evolution

From B-cell decisions to antibody repertoires

PROJECT SUMMARY/ABSTRACT Vaccine responses are highly variable across the population and not without risk for debilitating side-effects. Antibody-mediated immunity is generated by a Darwinian process to generate B-cells that contain B-cell receptors (BCR) that have high affinity for the pathogen-derived antigen, while also eliminating B-cells that happen to react to self-antigens. This process depends on cell fate decisions such as (i) death vs survival, (ii) entry into a proliferative program, (iii) differentiation into antibody-secreting plasma cells. According to clonal selection theory, B-cell fate decisions are made based on the genetically encoded affinity of the the BCR to the antigen (Signal 1) and the cognate T-cells’ TCR to the antigen peptide (Signal 2). However, single-cell resolution studies have revealed that fate decisions of genetically identical B-cells are remarkably heterogeneous. Our studies of the previous funding period revealed that B-cell epigenetic heterogeneity is in fact dynamically controlled: it is generated during the selection process but remains largely stable during the proliferative burst. This leads to our newly proposed Aim 1 to examine how the dynamic control of epigenetic state variability affects antibody responses. An innovative multi-scale model of Darwinian evolution directs and interprets experimental studies by life cell video microscopy in vitro and in immunization studies in vivo. Our previous studies also found that B-cells are capable of sensing the time gap between signal 1 and 2, suggesting a temporal proofreading mechanism for negative selection. This leads to newly proposed Aim 2 which seeks to identify the regulatory circuits that control the stringency of negative selection, as well as contextual germinal center (GC) cytokines that could be manipulable in vivo. These in silico and in vitro studies are followed by in vivo immunization to extend their physiological relevance. Finally, in Aim 3, we will ask what determines the time-gap of signal1 and signal 2, which occur in the immune- induced structure of the GC. We will develop a new model that simulates B-cell fate decisions as a function of their interactions with antigen-presenting stromal cells and T-cells that may be cognate or non-cognate. Model simulations will be used to interpret spatial transcriptomic data to test different adjuvants and predictions will be tested in in vivo immunization studies. With mouse models of inflammation and aging we will examine how adjuvants alter vaccine efficacy and risk.

Neuroinflammation in Cerebral Small Vessel Disease

Project Summary/Abstract Cerebral small vessel disease (cSVD) is a leading cause of vascular contributions to cognitive impairment and dementia (VCID), which is the 2nd leading cause of dementia and a significant contributor to Alzheimer’s disease (AD). Thus far, the underlying pathogenesis of cSVD is poorly understood. Several lines of evidence, including animal models, postmortem human brain pathology, and systemic inflammatory markers, demonstrated the damaging role of chronic neuroinflammation in cSVD. Direct evidence of neuroinflammation at the tissue level in patients with cSVD is still critically needed. The sphingosine-1-phosphate receptor 1 (S1PR1) regulates neuroinflammation through microglial and astrocyte activation and trafficking and has emerged as a promising target for neuroinflammation. In postmortem brains of patients with cSVD, we observed elevated S1PR1 expression and colocalization of S1PR1 with astrocytes and microglia. A novel 11C-CS1P1 PET radiotracer with high affinity and specificity targeting S1PR1 has been recently developed and validated in animal models and post-mortem human specimens. Under an FDA-approved eIND (IND 146548), we have successfully completed the safety and dosimetry study in healthy participants and performed preliminary studies in patients with cSVD. We found that 11C-CS1P1 PET uptake is significantly associated with WMH lesion burden in patients with cSVD after controlling for age, sex, race, vascular risk factors, and amyloid deposition. We hypothesize that 11C-CS1P1 PET uptake is a tissue-level biomarker of neuroinflammation to provide insight into cSVD severity, progression, and prognosis. We will 1) evaluate the relationship between 11C-CS1P1 PET uptake and cSVD neuroimaging abnormalities and cognitive impairment, 2) evaluate the test-retest repeatability and longitudinal evolution, and 3) determine whether 11C-CS1P1 PET uptake at baseline predict cSVD progression. The successful completion of this study will establish 11C-CS1P1 PET as an neuroinflammation imaging biomarker and investigate the role of neuroinflammation in cSVD pathogenesis and progression. It will lay a foundation for developing future therapies in modulating neuroinflammation.

Cytoskeletal connectors: Deciphering the fundamental mechanisms of cytoskeletal dynamics and transport

PROJECT SUMMARY The cytoskeleton is a dynamic network of filamentous structures, including microtubules and actin, that regulate essential cellular processes such as cell shape, growth, and signaling. Cytoskeleton also serves as tracks for molecular motors, which transport a variety of cellular cargoes, including organelles, macromolecules, and vesicles. These cargoes are linked to motors by specialized connector proteins. Disruptions in connector proteins are implicated in a range of neurodevelopmental and neurodegenerative diseases, as well as cancers. Despite their importance, these proteins continue to be understudied, primarily due to their perceived role as passive linkers and the technical challenges in working with them. However, recent discoveries suggest that connector proteins may play more active roles, in some cases even have enzymatic functions. This proposal aims to uncover mechanisms of connector protein functions through a detailed investigation of actin-microtubule and motor-cargo interactions. Actin and microtubules are linked by the spectraplakin family of large and evolutionarily conserved proteins, critical for neuronal development and differentiation. Recent discoveries of ATPase domains within these proteins suggest they may haves beyond simply linking cytoskeletal components. One goal of this proposal is to investigate the role of spectraplakin’s ATPase domains via structural, biochemical, and cell biology approaches. Another goal is to explore how dynamic changes in motor-cargo connectors facilitate the transport of diverse cargoes along microtubule tracks. The focus will be on the cytoplasmic dynein-1 (dynein) and the connectors (adaptors) that activate and link dynein to cargo. Dynein is a microtubule minus-end directed motor that plays essential roles in cell division, and transports hundreds of different cellular cargoes. While several motor-cargo connectors have been identified, the regulatory mechanisms enabling cargo transport are not fully understood. We are investigating whether connector proteins work together to activate dynein movement and/or facilitate cargo handoff between different dynein complexes. Using innovative approaches, including time- resolved cryo-EM, complex in-vitro reconstitutions, and live-cell imaging in induced neurons, we are uncovering critical mechanisms that govern cytoskeletal connector proteins, furthering our understanding of how the cytoskeleton regulates essential cellular processes.

Specific Affinity Requirements for Antibody Somatic Hypermutation

PROJECT SUMMARY Antibodies diversify through two distinct pathways. The first involves the combinatorial assembly of immunoglobulin (Ig) heavy and light chain variable region (V) exons, forming the antigen recognition domains of the B cell receptor (BCR), which is initially expressed as IgM on immature B cells. The second diversification pathway is somatic hypermutation (SHM) of V exons in germinal centers (GCs). In this setting, B cells that acquire mutations enhancing affinity for antigen receive limited cognate T cell help and are selected for clonal expansion, leading to affinity maturation. These primary and secondary diversification systems work together to generate protective antibody responses. The primary, or pre-immune, repertoire provides the foundation for initial antigen recognition. SHM and affinity maturation refine these baseline specificities. While it is well established that SHM improves affinities already present in the primary repertoire, this project explores the hypothesis that SHM can also generate new specificities in B cells that initially lack measurable antigen recognition. This process, termed affinity birth, may enable access to otherwise excluded V gene segments and expand the landscape of antibody evolution. This hypothesis will be tested through two specific aims: (i) To elucidate the extent of SHM-mediated Ig diversification in non-specific or bystander B cells. And, (ii) to define parameters that influence SHM-mediated antibody affinity birth. The significance of this work lies in its potential to reveal previously unappreciated flexibility in the antibody diversification process and to uncover modifiable factors that influence the emergence of new specificities. The proposed studies are innovative in suggesting that B cells possess intrinsic capacity to undergo SHM and selection regardless of their initial antigen specificity. This research may advance understanding of how germinal centers support antibody evolution and inform strategies to design vaccines that anticipate emerging pathogens.

