Neural circuits underlying sleep structure and functions

Sleep is an active state critical for processing emotional memories encoded during waking in both humans and animals. There is a remarkable overlap between the brain structures and circuits active during sleep, particularly rapid eye-movement (REM) sleep, and the those encoding emotions. Accordingly, disruptions in sleep quality or quantity, including REM sleep, are often associated with, and precede the onset of, nearly all affective psychiatric and mood disorders. In this context, a major biomedical challenge is to better understand the underlying mechanisms of the relationship between (REM) sleep and emotion encoding to improve treatments for mental health. This lecture will summarize our investigation of the cellular and circuit mechanisms underlying sleep architecture, sleep oscillations, and local brain dynamics across sleep-wake states using electrophysiological recordings combined with single-cell calcium imaging or optogenetics. The presentation will detail the discovery of a 'somato-dendritic decoupling'in prefrontal cortex pyramidal neurons underlying REM sleep-dependent stabilization of optimal emotional memory traces. This decoupling reflects a tonic inhibition at the somas of pyramidal cells, occurring simultaneously with a selective disinhibition of their dendritic arbors selectively during REM sleep. Recent findings on REM sleep-dependent subcortical inputs and neuromodulation of this decoupling will be discussed in the context of synaptic plasticity and the optimization of emotional responses in the maintenance of mental health.

Decoding ketamine: Neurobiological mechanisms underlying its rapid antidepressant efficacy

Unlike traditional monoamine-based antidepressants that require weeks to exert effects, ketamine alleviates depression within hours, though its clinical use is limited by side effects. While ketamine was initially thought to work primarily through NMDA receptor (NMDAR) inhibition, our research reveals a more complex mechanism. We demonstrate that NMDAR inhibition alone cannot explain ketamine's sustained antidepressant effects, as other NMDAR antagonists like MK-801 lack similar efficacy. Instead, the (2R,6R)-hydroxynorketamine (HNK) metabolite appears critical, exhibiting antidepressant effects without ketamine's side effects. Paradoxically, our findings suggest an inverted U-shaped dose-response relationship where excessive NMDAR inhibition may actually impede antidepressant efficacy, while some level of NMDAR activation is necessary. The antidepressant actions of ketamine and (2R,6R)-HNK require AMPA receptor activation, leading to synaptic potentiation and upregulation of AMPA receptor subunits GluA1 and GluA2. Furthermore, NMDAR subunit GluN2A appears necessary and possibly sufficient for these effects. This research establishes NMDAR-GluN2A activation as a common downstream effector for rapid-acting antidepressants, regardless of their initial targets, offering promising directions for developing next-generation antidepressants with improved efficacy and reduced side effects.

Digital Minds: Brain Development in the Age of Technology

Digital Minds: Brain Development in the Age of Technology examines how our increasingly connected world shapes mental and cognitive health. From screen time and social media to virtual interactions, this seminar delves into the latest research on how technology influences brain development, relationships, and emotional well-being. Join us to explore strategies for harnessing technology's benefits while mitigating its potential challenges, empowering you to thrive in a digital age.

Vision for perception versus vision for action: dissociable contributions of visual sensory drives from primary visual cortex and superior colliculus neurons to orienting behaviors

The primary visual cortex (V1) directly projects to the superior colliculus (SC) and is believed to provide sensory drive for eye movements. Consistent with this, a majority of saccade-related SC neurons also exhibit short-latency, stimulus-driven visual responses, which are additionally feature-tuned. However, direct neurophysiological comparisons of the visual response properties of the two anatomically-connected brain areas are surprisingly lacking, especially with respect to active looking behaviors. I will describe a series of experiments characterizing visual response properties in primate V1 and SC neurons, exploring feature dimensions like visual field location, spatial frequency, orientation, contrast, and luminance polarity. The results suggest a substantial, qualitative reformatting of SC visual responses when compared to V1. For example, SC visual response latencies are actively delayed, independent of individual neuron tuning preferences, as a function of increasing spatial frequency, and this phenomenon is directly correlated with saccadic reaction times. Such “coarse-to-fine” rank ordering of SC visual response latencies as a function of spatial frequency is much weaker in V1, suggesting a dissociation of V1 responses from saccade timing. Consistent with this, when we next explored trial-by-trial correlations of individual neurons’ visual response strengths and visual response latencies with saccadic reaction times, we found that most SC neurons exhibited, on a trial-by-trial basis, stronger and earlier visual responses for faster saccadic reaction times. Moreover, these correlations were substantially higher for visual-motor neurons in the intermediate and deep layers than for more superficial visual-only neurons. No such correlations existed systematically in V1. Thus, visual responses in SC and V1 serve fundamentally different roles in active vision: V1 jumpstarts sensing and image analysis, but SC jumpstarts moving. I will finish by demonstrating, using V1 reversible inactivation, that, despite reformatting of signals from V1 to the brainstem, V1 is still a necessary gateway for visually-driven oculomotor responses to occur, even for the most reflexive of eye movement phenomena. This is a fundamental difference from rodent studies demonstrating clear V1-independent processing in afferent visual pathways bypassing the geniculostriate one, and it demonstrates the importance of multi-species comparisons in the study of oculomotor control.

