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The ability to sequence movements in response to new task demands enables rich and adaptive behavior. Such flexibility, however, is computationally costly and can result in halting performances. Practicing the same motor sequence repeatedly can render its execution precise, fast, and effortless, i.e., ‘automatic’. The basal ganglia are thought to underlie both modes of sequence execution, yet whether and how their contributions differ is unclear. We parse this in rats trained to perform the same motor sequence in response to cues and in an overtrained, or ‘automatic’, condition. Neural recordings in the sensorimotor striatum revealed a kinematic code independent of execution mode. While lesions affected the detailed kinematics similarly across modes, they disrupted high-level sequence structure for automatic, but not visually-guided, behaviors. These results suggest that the basal ganglia contribute to learned movement kinematics and are essential for ‘automatic’ motor skills but can be dispensable for sensory-guided motor sequences.

Demultiplexing methods have facilitated the widespread use of single-cell RNA sequencing (scRNAseq) experiments by lowering costs and reducing technical variations. Here, we present demuxalot: a method for probabilistic genotype inference from aligned reads, with no assumptions about allele ratios and efficient incorporation of prior genotype information from historical experiments in a multi-batch setting. Our method efficiently incorporates additional information across reads originating from the same transcript, enabling up to 3x more calls per read relative to naive approaches. We also propose a novel and highly performant tradeoff between methods that rely on reference genotypes and methods that learn variants from the data, by selecting a small number of highly informative variants that maximize the marginal information with respect to reference single nucleotide variants (SNVs). Our resulting improved SNV-based demultiplex method is up to 3x faster, 3x more data efficient, and achieves significantly more accurate doublet discrimination than previously published methods. This approach renders scRNAseq feasible for the kind of large multi-batch, multi-donor studies that are required to prosecute diseases with heterogeneous genetic backgrounds.

Cerebral organoids provide unparalleled access to human brain development in vitro. However, variability induced by current culture methodologies precludes using organoids as robust disease models. To address this, we developed an automated Organoid Culture and Assay (ORCA) system to support longitudinal unbiased phenotyping of organoids at scale across multiple patient lines. We then characterized organoid variability using novel machine learning methods and found that the contribution of donor, clone, and batch is significant and remarkably consistent over gene expression, morphology, and cell-type composition. Next, we performed multi-factorial protocol optimization, producing a directed forebrain protocol compatible with 96-well culture that exhibits low variability while preserving tissue complexity. Finally, we used ORCA to study tuberous sclerosis, a disease with known genetics but poorly representative animal models. For the first time, we report highly reproducible early morphological and molecular signatures of disease in heterozygous TSC+/− forebrain organoids, demonstrating the benefit of a scaled organoid system for phenotype discovery in human disease models.

The learning of motor skills unfolds over multiple timescales, with rapid initial gains in performance followed by a longer period in which the behavior becomes more refined, habitual, and automatized. While recent lesion and inactivation experiments have provided hints about how various brain areas might contribute to such learning, their precise roles and the neural mechanisms underlying them are not well understood. In this work, we propose neural- and circuit-level mechanisms by which motor cortex, thalamus, and striatum support such learning. In this model, the combination of fast cortical learning and slow subcortical learning gives rise to a covert learning process through which control of behavior is gradually transferred from cortical to subcortical circuits, while protecting learned behaviors that are practiced repeatedly against overwriting by future learning. Together, these results point to a new computational role for thalamus in motor learning, and, more broadly, provide a framework for understanding the neural basis of habit formation and the automatization of behavior through practice.

Trained recurrent networks are powerful tools for modeling dynamic neural computations. We present a target-based method for modifying the full connectivity matrix of a recurrent network to train it to perform tasks involving temporally complex input/output transformations. The method introduces a second network during training to provide suitable "target" dynamics useful for performing the task. Because it exploits the full recurrent connectivity, the method produces networks that perform tasks with fewer neurons and greater noise robustness than traditional least-squares (FORCE) approaches. In addition, we show how introducing additional input signals into the target-generating network, which act as task hints, greatly extends the range of tasks that can be learned and provides control over the complexity and nature of the dynamics of the trained, task-performing network., 20 pages, 8 figures

We investigate the ability of algorithms developed for reverse engineering of transcriptional regulatory networks to reconstruct metabolic networks from high-throughput metabolite profiling data. For this, we generate synthetic metabolic profiles for benchmarking purposes based on a well-established model for red blood cell metabolism. A variety of data sets is generated, accounting for different properties of real metabolic networks, such as experimental noise, metabolite correlations, and temporal dynamics. These data sets are made available online. We apply ARACNE, a mainstream transcriptional networks reverse engineering algorithm, to these data sets and observe performance comparable to that obtained in the transcriptional domain, for which the algorithm was originally designed., 14 pages, 3 figures. Presented at the DIMACS Workshop on Dialogue on Reverse Engineering Assessment and Methods (DREAM), Sep 2006