Directing the Evolution of Common Human Precursors into HIV-1 Broadly Neutralizing Antibodies

Project Summary An effective HIV vaccine will likely elicit broadly neutralizing antibodies (bnAbs). Doing so, however, remains a major challenge because bnAbs usually require multiple rare and unusual changes that emerge after years of active infection. It is not clear that a practical number of immunizations can consistently recapitulate this process. Although investigators have successfully expanded defined precursors of known bnAbs, they have not moved these diversified precursors to a specific target in humans. Importantly here, the severity of this problem increases rapidly with the number changes needed. The problem further deepens if the required changes are in slow-to-mutate antibody framework regions or require specific indels. The need to move from precursor to bnAb in the fewest steps motivates our focus on the V2 apex epitope of the HIV-1 envelope glycoprotein (Env). Apex bnAbs are qualitatively different from other bnAb classes. They require far fewer mutations, located in their rapidly evolving heavy-chain CDR3 (HCDR3) regions. These HCDR3s are unusually important to their ability to neutralize virus. For example, we have shown that a diverse repertoire of mouse B cell receptors can be modified with apex bnAb HCDR3s, and the resulting mouse B cells generated potent neutralizing sera. Thus, apex precursors can largely be defined by their HCDR3s alone and are far more common than other defined bnAb precursors. Interestingly, these HCDR3 are very similar to those of another class of antibodies that recognize the CD4-induced co-receptor-binding site (CoRBS). Both antibody classes have unusually long HCDR3s with sulfated tyrosines at their tips. Unlike apex bnAbs, these non-neutralizing CoRBS antibodies are readily elicited through vaccination. We have recently shown that apex precursors also bind the CoRBS, suggesting that some apex bnAbs emerge from CoRBS antibodies. Thus, the first step of sequential vaccine strategies, expanding and diversifying a defined precursor pool, is straightforward. Here we divide the remaining goals into two: moving from a precursor that does not bind Env to one that does so and then broaden it to recognize the majority of circulating isolates. We have already made significant progress in the first step: we have shown in our original mouse vaccine model that we can generate potent apex- specific neutralizing antisera. However the breadth of this sera remains limited. Building on these studies, we will pursue three goals: (1) Define the essential mutations that transform a CoRBS antibody into one that binds the Env apex and then generate antigens that select for these mutations. (2) Define mutations and generate antigens that expand the breadth of these antibodies, transforming them to bnAbs, and (3) Evaluate these antigens in a novel system that models key features of the human apex response in mice, and iteratively refine this process using antibodies and HCDR3s drawn from a wide panel of HIV-naïve persons. In short, these studies develop original concepts and tools that can accelerate development of an HIV-1 vaccine and deepen our understanding of the antibody response to vaccines and pathogens.

Structure-Based Development of Nucleotide-Competing Inhibitors Against HIV-1 and LINE-1 Reverse Transcriptases

PROJECT SUMMARY Reverse transcriptases (RTs) from retroviruses and endogenous retroelements are essential polymerases that catalyze RNA- and DNA-dependent DNA synthesis. Nucleoside inhibitors (NIs) remain central to HIV-1 therapy and are also used against other viral infections and in cancer, but toxicity, limited selectivity, pharmacokinetic (PK) liabilities, and the emergence of drug resistance highlight the need for alternative RT inhibitor mechanisms. In contrast to NIs, nucleotide-competing inhibitors (NCIs) block the polymerase active site without requiring incorporation into nucleic acids. Structural studies by PI Ruiz have defined the NCI mechanism of action for HIV- 1 RT and revealed conserved binding modules shared across multiple polymerase families. These advances now enable rational discovery of improved NCIs. LINE-1 (L1) ORF2 RT is an emerging therapeutic target in cancer, autoimmunity, and aging, yet NIs are the only inhibitors known to act against L1 RT. Notably, the NCI-binding region is structurally similar between HIV-1 RT and L1 RT, suggesting that NCI recognition principles may extend across these two biologically distinct polymerases. This R21 seeks to establish proof-of-concept for NCI development against both enzymes. Aim 1 will discover and structurally optimize NCIs targeting HIV-1 RT by combining binding modules from known NCI chemotypes and determining their biochemical activity and co-crystal structures. Aim 2 will determine whether HIV-1 RT NCI principles translate to L1 RT by solving L1 RT/nucleic acid/NCI structures, evaluating enzymatic inhibition, and applying AI-based structure prediction and generative design to propose L1-specific NCI candidates. Cellular retrotransposition assays will test mechanism of action. Aim 3 will develop a fragment library tailored to protein–nucleic acid interfaces and perform fragment screening of HIV-1 and L1 RT/nucleic acid complexes to identify additional chemotypes that engage the NCI binding region. Successful completion will yield NCI scaffolds and mechanistic insights applicable to HIV-1 RT and L1 RT, define structural principles governing NCI recognition across two evolutionarily related polymerases, and establish new avenues for RT inhibitor development. The PI is highly qualified to lead this work, with extensive expertise in RT structural biology, drug design, and fragment-based discovery.

Multi-modal Micro Electrode Fluidic Array (MEFA) Shells for Brain Organoids

Abstract Brain organoids (BOs) derived from human stem cells bridge the gap between monolayer cell culture studies and animal models, which have well-documented limitations. Monolayer cell culture models fail to accurately replicate the 3D interconnectivity in the brain; animal models, while helpful, are limited due to interspecies differences, with most research focusing on rather phenotypical rather than mechanistic aspects. Concurrent with the advancement of BO models is the urgent need to develop 3D micro instrumentation supporting these organoids to investigate brain development and disease in their accurate physiological environment. Conventional microelectrode arrays (MEAs) used for neuronal cell culture studies are planar, which limits recording access to a small fraction of cells on the bottom side of the organoid. Also, conventional microfluidics is inherently planar, and while recent advances in 3D MEAs and 3D microfluidics have enabled electrical and chemical interrogation in 3D, combining both features with tunability and precision to allow independent and simultaneous control is challenging. Recently, we reported new 3D micro instrumentation in the form of 3D shell MEAs and demonstrated its applicability for electrical recording from BOs. They feature lithographically patterned and chip-integrated electrodes and self-folding polymer shells that can be triggered to wrap around BOs to measure electrical activity from the entire organoid surface. The 3D MEA shell system is modeled on and resembles a miniaturized electroencephalography (EEG) cap; the process used to make them is size-scalable, chip-integrated, and mass- producible. In the research, we aim to develop and validate 3D Micro Electrode Fluidic Array (MEFA) shells with multi-modal electrical recording and biochemical control capabilities, offering high spatiotemporal resolution, tunability, and scalability. Since 3D spatiotemporal patterns of neurochemicals play a critical role in molecular and cellular events of neural development and disease, we propose to apply and validate the MEFA shells in two studies that mimic neurodevelopment and monitor the spatiotemporal effects in neurological disorders and their treatments in vitro. We anticipate that the proposed 3D MEFAs would revolutionize brain sciences by permitting real-time, in-situ studies of electrical and chemical stimulation and interrogation of BOs in a high- throughput manner. The proposed 3D scalable, reproducible, and tunable 3D micro instrumentation for BOs has broad relevance to understanding brain development in utero and the development of anatomically accurate drug and toxicity screening platforms for brain sciences and neurological disorders.

