Seminars

Modern experimental techniques now reveal the structure and function of neural circuits at unprecedented scale and resolution. How can we use this wealth of data to understand how cells and circuits implement computations underlying behaviour? Achieving this goal requires models that are consistent with biophysical mechanisms and circuit dynamics, yet flexible enough to capture behaviourally relevant computations. We develop simulation-based machine learning methods that address this challenge. I will show how these approaches—in combination with connectomic measurements—make it possible to build large-scale mechanistic models of the fruit fly visual system. Our methods generalize across systems and scales, defining a new way to study biological systems by algorithmically learning interpretable models that reveal how structure and dynamics gives rise to behaviour. Presented in the van Vreeswijk Theoretical Neuroscience Seminar series (formerly WWTNS) on 2025-12-17. Recording duration: 00:45:20.

Predictive processing offers a unifying view of neural computation, proposing that brains continuously anticipate sensory input and update internal models based on prediction errors. In this talk, I will present converging evidence for the computational mechanisms underlying this framework across human neuroscience and deep neural networks. I will begin with recent work showing that large-scale distributed prediction-error encoding in the human brain directly predicts how sensory representations reorganize through predictive learning. I will then turn to PredNet, a popular predictive coding inspired deep network that has been widely used to model real-world biological vision systems. Using dynamic stimuli generated with our Spatiotemporal Style Transfer algorithm, we demonstrate that PredNet relies primarily on low-level spatiotemporal structure and remains insensitive to high-level content, revealing limits in its generalization capacity. Finally, I will discuss new recurrent vision models that integrate top-down feedback connections with intrinsic neural variability, uncovering a dual mechanism for robust sensory coding in which neural variability decorrelates unit responses, while top-down feedback stabilizes network dynamics. Together, these results outline how prediction error signaling and top-down feedback pathways shape adaptive sensory processing in biological and artificial systems.

Shimon Sakaguchi, Mary E. Brunkow and Fred Ramsdell explain how peripheral immune tolerance prevents the immune system from attacking the body. Sakaguchi follows the identification of regulatory T cells, the CD25 marker, and the relationship between central tolerance and active suppression of self-reactive cells. He considers how changing regulatory T-cell activity could support cancer treatment and transplantation. Brunkow describes genetic investigation of scurfy mice, identification of FOXP3, and the connection between mutations in this gene and human IPEX syndrome. The work establishes a molecular basis for the development and function of regulatory T cells. Ramsdell traces the move from these basic discoveries toward therapeutic strategies, including engineering a patient’s regulatory T cells to target inflammation in rheumatoid arthritis. He discusses early clinical investigation and the ambition of restoring immune balance; these approaches are presented as developing treatments rather than established cures.

Assessing how brain activity generalizes across individuals is a central challenge in experimental neuroscience. Traditional task- or stimulus-driven approaches align data through trial averaging and anatomical registration, but these methods fail for spontaneous activity, where no shared temporal reference exists. In this talk, I will introduce a statistical framework, called latent-aligned Restricted Boltzmann Machines, to build a common representational space from whole-brain recordings of spontaneous activity in multiple zebrafish larvae. This shared latent space, composed of spatially localized co-activation motifs or cell assemblies, allows bidirectional mapping of brain states: activity patterns from one fish can be encoded and decoded into another. The translated activity patterns retain their original spatial structure and show high plausibility within the recipient brain. We further use this shared space to segment spontaneous activity into discrete brain states and we quantify their Markovian transition statistics. Remarkably, these state-to-state dynamics are stereotyped across individuals, suggesting that spontaneous activity reflects intrinsic computational priors of neural processing. Together, these results demonstrate how probabilistic generative modeling can bridge individual variability and reveal conserved organizational principles of vertebrate brains. Presented in the van Vreeswijk Theoretical Neuroscience Seminar series (formerly WWTNS) on 2025-11-05. Recording duration: 00:36:37.

