO2 incubators and prevents the evaporative drift that typically plagues conventional open-culture vessels. Operating on the benchtop outside the cell culture suite, we demonstrate that our system supports continuous, multi-week live imaging of vascular organoids while maintaining metabolic viability, structural fidelity and electrophysiological activity in brain organoids comparable to traditional in-incubator cultures. TeaserA sealed benchtop device enables data-rich organoid culture beyond the constraints of the cell culture laboratory.

bioengineering↗

Self-Organizing Neural Networks in Organoids Reveal Principles of Forebrain Circuit Assembly

The mouse cortex is a canonical model for studying how functional neural networks emerge, yet it remains unclear which topological features arise from intrinsic cellular organization versus external regional cues. Mouse forebrain organoids provide a powerful system to investigate these intrinsic mechanisms. We generated dorsal (DF) and ventral (VF) forebrain organoids from mouse pluripotent stem cells and tracked their development using longitudinal electrophysiology. DF organoids showed progressively stronger network-wide correlations, while VF organoids developed more refined activity patterns, enhanced small-world topology, and increased modular organization. These differences emerged without extrinsic inputs and may be driven by the increased generation of Pvalb+ interneurons in VF organoids. Our findings demonstrate how variations in cellular composition influence the self-organization of neural circuits, establishing mouse forebrain organoids as a tractable platform to study how neuronal populations shape cortical network architecture.

neuroscience↗

HIPPIE: A Multimodal Deep Learning Model for Electrophysiological Classification of Neurons

Extracellular electrophysiological recordings present unique computational challenges for neuronal classification due to noise, technical variability, and batch effects across experimental systems. We introduce HIPPIE (High-dimensional Interpretation of Physiological Patterns In Extracellular recordings), a deep learning framework that combines self-supervised pretraining on unlabeled datasets with supervised fine-tuning to classify neurons from extracellular recordings. Using conditional convolutional joint autoencoders, HIPPIE learns robust, technology-adjusted representations of waveforms and spiking dynamics. This model can be applied to electrophysiological classification and clustering across diverse biological cultures and technologies. We validated HIPPIE on both in vivo mouse recordings and in vitro brain slices, where it demonstrated superior performance over other unsupervised methods in cell-type discrimination and aligned closely with anatomically defined classes. Its latent space organizes neurons along electrophysiological gradients, while enabling batch and individual corrected alignment of recordings across experiments. HIPPIE establishes a general framework for systematically decoding neuronal diversity in native and engineered systems.

neuroscience↗

Goal-Directed Learning in Cortical Organoids

Experimental neuroscience techniques are advancing rapidly, with major recent developments in high-density electrophysiology and targeted electrical stimulation. In combination with these techniques, cortical organoids derived from pluripotent stem cells show great promise as in vitro models of brain development and function. Although sensory input is vital to neurodevelopment in vivo, few studies have explored the effect of meaningful input to in vitro neural cultures over time. In this work, we demonstrate the first example of goal-directed learning in brain organoids. We developed a closed-loop electrophysiology framework to embody mouse cortical organoids into a simulated dynamical task (the inverted pendulum problem known as Cartpole) and evaluate learning through high-frequency training signals. Longitudinal experiments enabled by this framework illuminate how different methods of selecting training signals enable improvement on the tasks. We found that for most organoids, training signals chosen by artificial reinforcement learning yield better performance on the task than randomly chosen training signals or the absence of a training signal. This systematic approach to studying learning mechanisms in vitro opens new possibilities for therapeutic interventions and biological computation.

neuroscience↗

Pathological microcircuits initiate epileptiform events in patient hippocampal slices

How seizures begin at the level of microscopic neuronal circuits remains unknown. Advancements in high-density CMOS-based microelectrode arrays can be harnessed to study neuronal network activity with unprecedented spatial and temporal resolution. We use high-density electrophysiology recordings to probe the network activity of human hippocampal brain slices from six patients with mesial temporal lobe epilepsy. Two slices from the dentate gyrus exhibited epileptiform activity in the presence of low magnesium media with kainic acid. Both slices exhibit network oscillations indicative of a reciprocally connected circuit, which is unexpected under normal physiological conditions. Future studies may apply this approach to elucidate the network signals that underlie seizure initiation.

neuroscience↗

Multiscale Cloud-based Pipeline for Neuronal Electrophysiology Analysis and Visualization

Electrophysiology offers a high-resolution method for real-time measurement of neural activity. Longitudinal recordings from high-density microelectrode arrays (HD-MEAs) can be of considerable size for local storage and of substantial complexity for extracting neural features and network dynamics. Analysis is often demanding due to the need for multiple software tools with different runtime dependencies. To address these challenges, we developed an open-source cloud-based pipeline to store, analyze, and visualize neuronal electrophysiology recordings from HD-MEAs. This pipeline is dependency agnostic by utilizing cloud storage, cloud computing resources, and an Internet of Things messaging protocol. We containerized the services and algorithms to serve as scalable and flexible building blocks within the pipeline. In this paper, we applied this pipeline on two types of cultures, cortical organoids and ex vivo brain slice recordings to show that this pipeline simplifies the data analysis process and facilitates understanding neuronal activity.