Programming Offspring Metabolism: The Role of Milk Extracellular Vesicles in Fat Development

SUMMARY Obesity is a global health crisis, contributing significantly to the prevalence of metabolic disorders, cardiovascular diseases, and various chronic conditions. A growing body of evidence suggests that maternal obesity during pregnancy and lactation can predispose offspring to obesity and metabolic dysfunction later in life. However, the mechanisms by which maternal obesity programs these adverse outcomes in offspring remain poorly understood. Breast milk is not only a source of essential nutrients but also contains bioactive components, including extracellular vesicles (EVs), which play crucial roles in cellular communication and development. Recent studies have shown that EVs can survive digestion and enter the infant’s circulation, influencing immune and metabolic development. Despite the established link between maternal obesity and altered breast milk composition, no study has investigated the role of milk-derived EVs (mEVs) in programming offspring fat development and metabolism. Understanding this novel pathway could revolutionize our approach to preventing intergenerational transmission of obesity. Our preliminary studies using a mouse model of maternal high-fat diet-induced obesity revealed significant alterations in mEV biogenesis and cargo composition, including changes in specific miRNAs. Oral administration of mEVs from obese dams to neonatal mice increased adiposity and impaired lipid metabolism, indicating that mEVs are crucial in modulating fat development and metabolic pathways in offspring. Several key miRNAs found in mouse mEVs are conserved in human milk EVs, highlighting the potential translational relevance of our findings to human health. We hypothesize that mEVs are critical mediators of maternal obesity’s programming effects on offspring metabolism and adiposity. In specific aim 1, we will use mouse models and advanced molecular techniques (miRNA sequencing, proteomics, and lipidomics) to characterize how maternal obesity affects mEV biogenesis and the composition of their bioactive cargo. We will also evaluate how maternal dietary intake, independent of obesity, influences mEV composition. Specific aim 2 will define the programming effects of mEVs on offspring energy metabolism and obesity. In addition, we will explore whether human milk EVs from lean and obese mothers exert similar programming effects on fat development and metabolism in a mouse model. This R21 application embodies a high-risk, high-reward approach to obesity research. It ventures into uncharted territory by proposing that mEVs are novel regulators of metabolic programming, a concept that has not been explored in prior studies. The potential reward is substantial: discovering a new mechanism by which maternal obesity influences offspring health could fundamentally shift our understanding of early-life metabolic programming and lead to innovative strategies for obesity prevention. If successful, this research could open a new field of study with broad implications for maternal and child health.

Developing a novel technology for studying T cell differentiation in vivo

Summary CRISPR-based genetic screens have revolutionized our understanding of gene functions and molecular mechanisms across various biological processes. In the field of T cell biology, CRISPR screens have played a pivotal role in identifying genes that impact critical aspects, such as T cell development, differentiation, and function. However, traditional screens have struggled to distinguish genes with diverse mechanisms of action, necessitating further investigations. To address this challenge, researchers have harnessed the power of CRISPR screens combined with single-cell sequencing (scCRISPR-seq), enabling the simultaneous assessment of genetic perturbations and high-dimensional phenotypes at the single-cell level. While scCRISPR- seq has predominantly been performed in vitro using immortalized cell lines, its physiological relevance is limited due to oversimplified biological context and disparities compared to primary cells. This limitation highlights the urgent need for large-scale in vivo scCRISPR-seq with primary T cells. However, various challenges have discouraged its widespread adoption. The use of viral vectors for sgRNA delivery compromises physiological relevance, as the in vitro activation conditions fail to faithfully represent the intricate T cell priming process in vivo. Moreover, viral vector components and continuous Cas9 expression can trigger immunogenicity and cytotoxicity, leading to cell depletion and hindering long-term studies. Additionally, current scCRISPR-seq methods face technical limitations, including low editing efficiency and inadequate perturbation identity recovery rates, which impede efficient large-scale in vivo applications. Fortunately, recent advances in ribonucleoprotein complex (RNP) transfection have addressed many of these challenges. This cutting-edge technology enables efficient gene editing in primary T cells without the need for in vitro activation or permanent Cas9 expression. Leveraging the high editing efficiency of RNP transfection, the investigator’s team aims to develop a novel strategy for in vivo T cell CRISPR screens. This innovative approach involves arrayed RNP transfection and co- transfer of T cells that recognize the relevant antigens. Instead of traditional genetic barcodes, the strategy utilizes congenic markers (CD45.1/45.2 and CD90.1/CD90.2) from donor TCR transgenic T cells as "external barcodes." These markers facilitate the recovery of gene perturbation identity at the single-cell level through the application of CITE-seq. Importantly, this RNP-based strategy seamlessly integrates with existing single-cell sequencing protocols, enabling the comprehensive assessment of transcripts, epitopes, and chromatin accessibility simultaneously. To demonstrate the efficacy of this strategy, the team plans to develop two benchmarking approaches: RNP-CET-seq to investigate the role of TCR regulators in T cell exhaustion and RNP-CATE-seq to map the gene regulatory atlas of exhausted CD8 T cells. In summary, the proposed RNP- based scCRISPR-seq strategy overcomes the limitations of current approaches, enabling large-scale, multi- module in vivo genetic screens within a physiologically relevant context across various disease models.

Cellular Crosstalk in Brain Development, Evolution and Disease

Cellular crosstalk is an essential process during brain development and is influenced by numerous factors, including cell morphology, adhesion, the local extracellular matrix and secreted vesicles. Inspired by mutations associated with neurodevelopmental disorders, we focus on understanding the role of extracellular mechanisms essential for the proper development of the human brain. Therefore, we combine 2D and 3D in vitro human models to better understand the molecular and cellular mechanisms involved in progenitor proliferation and fate, migration and maturation of excitatory and inhibitory neurons during human brain development and tackle the causes of neurodevelopmental disorders.

Understanding reward-guided learning using large-scale datasets

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.

Developmental and evolutionary perspectives on thalamic function

Brain organization and function is a complex topic. We are good at establishing correlates of perception and behavior across forebrain circuits, as well as manipulating activity in these circuits to affect behavior. However, we still lack good models for the large-scale organization and function of the forebrain. What are the contributions of the cortex, basal ganglia, and thalamus to behavior? In addressing these questions, we often ascribe function to each area as if it were an independent processing unit. However, we know from the anatomy that the cortex, basal ganglia, and thalamus, are massively interconnected in a large network. One way to generate insight into these questions is to consider the evolution and development of forebrain systems. In this talk, I will discuss the developmental and evolutionary (comparative anatomy) data on the thalamus, and how it fits within forebrain networks. I will address questions including, when did the thalamus appear in evolution, how is the thalamus organized across the vertebrate lineage, and how can the change in the organization of forebrain networks affect behavioral repertoires.

Understanding reward-guided learning using large-scale datasets

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.

Rethinking brain mechanisms in the light of evolution

Relating circuit dynamics to computation: robustness and dimension-specific computation in cortical dynamics

Neural dynamics represent the hard-to-interpret substrate of circuit computations. Advances in large-scale recordings have highlighted the sheer spatiotemporal complexity of circuit dynamics within and across circuits, portraying in detail the difficulty of interpreting such dynamics and relating it to computation. Indeed, even in extremely simplified experimental conditions, one observes high-dimensional temporal dynamics in the relevant circuits. This complexity can be potentially addressed by the notion that not all changes in population activity have equal meaning, i.e., a small change in the evolution of activity along a particular dimension may have a bigger effect on a given computation than a large change in another. We term such conditions dimension-specific computation. Considering motor preparatory activity in a delayed response task we utilized neural recordings performed simultaneously with optogenetic perturbations to probe circuit dynamics. First, we revealed a remarkable robustness in the detailed evolution of certain dimensions of the population activity, beyond what was thought to be the case experimentally and theoretically. Second, the robust dimension in activity space carries nearly all of the decodable behavioral information whereas other non-robust dimensions contained nearly no decodable information, as if the circuit was setup to make informative dimensions stiff, i.e., resistive to perturbations, leaving uninformative dimensions sloppy, i.e., sensitive to perturbations. Third, we show that this robustness can be achieved by a modular organization of circuitry, whereby modules whose dynamics normally evolve independently can correct each other’s dynamics when an individual module is perturbed, a common design feature in robust systems engineering. Finally, we will recent work extending this framework to understanding the neural dynamics underlying preparation of speech.

Gene regulatory mechanisms of neocortex development and evolution

The neocortex is considered to be the seat of higher cognitive functions in humans. During its evolution, most notably in humans, the neocortex has undergone considerable expansion, which is reflected by an increase in the number of neurons. Neocortical neurons are generated during development by neural stem and progenitor cells. Epigenetic mechanisms play a pivotal role in orchestrating the behaviour of stem cells during development. We are interested in the mechanisms that regulate gene expression in neural stem cells, which have implications for our understanding of neocortex development and evolution, neural stem cell regulation and neurodevelopmental disorders.