This talk aims to answer these questions along four dimensions. First is history. RL was the basis of AI long before the term AI was introduced in 1956. The first machine learning (ML) systems were based on RL even before digital computers existed. Despite notable early successes of ML based on RL, RL essentially disappeared from ML until relatively recently. A second reason for renewed interest in RL is the clarification of some misunderstandings that have been prevalent in the ML community. A third, and most important, reason for this resurgence is that new, or rediscovered, algorithms and connections to well developed mathematical and engineering methods have been worked out. Finally, a fourth reason for the renewed interest in RL is its strong links to animal reward systems, in particular, to the role that dopamine plays in motivation and learning. VVTNS Sixth Season Opening Lecture. Presented in the van Vreeswijk Theoretical Neuroscience Seminar series (formerly WWTNS) on 2025-10-29. Recording duration: 00:55:21.

The cortex comprises many neuronal types, which can be distinguished by their transcriptomes: the sets of genes they express. Little is known about the in vivo activity of these cell types, particularly as regards the structure of their spike trains, which might provide clues to cortical circuit function. To address this question, we used Neuropixels electrodes to record layer 5 excitatory populations in mouse V1, then transcriptomically identified the recorded cell types. To do so, we performed a subsequent recording of the same cells using 2-photon (2p) calcium imaging, identifying neurons between the two recording modalities by fingerprinting their responses to a “zebra noise” stimulus and estimating the path of the electrode through the 2p stack with a probabilistic method. We then cut brain slices and performed in situ transcriptomics to localize ~300 genes using coppaFISH3d, a new open source method, and aligned the transcriptomic data to the 2p stack. Analysis of the data is ongoing, and suggests substantial differences in spike time coordination between ET and IT neurons, as well as between transcriptomic subtypes of both these excitatory types.

Explore how microfluidic chips can enhance your imaging experiments by increasing control, throughput, or flexibility. In this remote, personalized workshop, participants will receive expert guidance, support and chips to run tests on their own microscopes.

Nervous system function relies on the polarized architecture of neurons, established by directional transport of pre- and postsynaptic cargoes. While delivery of postsynaptic components depends on the secretory pathway, the identity of the membrane compartment(s) that supply presynaptic active zone (AZ) and synaptic vesicle (SV) proteins is largely unknown. I will discuss our recent advances in our understanding of how key components of the presynaptic machinery for neurotransmitter release are transported and assembled focussing on our studies in genome-engineered human induced pluripotent stem cell-derived neurons. Specifically, I will focus on the composition and cell biological identity of the axonal transport vesicles that shuttle key components of neurotransmission to nascent synapses and on machinery for axonal transport and its control by signaling lipids. Our studies identify a crucial mechanism mediating the delivery of SV and active zone proteins to developing synapses and reveal connections to neurological disorders. In the second part of my talk, I will discuss how exocytosis and endocytosis are coupled to maintain presynaptic membrane homeostasis. I will present unpublished data regarding the role of membrane tension in the coupling of exocytosis and endocytosis at synapses. We have identified an endocytic BAR domain protein that is capable of sensing alterations in membrane tension caused by the exocytotic fusion of SVs to initiate compensatory endocytosis to restore plasma membrane area. Interference with this mechanism results in defects in the coupling of presynaptic exocytosis and SV recycling at human synapses.

Binary and analog variation of synapses between cortical pyramidal neurons

Understanding the neural mechanisms of reward-guided learning is a long-standing goal of computational neuroscience. Recent methodological innovations enable us to collect ever larger neural and behavioral datasets. This presents opportunities to achieve greater understanding of learning in the brain at scale, as well as methodological challenges. In the first part of the talk, I will discuss our recent insights into the mechanisms by which zebra finch songbirds learn to sing. Dopamine has been long thought to guide reward-based trial-and-error learning by encoding reward prediction errors. However, it is unknown whether the learning of natural behaviours, such as developmental vocal learning, occurs through dopamine-based reinforcement. Longitudinal recordings of dopamine and bird songs reveal that dopamine activity is indeed consistent with encoding a reward prediction error during naturalistic learning. In the second part of the talk, I will talk about recent work we are doing at DeepMind to develop tools for automatically discovering interpretable models of behavior directly from animal choice data. Our method, dubbed CogFunSearch, uses LLMs within an evolutionary search process in order to "discover" novel models in the form of Python programs that excel at accurately predicting animal behavior during reward-guided learning. The discovered programs reveal novel patterns of learning and choice behavior that update our understanding of how the brain solves reinforcement learning problems.