neuroscience↗

RT-Sort: an action potential propagation-based algorithm for real time spike detection and sorting with millisecond latencies

With the use of high density multi electrode recording devices, electrophysiological signals resulting from action potentials of individual neurons can now be reliably detected on multiple adjacent recording electrodes both in vivo and in vitro. Spike sorting assigns these signals to putative neural sources. However, until now, spike sorting can only be performed after completion of the recording, preventing true real time usage of spike sorting algorithms. Utilizing the unique propagation patterns of action potentials along axons detected as high fidelity sequential activations on adjacent electrodes, together with a convolutional neural network based spike detection algorithm, we introduce RT-Sort (Real Time Sorting), a spike sorting algorithm that enables the sorted detection of action potentials within 7.5ms{+/-}1.5ms (mean{+/-}STD) after the waveform trough while the recording remains ongoing. RT-Sorts true real-time spike sorting capabilities enable closed loop experiments with latencies comparable to synaptic delay times. We show RT-Sorts performance on both Multi-Electrode Arrays as well as Neuropixels probes to exemplify RT-Sorts functionality on different types of recording hardware and electrode configurations.

neuroscience↗

A feedback-driven IoT microfluidic, electrophysiology, and imaging platform for brain organoid studies

The analysis of tissue cultures, particularly brain organoids, requires a sophisticated integration and coordination of multiple technologies for monitoring and measuring. We have developed an automated research platform enabling independent devices to achieve collaborative objectives for feedback-driven cell culture studies. Our approach enables continuous, communicative, non-invasive interactions within an Internet of Things (IoT) architecture among various sensing and actuation devices, achieving precisely timed control of in vitro biological experiments. The framework integrates microfluidics, electrophysiology, and imaging devices to maintain cerebral cortex organoids while measuring their neuronal activity. The organoids are cultured in custom, 3D-printed chambers affixed to commercial microelectrode arrays. Periodic feeding is achieved using programmable microfluidic pumps. We developed a computer vision fluid volume estimator used as feedback to rectify deviations in microfluidic perfusion during media feeding/aspiration cycles. We validated the system with a set of 7-day studies of mouse cerebral cortex organoids, comparing manual and automated protocols. The automated protocols were validated in maintaining robust neural activity throughout the experiment. The automated system enabled hourly electrophysiology recordings for the 7-day studies. Median neural unit firing rates increased for every sample and dynamic patterns of organoid firing rates were revealed by high-frequency recordings. Surprisingly, feeding did not affect firing rate. Furthermore, performing media exchange during a recording showed no acute effects on firing rate, enabling the use of this automated platform for reagent screening studies.

neuroscience↗

Model-Agnostic Neural Mean Field With The Refractory SoftPlus Transfer Function

Due to the complexity of neuronal networks and the nonlinear dynamics of individual neurons, it is challenging to develop a systems-level model which is accurate enough to be useful yet tractable enough to apply. Mean-field models which extrapolate from single-neuron descriptions to large-scale models can be derived from the neurons transfer function, which gives its firing rate as a function of its synaptic input. However, analytically derived transfer functions are applicable only to the neurons and noise models from which they were originally derived. In recent work, approximate transfer functions have been empirically derived by fitting a sigmoidal curve, which imposes a maximum firing rate and applies only in the diffusion limit, restricting applications. In this paper, we propose an approximate transfer function called Refractory SoftPlus, which is simple yet applicable to a broad variety of neuron types. Refractory SoftPlus activation functions allow the derivation of simple empirically approximated mean-field models using simulation results, which enables prediction of the response of a network of randomly connected neurons to a time-varying external stimulus with a high degree of accuracy. These models also support an accurate approximate bifurcation analysis as a function of the level of recurrent input. Finally, the model works without assuming large presynaptic rates or small postsynaptic potential size, allowing mean-field models to be developed even for populations with large interaction terms. Author SummaryAs one of the most complex systems known to science, modeling brain behavior and function is both fascinating and extremely difficult. Empirical data is increasingly available from ex vivo human brain organoids and surgical samples, as well as in vivo animal models, so the problem of modeling the behavior of large-scale neuronal systems is more relevant than ever. The statistical physics concept of a mean-field model offers a tractable approach by modeling the behavior of a single representative neuron and extending this to the population. However, most mean-field models work only in the limit of weak interactions between neurons, where synaptic input behaves more like a diffusion process than the sum of discrete synaptic events. This paper introduces a data-driven mean-field model, estimated by curve-fitting a simple transfer function, which works with larger interaction strengths. The resulting model can predict population firing rates and bifurcations of equilibria, as well as providing a simple dynamical model that can be the basis for further analysis.

neuroscience↗