Rett syndrome, MECP2 and therapeutic strategies

The development of the iPS cell technology has revolutionized our ability to study development and diseases in defined in vitro cell culture systems. The talk will focus on Rett Syndrome and discuss two topics: (i) the use of gene editing as an approach to therapy and (ii) the role of MECP2 in gene expression (i) The mutation of the X-linked MECP2 gene is causative for the disease. In a female patient, every cell has a wt copy that is, however, in 50% of the cells located on the inactive X chromosome. We have used epigenetic gene editing tools to activate the wt MECP2 allele on the inactive X chromosome. (ii) MECP2 is thought to act as repressor of gene expression. I will present data which show that MECP2 binds to Pol II and acts as an activator for thousands of genes. The target genes are significantly enriched for Autism related genes. Our data challenge the established model of MECP2’s role in gene expression and suggest novel therapeutic approaches.

Brain circuits for spatial navigation

In this webinar on spatial navigation circuits, three researchers—Ann Hermundstad, Ila Fiete, and Barbara Webb—discussed how diverse species solve navigation problems using specialized yet evolutionarily conserved brain structures. Hermundstad illustrated the fruit fly’s central complex, focusing on how hardwired circuit motifs (e.g., sinusoidal steering curves) enable rapid, flexible learning of goal-directed navigation. This framework combines internal heading representations with modifiable goal signals, leveraging activity-dependent plasticity to adapt to new environments. Fiete explored the mammalian head-direction system, demonstrating how population recordings reveal a one-dimensional ring attractor underlying continuous integration of angular velocity. She showed that key theoretical predictions—low-dimensional manifold structure, isometry, uniform stability—are experimentally validated, underscoring parallels to insect circuits. Finally, Webb described honeybee navigation, featuring path integration, vector memories, route optimization, and the famous waggle dance. She proposed that allocentric velocity signals and vector manipulation within the central complex can encode and transmit distances and directions, enabling both sophisticated foraging and inter-bee communication via dance-based cues.

Brain-Wide Compositionality and Learning Dynamics in Biological Agents

Biological agents continually reconcile the internal states of their brain circuits with incoming sensory and environmental evidence to evaluate when and how to act. The brains of biological agents, including animals and humans, exploit many evolutionary innovations, chiefly modularity—observable at the level of anatomically-defined brain regions, cortical layers, and cell types among others—that can be repurposed in a compositional manner to endow the animal with a highly flexible behavioral repertoire. Accordingly, their behaviors show their own modularity, yet such behavioral modules seldom correspond directly to traditional notions of modularity in brains. It remains unclear how to link neural and behavioral modularity in a compositional manner. We propose a comprehensive framework—compositional modes—to identify overarching compositionality spanning specialized submodules, such as brain regions. Our framework directly links the behavioral repertoire with distributed patterns of population activity, brain-wide, at multiple concurrent spatial and temporal scales. Using whole-brain recordings of zebrafish brains, we introduce an unsupervised pipeline based on neural network models, constrained by biological data, to reveal highly conserved compositional modes across individuals despite the naturalistic (spontaneous or task-independent) nature of their behaviors. These modes provided a scaffolding for other modes that account for the idiosyncratic behavior of each fish. We then demonstrate experimentally that compositional modes can be manipulated in a consistent manner by behavioral and pharmacological perturbations. Our results demonstrate that even natural behavior in different individuals can be decomposed and understood using a relatively small number of neurobehavioral modules—the compositional modes—and elucidate a compositional neural basis of behavior. This approach aligns with recent progress in understanding how reasoning capabilities and internal representational structures develop over the course of learning or training, offering insights into the modularity and flexibility in artificial and biological agents.

Sophie Scott - The Science of Laughter from Evolution to Neuroscience

Keynote Address to British Association of Cognitive Neuroscience, London, 10th September 2024

Personalized medicine and predictive health and wellness: Adding the chemical component

Wearable sensors that detect and quantify biomarkers in retrievable biofluids (e.g., interstitial fluid, sweat, tears) provide information on human dynamic physiological and psychological states. This information can transform health and wellness by providing actionable feedback. Due to outdated and insufficiently sensitive technologies, current on-body sensing systems have capabilities limited to pH, and a few high-concentration electrolytes, metabolites, and nutrients. As such, wearable sensing systems cannot detect key low-concentration biomarkers indicative of stress, inflammation, metabolic, and reproductive status.  We are revolutionizing sensing. Our electronic biosensors detect virtually any signaling molecule or metabolite at ultra-low levels. We have monitored serotonin, dopamine, cortisol, phenylalanine, estradiol, progesterone, and glucose in blood, sweat, interstitial fluid, and tears. The sensors are based on modern nanoscale semiconductor transistors that are straightforwardly scalable for manufacturing. We are developing sensors for >40 biomarkers for personalized continuous monitoring (e.g., smartwatch, wearable patch) that will provide feedback for treating chronic health conditions (e.g., perimenopause, stress disorders, phenylketonuria). Moreover, our sensors will enable female fertility monitoring and the adoption of more healthy lifestyles to prevent disease and improve physical and cognitive performance.

How can marsupials help us to understand neocortical evolution and plasticity?

Evolution of convulsive therapy from electroconvulsive therapy to Magnetic Seizure Therapy; Interventional Neuropsychiatry

In April, we will host Nolan Williams and Mustafa Husain. Be prepared to embark on a journey from early brain stimulation with ECT to state-of-the art TMS protocols and magnetic seizure therapy! The talks will be held on Thursday, April 25th at noon ET / 6PM CET. Nolan Williams, MD, is an associate professor of Psychiatry and Behavioral Science at Stanford University. He developed the SAINT protocol, which is the first FDA-cleared non-invasive, rapid-acting neuromodulation treatment for treatment-resistant depression. Mustafa Husain, MD, is an adjunct professor of Psychiatry and Behavioral Sciences at Duke University and a professor of Psychiatry and Neurology at UT Southwestern Medical Center, Dallas. He will tell us about “Evolution of convulsive therapy from electroconvulsive therapy to Magnetic Seizure Therapy”. As always, we will also get a glimpse at the “Person behind the science”. Please register va talks.stimulatingbrains.org to receive the (free) Zoom link, subscribe to our newsletter, or follow us on Twitter/X for further updates!

Molecular Characterization of Retinal Cell Types: Insights into Evolutionary Origins and Regional Specializations

Of glia and macrophages, signaling hubs in development and homeostasis

We are interested in the biology of macrophages, which represent the first line of defense against pathogens. In Drosophila, the embryonic hemocytes arise from the mesoderm whereas glial cells arise from multipotent precursors in the neurogenic region. These cell types represent, respectively, the macrophages located outside and within the nervous system (similar to vertebrate microglia). Thus, despite their different origin, hemocytes and glia display common functions. In addition, both cell types express the Glide/Gcm transcription factor, which plays an evolutionarily conserved role as an anti-inflammatory factor. Moreover, embryonic hemocytes play an evolutionarily conserved and fundamental role in development. The ability to migrate and to contact different tissues/organs most likely allow macrophages to function as signaling hubs. The function of macrophages beyond the recognition of the non-self calls for revisiting the biology of these heterogeneous and plastic cells in physiological and pathological conditions across evolution.

Reimagining the neuron as a controller: A novel model for Neuroscience and AI

We build upon and expand the efficient coding and predictive information models of neurons, presenting a novel perspective that neurons not only predict but also actively influence their future inputs through their outputs. We introduce the concept of neurons as feedback controllers of their environments, a role traditionally considered computationally demanding, particularly when the dynamical system characterizing the environment is unknown. By harnessing a novel data-driven control framework, we illustrate the feasibility of biological neurons functioning as effective feedback controllers. This innovative approach enables us to coherently explain various experimental findings that previously seemed unrelated. Our research has profound implications, potentially revolutionizing the modeling of neuronal circuits and paving the way for the creation of alternative, biologically inspired artificial neural networks.

