Publications

The brain encodes external stimuli through patterns of neural activity, forming internal representations of the world. Increasing experimental evidence showed that neural representations for a specific stimulus can change over time in a phenomenon called “representational drift” (RD). However, the underlying mechanisms for this widespread phenomenon remain poorly understood. Here, we study RD in the piriform cortex of the olfactory system with a realistic neural network model that incorporates two general mechanisms for synaptic weight dynamics operating at two well-separated timescales: spontaneous multiplicative fluctuations on a scale of days and spike-timing-dependent plasticity (STDP) effects on a scale of seconds. We show that the slow multiplicative fluctuations in synaptic sizes, which lead to a steady-state distribution of synaptic weights consistent with experiments, can induce RD effects that are in quantitative agreement with recent empirical evidence. Furthermore, our model reveals that the fast STDP learning dynamics during presentation of a given odor drives the system toward a low-dimensional representational manifold, which effectively reduces the dimensionality of synaptic weight fluctuations and thus suppresses RD. Specifically, our model explains why representations of already “learned” odors drift slower than unfamiliar ones, as well as the dependence of the drift rate with the frequency of stimulus presentation—both of which align with recent experimental data. The proposed model not only offers a simple explanation for the emergence of RD and its relation to learning in the piriform cortex, but also provides a general theoretical framework for studying representation dynamics in other neural systems.

Studies in Drosophila have contributed a great deal to our understanding of developmental mechanisms. Indeed, familiar names of critical signaling components, such as Hedgehog and Notch, have their origins in the readily identifiable morphological phenotypes of Drosophila. Most studies that led to the identification of these and many other highly conserved genes were based on the end-point phenotypes, such as the larval cuticle or the adult wing. Additional information can be extracted from longitudinal studies, which can reveal how the phenotypes emerge over time. Here we present the Fruit Fly Auxodrome, an experimental setup that enables monitoring and quantitative analysis of the entirety of development of 96 individually housed Drosophila from hatching to eclosion. The Auxodrome combines an inexpensive live imaging setup and a computer vision pipeline that provides access to a wide range of quantitative information, such as the times of hatching and pupation, as well as dynamic patterns of larval activity. We demonstrate the Auxodrome in action by recapitulating several previously reported features of wild-type development as well as developmental delay in a Drosophila model of a human disease. The scalability of the presented design makes it readily suitable for large-scale longitudinal studies in multiple developmental contexts.

Although canonical protein design has benefited from machine learning methods trained on databases of protein sequences and structures, synthetic heteropolymer design still relies heavily on physics-based methods. The Rosetta software, which provides diverse physics-based methods for designing sequences, exploring conformations, docking molecules, and performing analysis, has proven invaluable to this field. Nevertheless, Rosetta’s aging architecture, monolithic structure, non-open source code, and steep development learning curve are beginning to hinder new methods development. Here, we introduce the Masala software suite, a free, open-source set of C++ libraries intended to extend Rosetta and other software, and ultimately to be a successor to Rosetta. Masala is structured for modern computing hardware, and its build system automates the creation of application programming interface (API) layers, permitting Masala’s use as an extension library for existing software, including Rosetta. Masala features modular architecture in which it is easy for novice developers to add new plugin modules, which can be independently compiled and loaded at runtime, extending functionality of software linking Masala without source code alteration. Here, we describe implementation of Masala modules that accelerate protein and synthetic peptide design. We describe the implementation of Masala real-valued local optimizers and cost function network optimizers that can be used as drop-in replacements for Rosetta’s minimizer and packer when designing heteropolymers. We explore design-centric guidance terms for promoting desirable features, such as hydrogen bond networks, or discouraging undesirable features, such as unsatisfied buried hydrogen bond donors and acceptors, which we have re-implemented far more efficiently in Masala, providing up to two orders of magnitude of speedup in benchmarks. Finally, we discuss development goals for future versions of Masala.

Unraveling the phenotypic and genetic complexity of autism is extremely challenging yet critical for understanding the biology, inheritance, trajectory and clinical manifestations of the many forms of the condition. Using a generative mixture modeling approach, we leverage broad phenotypic data from a large cohort with matched genetics to identify robust, clinically relevant classes of autism and their patterns of core, associated and co-occurring traits, which we further validate and replicate in an independent cohort. We demonstrate that phenotypic and clinical outcomes correspond to genetic and molecular programs of common, de novo and inherited variation and further characterize distinct pathways disrupted by the sets of mutations in each class. Remarkably, we discover that class-specific differences in the developmental timing of affected genes align with clinical outcome differences. These analyses demonstrate the phenotypic complexity of children with autism, identify genetic programs underlying their heterogeneity, and suggest specific biological dysregulation patterns and mechanistic hypotheses.

We prove analytically that the two fundamental rheological equations for (elastic) disc suspensions and long flexible polymers, the so-called Oldroyd-A and -B models, respectively, predict the same flow and total stress fields in any planar incompressible flow. We illustrate this equivalence for creeping flow in a cross-slot channel and investigate differences arising from three-dimensional effects in a weakly elastic Taylor-Couette flow. Finally, we discuss implications for understanding elastic instabilities, controlling inertial turbulence, and deriving constitutive models for complex fluids.