Mechanisms of visual diversity: from evolutionary processes to instantaneous responses

Prefrontal mechanisms involved in learning distractor-resistant working memory in a dual task

Working memory (WM) is a cognitive function that allows the short-term maintenance and manipulation of information when no longer accessible to the senses. It relies on temporarily storing stimulus features in the activity of neuronal populations. To preserve these dynamics from distraction it has been proposed that pre and post-distraction population activity decomposes into orthogonal subspaces. If orthogonalization is necessary to avoid WM distraction, it should emerge as performance in the task improves. We sought evidence of WM orthogonalization learning and the underlying mechanisms by analyzing calcium imaging data from the prelimbic (PrL) and anterior cingulate (ACC) cortices of mice as they learned to perform an olfactory dual task. The dual task combines an outer Delayed Paired-Association task (DPA) with an inner Go-NoGo task. We examined how neuronal activity reflected the process of protecting the DPA sample information against Go/NoGo distractors. As mice learned the task, we measured the overlap between the neural activity onto the low-dimensional subspaces that encode sample or distractor odors. Early in the training, pre-distraction activity overlapped with both sample and distractor subspaces. Later in the training, pre-distraction activity was strictly confined to the sample subspace, resulting in a more robust sample code. To gain mechanistic insight into how these low-dimensional WM representations evolve with learning we built a recurrent spiking network model of excitatory and inhibitory neurons with low-rank connections. The model links learning to (1) the orthogonalization of sample and distractor WM subspaces and (2) the orthogonalization of each subspace with irrelevant inputs. We validated (1) by measuring the angular distance between the sample and distractor subspaces through learning in the data. Prediction (2) was validated in PrL through the photoinhibition of ACC to PrL inputs, which induced early-training neural dynamics in well-trained animals. In the model, learning drives the network from a double-well attractor toward a more continuous ring attractor regime. We tested signatures for this dynamical evolution in the experimental data by estimating the energy landscape of the dynamics on a one-dimensional ring. In sum, our study defines network dynamics underlying the process of learning to shield WM representations from distracting tasks.

A synergistic core for human brain evolution and cognition

Comparative transcriptomics of retinal cell types

NOTE: DUE TO A CYBER ATTACK OUR UNIVERSITY WEB SYSTEM IS SHUT DOWN - TALK WILL BE RESCHEDULED

The size and structure of the dendritic arbor play important roles in determining how synaptic inputs of neurons are converted to action potential output and how neurons are integrated in the surrounding neuronal network. Accordingly, neurons with aberrant morphology have been associated with neurological disorders. Dysmorphic, enlarged neurons are, for example, a hallmark of focal epileptogenic lesions like focal cortical dysplasia (FCDIIb) and gangliogliomas (GG). However, the regulatory mechanisms governing the development of dendrites are insufficiently understood. The evolutionary conserved Ste20/Hippo kinase pathway has been proposed to play an important role in regulating the formation and maintenance of dendritic architecture. A key element of this pathway, Ste20-like kinase (SLK), regulates cytoskeletal dynamics in non-neuronal cells and is strongly expressed throughout neuronal development. Nevertheless, its function in neurons is unknown. We found that during development of mouse cortical neurons, SLK has a surprisingly specific role for proper elaboration of higher, ≥ 3rd, order dendrites both in cultured neurons and living mice. Moreover, SLK is required to maintain excitation-inhibition balance. Specifically, SLK knockdown causes a selective loss of inhibitory synapses and functional inhibition after postnatal day 15, while excitatory neurotransmission is unaffected. This mechanism may be relevant for human disease, as dysmorphic neurons within human cortical malformations exhibit significant loss of SLK expression. To uncover the signaling cascades underlying the action of SLK, we combined phosphoproteomics, protein interaction screens and single cell RNA seq. Overall, our data identifies SLK as a key regulator of both dendritic complexity during development and of inhibitory synapse maintenance.

The embodied brain

Understanding the brain is not only intrinsically fascinating, but also highly relevant to increase our well-being since our brain exhibits a power over the body that makes it capable both of provoking illness or facilitating the healing process. Bearing in mind this dark force, brain sciences have undergone and will undergo an important revolution, redefining its boundaries beyond the cranial cavity. During this presentation, we will discuss about the communication between the brain and other systems that shapes how we feel the external word and how we think. We are starting to unravel how our organs talk to the brain and how the brain talks back. That two-way communication encompasses a complex, body-wide system of nerves, hormones and other signals that will be discussed. This presentation aims at challenging a long history of thinking of bodily regulation as separate from "higher" mental processes. Four centuries ago, René Descartes famously conceptualized the mind as being separate from the body, it is time now to embody our mind.

My evolution in invasive human neurophysiology: From basal ganglia single units to chronic electrocorticography; Therapies orchestrated by patients' own rhythms

On Thursday, April 27th, we will host Hayriye Cagnan and Philip A. Starr. Hayriye Cagnan, PhD, is an associate professor at the MRC Brain Network Dynamics Unit and University of Oxford. She will tell us about “Therapies orchestrated by patients’ own rhythms”. Philip A. Starr, MD, PhD, is a neurosurgeon and professor of Neurological Surgery at the University of California San Francisco. Besides his scientific presentation on “My evolution in invasive human neurophysiology: from basal ganglia single units to chronic electrocorticography”, he will give us a glimpse at the person behind the science. The talks will be followed by a shared discussion. You can register via talks.stimulatingbrains.org to receive the (free) Zoom link!

The embodied brain

Understanding the brain is not only intrinsically fascinating, but also highly relevant to increase our well-being since our brain exhibits a power over the body that makes it capable both of provoking illness or facilitating the healing process. Bearing in mind this dark force, brain sciences have undergone and will undergo an important revolution, redefining its boundaries beyond the cranial cavity. During this presentation, we will discuss about the communication between the brain and other systems that shapes how we feel the external word and how we think. We are starting to unravel how our organs talk to the brain and how the brain talks back. That two-way communication encompasses a complex, body-wide system of nerves, hormones and other signals that will be discussed. This presentation aims at challenging a long history of thinking of bodily regulation as separate from "higher" mental processes. Four centuries ago, René Descartes famously conceptualized the mind as being separate from the body, it is time now to embody our mind.

Exploring emotion in the expression of ape gesture

Language appears to be the most complex system of animal communication described to date. However, its precursors were present in the communication of our evolutionary ancestors and are likely shared by our modern ape cousins.  All great apes, including humans, employ a rich repertoire of vocalizations, facial expressions, and gestures. Great ape gestural repertoires are particularly elaborate, with ape species employing over 80 different gesture types intentionally: that is towards a recipient with a specific goal in mind. Intentional usage allows us to ask not only what information is encoded in ape gestures, but what do apes mean when they use them. I will discuss recent research on ape gesture, on how we approach the question of decoding meaning, and how with new methods we are starting to integrate long overlooked aspects of ape gesture such as group and individual variation, and expression and emotion into our study of these signals.

Development and evolution of neuronal connectivity

In most animal species including humans, commissural axons connect neurons on the left and right side of the nervous system. In humans, abnormal axon midline crossing during development causes a whole range of neurological disorders ranging from congenital mirror movements, horizontal gaze palsy, scoliosis or binocular vision deficits. The mechanisms which guide axons across the CNS midline were thought to be evolutionary conserved but our recent results suggesting that they differ across vertebrates.  I will discuss the evolution of visual projection laterality during vertebrate evolution.  In most vertebrates, camera-style eyes contain retinal ganglion cell (RGC) neurons projecting to visual centers on both sides of the brain. However, in fish, RGCs are thought to only innervate the contralateral side. Using 3D imaging and tissue clearing we found that bilateral visual projections exist in non-teleost fishes. We also found that the developmental program specifying visual system laterality differs between fishes and mammals. We are currently using various strategies to discover genes controlling the development of visual projections. I will also present ongoing work using 3D imaging techniques to study the development of the visual system in human embryo.

Theories of consciousness: beyond the first/higher-order distinction

Theories of consciousness are commonly grouped into "first-order" and "higher-order" families. As conventional wisdom has it, many more animals are likely to be conscious if a first-order theory is correct. But two recent developments have put pressure on the first/higher-order distinction. One is the argument (from Shea and Frith) that an effective global workspace mechanism must involve a form of metacognition. The second is Lau's "perceptual reality monitoring" (PRM) theory, a member of the "higher-order" family in which conscious sensory content is not re-represented, only tagged with a temporal index and marked as reliable. I argue that the first/higher-order distinction has become so blurred that it is no longer particularly useful. Moreover, the conventional wisdom about animals should not be trusted. It could be, for example, that the distribution of PRM in the animal kingdom is wider than the distribution of global broadcasting.

The brain: A coincidence detector between sensory experiences and internal milieu

Understanding the brain is not only intrinsically fascinating, but also highly relevant to increase our well-being since our brain exhibits a power over the body that makes it capable both of provoking illness or facilitating the healing process. Bearing in mind this dark force, brain sciences have undergone and will undergo an important revolution, redefining its boundaries beyond the cranial cavity. During this presentation, we will discuss about the communication between the brain and other systems that shapes how we feel the external word and how we think. We are starting to unravel how our organs talk to the brain and how the brain talks back. That two-way communication encompasses a complex, bodywide system of nerves, hormones and other signals that we will discussed. This presentation aims at challenging a long history of thinking of bodily regulation as separate from "higher" mental processes. Four centuries ago, René Descartes famously conceptualized the mind as being separate from the body, it is time now to embody our mind.

Epigenome regulation in neocortex expansion and generation of neuronal subtypes

Evolutionarily, the expansion of the human neocortex accounts for many of the unique cognitive abilities of humans. This expansion appears to reflect the increased proliferative potential of basal progenitors (BPs) in mammalian evolution. Further cortical progenitors generate both glutamatergic excitatory neurons (ENs) and GABAergic inhibitory interneurons (INs) in human cortex, whereas they produce exclusively ENs in rodents. The increased proliferative capacity and neuronal subtype generation of cortical progenitors in mammalian evolution may have evolved through epigenetic alterations. However, whether or how the epigenome in cortical progenitors differs between humans and other species is unknown. Here, we report that histone H3 acetylation is a key epigenetic regulation in BP profiling of sorted BPs, we show that H3K9 acetylation is low in murine BPs and high in amplification, neuronal subtype generation and cortical expansion. Through epigenetic profiling of sorted BPs, we show that H3K9 acetylation is low in murine BPs and high in human BPs. Elevated H3K9ac preferentially increases BP proliferation, increasing the size and folding of the normally smooth mouse neocortex. Furthermore, we found that the elevated H3 acetylation activates expression of IN genes in in developing mouse cortex and promote proliferation of IN progenitor-like cells in cortex of Pax6 mutant mouse models. Mechanistically, H3K9ac drives the BP amplification and proliferation of these IN progenitor-like cells by increasing expression of the evolutionarily regulated gene, TRNP1. Our findings demonstrate a previously unknown mechanism that controls neocortex expansion and generation of neuronal subtypes. Keywords: Cortical development, neurogenesis, basal progenitors, cortical size, gyrification, excitatory neuron, inhibitory interneuron, epigenetic profiling, epigenetic regulation, H3 acetylation, H3K9ac, TRNP1, PAX6

Color vision circuits for primate intrinsically photosensitive retinal ganglion cells

The rising and setting of the sun is accompanied by changes in both the irradiance and the spectral distribution of the sky. Since the discovery of intrinsically photosensitive retinal ganglion cells (ipRGCs) 20 years ago, considerable progress has been made in understanding melanopsin's contributions to encoding irradiance. Much less is known about the cone inputs to ipRGCs and how they could encode changes in the color of the sky. I will summarize our recent connectomic investigation into the cone-opponent inputs to primate ipRGCs and the implications of this work on our understanding of circadian photoentrainment and the evolution of color vision.

A mind set in stone: fossil traces of human brain evolution

Brains do not fossilise, but as they grow and expand during fetal and infant development, they leave an imprint in the bony braincase. Such imprints of fossilised braincases provide direct evidence of brain evolution, but the underlying biological changes have remained elusive. Combining data from fossil skulls, ancient genomes, brain imaging and gene expression helps shed light on the evolutionary changes shaping the human brain. I will highlight two examples separated by more than 3 million years: the evolution of brain growth in Lucy and her kind, and differences between modern humans and Neanderthals.

Drifting assemblies for persistent memory: Neuron transitions and unsupervised compensation

Change is ubiquitous in living beings. In particular, the connectome and neural representations can change. Nevertheless behaviors and memories often persist over long times. In a standard model, associative memories are represented by assemblies of strongly interconnected neurons. For faithful storage these assemblies are assumed to consist of the same neurons over time. We propose a contrasting memory model with complete temporal remodeling of assemblies, based on experimentally observed changes of synapses and neural representations. The assemblies drift freely as noisy autonomous network activity or spontaneous synaptic turnover induce neuron exchange. The exchange can be described analytically by reduced, random walk models derived from spiking neural network dynamics or from first principles. The gradual exchange allows activity-dependent and homeostatic plasticity to conserve the representational structure and keep inputs, outputs and assemblies consistent. This leads to persistent memory. Our findings explain recent experimental results on temporal evolution of fear memory representations and suggest that memory systems need to be understood in their completeness as individual parts may constantly change.

Reprogramming the nociceptive circuit topology reshapes sexual behavior in C. elegans

In sexually reproducing species, males and females respond to environmental sensory cues and transform the input into sexually dimorphic traits. Yet, how sexually dimorphic behavior is encoded in the nervous system is poorly understood. We characterize the sexually dimorphic nociceptive behavior in C. elegans – hermaphrodites present a lower pain threshold than males in response to aversive stimuli, and study the underlying neuronal circuits, which are composed of the same neurons that are wired differently. By imaging receptor expression, calcium responses and glutamate secretion, we show that sensory transduction is similar in the two sexes, and therefore explore how downstream network topology shapes dimorphic behavior. We generated a computational model that replicates the observed dimorphic behavior, and used this model to predict simple network rewirings that would switch the behavior between the sexes. We then showed experimentally, using genetic manipulations, artificial gap junctions, automated tracking and optogenetics, that these subtle changes to male connectivity result in hermaphrodite-like aversive behavior in-vivo, while hermaphrodite behavior was more robust to perturbations. Strikingly, when presented with aversive cues, rewired males were compromised in finding mating partners, suggesting that the network topology that enables efficient avoidance of noxious cues would have a reproductive "cost". To summarize, we present a deconstruction of a sex-shared neural circuit that affects sexual behavior, and how to reprogram it. More broadly, our results are an example of how common neuronal circuits changed their function during evolution by subtle topological rewirings to account for different environmental and sexual needs.

The evolution of computation in the brain: Insights from studying the retina

The retina is probably the most accessible part of the vertebrate central nervous system. Its computational logic can be interrogated in a dish, from patterns of lights as the natural input, to spike trains on the optic nerve as the natural output. Consequently, retinal circuits include some of the best understood computational networks in neuroscience. The retina is also ancient, and central to the emergence of neurally complex life on our planet. Alongside new locomotor strategies, the parallel evolution of image forming vision in vertebrate and invertebrate lineages is thought to have driven speciation during the Cambrian. This early investment in sophisticated vision is evident in the fossil record and from comparing the retina’s structural make up in extant species. Animals as diverse as eagles and lampreys share the same retinal make up of five classes of neurons, arranged into three nuclear layers flanking two synaptic layers. Some retina neuron types can be linked across the entire vertebrate tree of life. And yet, the functions that homologous neurons serve in different species, and the circuits that they innervate to do so, are often distinct to acknowledge the vast differences in species-specific visuo-behavioural demands. In the lab, we aim to leverage the vertebrate retina as a discovery platform for understanding the evolution of computation in the nervous system. Working on zebrafish alongside birds, frogs and sharks, we ask: How do synapses, neurons and networks enable ‘function’, and how can they rearrange to meet new sensory and behavioural demands on evolutionary timescales?