Endurance exercise induces multisystem adaptations that improve performance and benefit health. Gene regulatory circuit responses within individual skeletal muscle cell types, which are key mediators of exercise effects, have not been studied. Here, we map transcriptome, chromatin, and regulatory circuit responses to acute endurance exercise in muscle using same-cell RNA-seq/ATAC-seq multiome assays. High-quality data were obtained from 37,154 nuclei comprising 14 cell types in vastus lateralis samples collected before and 3.5 h after either 40 min cycling exercise at 70% VO2max or 40 min supine rest. Both shared and cell-type-specific regulatory programs were identified. Differential gene expression and accessibility sites are largely distinct within nuclei for each cell type and muscle fiber, with the largest numbers of regulatory events observed in the three muscle fiber types (slow, fast, and intermediate) and lumican (LUM)-expressing fibro-adipogenic progenitor cells. Single-cell regulatory circuit triad reconstruction (transcription factor, chromatin interaction site, regulated gene) also identifies largely distinct gene regulatory circuits modulated by exercise in the three muscle fiber types and LUM-expressing fibro-adipogenic progenitor cells, involving a total of 328 transcription factors acting at chromatin sites regulating 2025 genes. This web-accessible single-cell data set and regulatory circuitry map serve as a resource for understanding the molecular underpinnings of the metabolic and physiological effects of exercise and for guiding interpretation of the exercise response literature in bulk tissue.

An isolated charge-neutral drop suspended in an unbounded medium does not migrate in a uniform dc electric field. A nearby wall breaks the symmetry and causes the drop to drift towards or away from the boundary, depending on the electric properties of the fluids and the wall. In the case of an electrically insulating wall and an electric field applied tangentially to the wall, the interaction of the drop with its electrostatic image gives rise to repulsion by the wall. However, the electrohydrodynamic flow causes either repulsion for a drop with R/P1. We experimentally measure droplet trajectories and quantify the wall-induced electrohydrodynamic lift in the case R/P1 case. The results show that the lateral migration of a drop in a uniform electric field applied parallel to an insulating wall is dominated by the long-range flow due to the image stresslet.

Dendrites grow by stochastic branching, elongation, and retraction. A key question is whether such a mechanism is sufficient to form highly branched dendritic morphologies. Alternatively, does dendrite geometry depend on signals from other cells or from the topological hierarchy of the growing network? To answer these questions, we developed an isotropic and homogenous mean-field model in which branch dynamics depends only on average lengths and densities: that is, without external influence. Branching was modeled as density-dependent nucleation so that no tree structures or network topology was present. Despite its simplicity, the model predicted several key morphological properties of class IV Drosophila sensory dendrites, including the exponential distribution of branch lengths, the parabolic scaling between dendrite number and length densities, the tight spacing of the dendritic meshwork (which required minimal total branch length), and the radial orientation of branches. Stochastic growth also accelerated the overall expansion rate of the arbor. We show that stochastic dynamics is an economical and rapid space-filling mechanism for building dendritic arbors without external guidance or hierarchical branching mechanisms. Our work therefore provides a general theoretical framework for understanding how macroscopic branching patterns emerge from microscopic dynamics.

Viruses exploit host cell reliance on compartmentalization to facilitate their replication. Herpes simplex virus type 1 (HSV-1) modulates the subcellular localization of host proteins to suppress immune activation, license viral gene expression, and achieve translational shutoff. To spatially resolve dynamic protein-protein interaction (PPI) networks during infection with an immunostimulatory HSV-1 strain, we integrated nuclear/cytoplasmic fractionation with thermal proximity coaggregation analysis (N/C-TPCA). The resulting expanded depth and spatial resolution of PPIs charted compartment-specific assemblies of protein complexes throughout infection. We find that a broader suite of host chaperones than previously anticipated exhibits nuclear recruitment to form condensates known as virus-induced chaperone-enriched (VICE) domains. Monitoring protein and RNA constituents and ribosome activity, we establish that VICE domains sequester ribosome biogenesis factors from ribosomal RNA, accompanying a cell-wide defect in ribosome supply. These findings highlight infection-driven VICE domains as nodes of translational remodeling and demonstrate the utility of N/C-TPCA to study dynamic biological contexts.

A lack of tools for detecting receptor activity in vivo has limited our ability to fully explore receptor-level control of developmental patterning. Here, we extend phospho-tyrosine tag (pYtag) biosensors to visualize endogenous receptor tyrosine kinase (RTK) activity in Drosophila. We build biosensors for three RTKs that function across developmental stages and tissues. By characterizing Torso::pYtag during embryonic terminal patterning, we find that Torso activity differs from downstream extracellular signal-regulated kinase (ERK) activity in two surprising ways: Torso activity is narrowly restricted to the poles but produces a broader gradient of ERK and decreases over developmental time, while ERK activity is sustained, an effect mediated by ERK pathway-dependent negative feedback. Our results suggest that a narrow domain of Torso activity, tuned in amplitude by negative feedback, locally activates signaling effectors, which diffuse through the syncytial embryo to form the ERK gradient. Altogether, the results of this work highlight the usefulness of pYtags for investigating receptor-level regulation of developmental patterning.