How communication networks promote cross-cultural similarities: The case of category formation

Individuals vary widely in how they categorize novel phenomena. This individual variation has led canonical theories in cognitive and social science to suggest that communication in large social networks leads populations to construct divergent category systems. Yet, anthropological data indicates that large, independent societies consistently arrive at similar categories across a range of topics. How is it possible for diverse populations, consisting of individuals with significant variation in how they view the world, to independently construct similar categories? Through a series of online experiments, I show how large communication networks within cultures can promote the formation of similar categories across cultures. For this investigation, I designed an online “Grouping Game” to observe how people construct categories in both small and large populations when tasked with grouping together the same novel and ambiguous images. I replicated this design for English-speaking subjects in the U.S. and Mandarin-speaking subjects in China. In both cultures, solitary individuals and small social groups produced highly divergent category systems. Yet, large social groups separately and consistently arrived at highly similar categories both within and across cultures. These findings are accurately predicted by a simple mathematical model of critical mass dynamics. Altogether, I show how large communication networks can filter lexical diversity among individuals to produce replicable society-level patterns, yielding unexpected implications for cultural evolution. In particular, I discuss how participants in both cultures readily harnessed analogies when categorizing novel stimuli, and I examine the role of communication networks in promoting cross-cultural similarities in analogy-making as the key engine of category formation.

Untitled Seminar

G. Quattrocolo: Cajal-Retzius cells in the postnatal hippocampus; F. Garcia-Moreno: Mosaic evolutionary history of brain circuits through the lens of neurogenesis

Alternative Applications of Foraging Theory

Why do some animals have more than two eyes?

The evolution of vision revolutionised animal biology, and eyes have evolved in a stunning array of diverse forms over the past half a billion years. Among these are curious duplicated visual systems, where eyes can be spread across the body and specialised for different tasks. Although it sounds radical, duplicated vision is found in most major groups across the animal kingdom, but remains poorly understood. We will explore how and why animals collect information about their environment in this unusual way, looking at examples from tropical forests to the sea floor, and from ancient arthropods to living jellyfish. Have we been short-changed with just two eyes? Dr Lauren Sumner-Rooney is a Research Fellow at the OUMNH studying the function and evolution of animal visual systems. Lauren completed her undergraduate degree at Oxford in 2012, and her PhD at Queen’s University Belfast in 2015. She worked as a research technician and science communicator at the Royal Veterinary College (2015-2016) and held a postdoctoral research fellowship at the Museum für Naturkunde, Berlin (2016-2017) before arriving at the Museum in 2017.

The evolution and development of visual complexity: insights from stomatopod visual anatomy, physiology, behavior, and molecules

Bioluminescence, which is rare on land, is extremely common in the deep sea, being found in 80% of the animals living between 200 and 1000 m. These animals rely on bioluminescence for communication, feeding, and/or defense, so the generation and detection of light is essential to their survival. Our present knowledge of this phenomenon has been limited due to the difficulty in bringing up live deep-sea animals to the surface, and the lack of proper techniques needed to study this complex system. However, new genomic techniques are now available, and a team with extensive experience in deep-sea biology, vision, and genomics has been assembled to lead this project. This project is aimed to study three questions 1) What are the evolutionary patterns of different types of bioluminescence in deep-sea shrimp? 2) How are deep-sea organisms’ eyes adapted to detect bioluminescence? 3) Can bioluminescent organs (called photophores) detect light in addition to emitting light? Findings from this study will provide valuable insight into a complex system vital to communication, defense, camouflage, and species recognition. This study will bring monumental contributions to the fields of deep sea and evolutionary biology, and immediately improve our understanding of bioluminescence and light detection in the marine environment. In addition to scientific advancement, this project will reach K-college aged students through the development and dissemination of educational tools, a series of molecular and organismal-based workshops, museum exhibits, public seminars, and biodiversity initiatives.

The Synaptome Architecture of the Brain: Lifespan, disease, evolution and behavior

The overall aim of my research is to understand how the organisation of the synapse, with particular reference to the postsynaptic proteome (PSP) of excitatory synapses in the brain, informs the fundamental mechanisms of learning, memory and behaviour and how these mechanisms go awry in neurological dysfunction. The PSP indeed bears a remarkable burden of disease, with components being disrupted in disorders (synaptopathies) including schizophrenia, depression, autism and intellectual disability. Our work has been fundamental in revealing and then characterising the unprecedented complexity (>1000 highly conserved proteins) of the PSP in terms of the subsynaptic architecture of postsynaptic proteins such as PSD95 and how these proteins assemble into complexes and supercomplexes in different neurons and regions of the brain. Characterising the PSPs in multiple species, including human and mouse, has revealed differences in key sets of functionally important proteins, correlates with brain imaging and connectome data, and a differential distribution of disease-relevant proteins and pathways. Such studies have also provided important insight into synapse evolution, establishing that vertebrate behavioural complexity is a product of the evolutionary expansion in synapse proteomes that occurred ~500 million years ago. My lab has identified many mutations causing cognitive impairments in mice before they were found to cause human disorders. Our proteomic studies revealed that >130 brain diseases are caused by mutations affecting postsynaptic proteins. We uncovered mechanisms that explain the polygenic basis and age of onset of schizophrenia, with postsynaptic proteins, including PSD95 supercomplexes, carrying much of the polygenic burden. We discovered the “Genetic Lifespan Calendar”, a genomic programme controlling when genes are regulated. We showed that this could explain how schizophrenia susceptibility genes are timed to exert their effects in young adults. The Genes to Cognition programme is the largest genetic study so far undertaken into the synaptic molecular mechanisms underlying behaviour and physiology. We made important conceptual advances that inform how the repertoire of both innate and learned behaviours is built from unique combinations of postsynaptic proteins that either amplify or attenuate the behavioural response. This constitutes a key advance in understanding how the brain decodes information inherent in patterns of nerve impulses, and provides insight into why the PSP has evolved to be so complex, and consequently why the phenotypes of synaptopathies are so diverse. Our most recent work has opened a new phase, and scale, in understanding synapses with the first synaptome maps of the brain. We have developed next-generation methods (SYNMAP) that enable single-synapse resolution molecular mapping across the whole mouse brain and extensive regions of the human brain, revealing the molecular and morphological features of a billion synapses. This has already uncovered unprecedented spatiotemporal synapse diversity organised into an architecture that correlates with the structural and functional connectomes, and shown how mutations that cause cognitive disorders reorganise these synaptome maps; for example, by detecting vulnerable synapse subtypes and synapse loss in Alzheimer’s disease. This innovative synaptome mapping technology has huge potential to help characterise how the brain changes during normal development, including in specific cell types, and with degeneration, facilitating novel pathways to diagnosis and therapy.

Four questions about brain and behaviour

Tinbergen encouraged ethologists to address animal behaviour by answering four questions, covering physiology, adaptation, phylogeny, and development. This broad approach has implications for neuroscience and psychology, yet, questions about phylogeny are rarely considered in these fields. Here I describe how phylogeny can shed light on our understanding of brain structure and function. Further, I show that we now have or are developing the data and analytical methods necessary to study the natural history of the human mind.

Do Capuchin Monkeys, Chimpanzees and Children form Overhypotheses from Minimal Input? A Hierarchical Bayesian Modelling Approach

Abstract concepts are a powerful tool to store information efficiently and to make wide-ranging predictions in new situations based on sparse data. Whereas looking-time studies point towards an early emergence of this ability in human infancy, other paradigms like the relational match to sample task often show a failure to detect abstract concepts like same and different until the late preschool years. Similarly, non-human animals have difficulties solving those tasks and often succeed only after long training regimes. Given the huge influence of small task modifications, there is an ongoing debate about the conclusiveness of these findings for the development and phylogenetic distribution of abstract reasoning abilities. Here, we applied the concept of “overhypotheses” which is well known in the infant and cognitive modeling literature to study the capabilities of 3 to 5-year-old children, chimpanzees, and capuchin monkeys in a unified and more ecologically valid task design. In a series of studies, participants themselves sampled reward items from multiple containers or witnessed the sampling process. Only when they detected the abstract pattern governing the reward distributions within and across containers, they could optimally guide their behavior and maximize the reward outcome in a novel test situation. We compared each species’ performance to the predictions of a probabilistic hierarchical Bayesian model capable of forming overhypotheses at a first and second level of abstraction and adapted to their species-specific reward preferences.

Neural stem cells, human-specific genes, and neocortex expansion in development and human evolution

Cognitive Maps

Ample evidence suggests that the brain generates internal simulations of the outside world to guide our thoughts and actions. These mental representations, or cognitive maps, are thought to be essential for our very comprehension of reality. I will discuss what is known about the informational structure of cognitive maps, their neural underpinnings, and how they relate to behavior, evolution, disease, and the current revolution in artificial intelligence.

Dissecting the 3D regulatory landscape of the developing cerebral cortex with single-cell epigenomics

Understanding how different epigenetic layers are coordinated to facilitate robust lineage decisions during development is one of the fundamental questions in regulatory genomics. Using single-cell epigenomics coupled with cell-type specific high-throughput mapping of enhancer activity, DNA methylation and the 3D genome landscape in vivo, we dissected how the epigenome is rewired during cortical development. We identified and functionally validated key transcription factors such as Neurog2 which underlie regulatory dynamics and coordinate rewiring across multiple epigenetic layers to ensure robust lineage specification. This work showcases the power of high-throughput integrative genomics to dissect the molecular rules of cell fate decisions in the brain and more broadly, how to apply them to evolution and disease.

Chapter 3. The origin of jaws and paired fin

Leonard Maler will focus on a specialized caudal portion of the cerebellum of teleost fish whose structure and physiology has been especially well studies to the point that we now have detailed computational analyses of its function. Idoia Quintana-Urzainqui will talk about what sharks can tell us about the evolution of the telencephalon, mainly focusing on the evolutionary expansion of the pallium and how shark embryos can hold key information to interpret the origin of the developmental processes that triggered this phenomenon.

Attention to visual motion: shaping sensation into perception

Evolution has endowed primates, including humans, with a powerful visual system, seemingly providing us with a detailed perception of our surroundings. But in reality the underlying process is one of active filtering, enhancement and reshaping. For visual motion perception, the dorsal pathway in primate visual cortex and in particular area MT/V5 is considered to be of critical importance. Combining physiological and psychophysical approaches we have used the processing and perception of visual motion and area MT/V5 as a model for the interaction of sensory (bottom-up) signals with cognitive (top-down) modulatory influences that characterizes visual perception. Our findings document how this interaction enables visual cortex to actively generate a neural representation of the environment that combines the high-performance sensory periphery with selective modulatory influences for producing an “integrated saliency map’ of the environment.

Brain Basics: A peak into the Brain!

My talk will be a ’Neuro 101’ - also called ‘Basics of Neuroscience’. I hope to introduce the field of Neuroscience and give a brief glimpse into the function, history and evolution of the brain. I will guide you through questions such as - What is a brain? What are its basic building blocks and functions?

Frontal circuit specialisations for information search and decision making

During primate evolution, prefrontal cortex (PFC) expanded substantially relative to other cortical areas. The expansion of PFC circuits likely supported the increased cognitive abilities of humans and anthropoids to sample information about their environment, evaluate that information, plan, and decide between different courses of action. What quantities do these circuits compute as information is being sampled towards and a decision is being made? And how can they be related to anatomical specialisations within and across PFC? To address this, we recorded PFC activity during value-based decision making using single unit recording in non-human primates and magnetoencephalography in humans. At a macrocircuit level, we found that value correlates differ substantially across PFC subregions. They are heavily shaped by each subregion’s anatomical connections and by the decision-maker’s current locus of attention. At a microcircuit level, we found that the temporal evolution of value correlates can be predicted using cortical recurrent network models that temporally integrate incoming decision evidence. These models reflect the fact that PFC circuits are highly recurrent in nature and have synaptic properties that support persistent activity across temporally extended cognitive tasks. Our findings build upon recent work describing economic decision making as a process of attention-weighted evidence integration across time.

Electrogenic Na+/K+-ATPases constrain excitable cell activity and pose additional evolutionary pressure

Bernstein Conference 2024

The evolution of communication axes in the developing brain

Bernstein Conference 2024

Evolutionary algorithms support recurrent plasticity in spiking neural network models of neocortical task learning

Bernstein Conference 2024

Capturing the evolution of low-dimensional dynamics in large scale neural recordings with sliceTCA

COSYNE 2022

Evolution of neural activity in circuits bridging sensory and abstract knowledge

COSYNE 2022

Discrete actions are a unit of both behavior and evolutionary selection

COSYNE 2025

Brain region evolution by duplication-and-divergence

Brain size, gut size and cognitive abilities: experimental evolution of energy trade-offs

Decoding of a broad spectrum of actions from temporal evolution of neural activity in monkey premotor cortex

Drifting Memories: spontaneous long-term evolution of memory representations in the hippocampus

Dynamical evolution of electrically coupled neurons that participate in the coordination of sequential neural activity

Evolution of cross-frequency coupling between endogenous oscillations over the temporal cortex in very premature neonates

Evolution of hippocampal and neocortical sleep oscillations during gradual learning of a Y-maze allocentric task in mice

Evolution of hippocampal place cell representations in slowly morphing environments

Evolution increases stress-response complexity in higher primates extending RbFOX1 splicing activity to LSD1 modulation

Evolution of the sleep-waking cycle in transgenic mice with an age-dependent accumulation of neuromelanin in catecholaminergic neurons, a new humanized model of Parkinson’s Disease

Evolutionary Development of Excitatory Projection Neurons in Mammalian Sound Localization Circuits

Recapitulating the evolutionary transformation of visual cortex architecture in a tabletop experiment

What is the ethological role of the zebrafish pallium - the evolutionary ancestor of the mammalian cortex?

Cross species single-cell/nucleus RNA-seq uncovers the evolutionarily conserved pathological mechanisms of vascular contribution to Alzheimer’s disease

FENS Forum 2024

Evolution of prefrontal-hippocampal activity during gradual learning on a radial eight-arm maze

FENS Forum 2024

Evolution of the psychiatric phenotype in the early stages of a Huntington's disease preclinical model

FENS Forum 2024

The evolutionarily conserved choroid plexus maintains the homeostasis of brain ventricles in zebrafish

FENS Forum 2024

The interaction of learning and evolution in innate olfactory behaviour of Mus musculus and Mus caroli

FENS Forum 2024

Molecular and cellular evolution of the amygdala across species analyzed by single-nucleus transcriptome profiling

FENS Forum 2024

A mouse model to explore clonal evolution in fast-proliferating neuronal progenitor cells during early neurodevelopment

FENS Forum 2024

Reconstructing the neural architecture of the cnidarian Nematostella vectensis to understand evolution of the nervous system

FENS Forum 2024

Retracing the evolution of human socio-affective traits through computational archeology

FENS Forum 2024

Single cell mapping the evolution of the spatial processing centre in the brain

FENS Forum 2024

Single neuron activity evolution in goal-directed learning during an operant task: Differences between direct and indirect striatal projection neurons

FENS Forum 2024

Strong sexual dimorphism in the evolution of fear memory revealed by brain-wide activation analysis

FENS Forum 2024

Temporal evolution of glial cell phenotype in the midbrain and striatum of A53T-alpha-synuclein transgenic mice: New disease-related mechanisms?

FENS Forum 2024

Temporal evolution of traumatic memory engrams in a mouse model of early-life stress

FENS Forum 2024

A synergistic core for human brain evolution and cognition

Neuromatch 5