Analyzing Network-Level Brain Processing and Plasticity Using Molecular Neuroimaging

Behavior and cognition depend on the integrated action of neural structures and populations distributed throughout the brain. We recently developed a set of molecular imaging tools that enable multiregional processing and plasticity in neural networks to be studied at a brain-wide scale in rodents and nonhuman primates. Here we will describe how a novel genetically encoded activity reporter enables information flow in virally labeled neural circuitry to be monitored by fMRI. Using the reporter to perform functional imaging of synaptically defined neural populations in the rat somatosensory system, we show how activity is transformed within brain regions to yield characteristics specific to distinct output projections. We also show how this approach enables regional activity to be modeled in terms of inputs, in a paradigm that we are extending to address circuit-level origins of functional specialization in marmoset brains. In the second part of the talk, we will discuss how another genetic tool for MRI enables systematic studies of the relationship between anatomical and functional connectivity in the mouse brain. We show that variations in physical and functional connectivity can be dissociated both across individual subjects and over experience. We also use the tool to examine brain-wide relationships between plasticity and activity during an opioid treatment. This work demonstrates the possibility of studying diverse brain-wide processing phenomena using molecular neuroimaging.

CNS Control of Peripheral Mitochondrial Form and Function: Mitokines

My laboratory has made an intriguing discovery that mitochondrial stress in one tissue can be communicated to distal tissues. We find that mitochondrial stress in the nervous system triggers the production of entities known as mitokines. These mitokines are discharged from the nervous system, orchestrating a response in peripheral tissues that extends the lifespan of C. elegans. The revelation came as a surprise, given the prevalent belief that cell autonomous mechanisms would underlie the relationship between mitochondrial function and aging. It was also surprising given the prevailing dogma that mitochondrial function must be increased, not decreased, to improve health and longevity. Our work also underscores the fact that mitochondria, which originated as a microbial entity and later evolved into an intracellular symbiont, have retained their capacity for intercommunication, now facilitated by signals from the nervous system. We hypothesize that this communication has evolved as a mechanism to reduce infection from pathogens.

Mouse Motor Cortex Circuits and Roles in Oromanual Behavior

I’m interested in structure-function relationships in neural circuits and behavior, with a focus on motor and somatosensory areas of the mouse’s cortex involved in controlling forelimb movements. In one line of investigation, we take a bottom-up, cellularly oriented approach and use optogenetics, electrophysiology, and related slice-based methods to dissect cell-type-specific circuits of corticospinal and other neurons in forelimb motor cortex. In another, we take a top-down ethologically oriented approach and analyze the kinematics and cortical correlates of “oromanual” dexterity as mice handle food. I'll discuss recent progress on both fronts.

Sensory cognition

This webinar features presentations from SueYeon Chung (New York University) and Srinivas Turaga (HHMI Janelia Research Campus) on theoretical and computational approaches to sensory cognition. Chung introduced a “neural manifold” framework to capture how high-dimensional neural activity is structured into meaningful manifolds reflecting object representations. She demonstrated that manifold geometry—shaped by radius, dimensionality, and correlations—directly governs a population’s capacity for classifying or separating stimuli under nuisance variations. Applying these ideas as a data analysis tool, she showed how measuring object-manifold geometry can explain transformations along the ventral visual stream and suggested that manifold principles also yield better self-supervised neural network models resembling mammalian visual cortex. Turaga described simulating the entire fruit fly visual pathway using its connectome, modeling 64 key cell types in the optic lobe. His team’s systematic approach—combining sparse connectivity from electron microscopy with simple dynamical parameters—recapitulated known motion-selective responses and produced novel testable predictions. Together, these studies underscore the power of combining connectomic detail, task objectives, and geometric theories to unravel neural computations bridging from stimuli to cognitive functions.

Gender, trait anxiety and attentional processing in healthy young adults: is a moderated moderation theory possible?

Three studies conducted in the context of PhD work (UNIL) aimed at proving evidence to address the question of potential gender differences in trait anxiety and executive control biases on behavioral efficacy. In scope were male and female non-clinical samples of adult young age that performed non-emotional tasks assessing basic attentional functioning (Attention Network Test – Interactions, ANT-I), sustained attention (Test of Variables of Attention, TOVA), and visual recognition abilities (Object in Location Recognition Task, OLRT). Results confirmed the intricate nature of the relationship between gender and health trait anxiety through the lens of their impact on processing efficacy in males and females. The possibility of a gendered theory in trait anxiety biases is discussed.

Navigating semantic spaces: recycling the brain GPS for higher-level cognition

Humans share with other animals a complex neuronal machinery that evolved to support navigation in the physical space and that supports wayfinding and path integration. In my talk I will present a series of recent neuroimaging studies in humans performed in my Lab aimed at investigating the idea that this same neural navigation system (the “brain GPS”) is also used to organize and navigate concepts and memories, and that abstract and spatial representations rely on a common neural fabric. I will argue that this might represent a novel example of “cortical recycling”, where the neuronal machinery that primarily evolved, in lower level animals, to represent relationships between spatial locations and navigate space, in humans are reused to encode relationships between concepts in an internal abstract representational space of meaning.

The Role of Cognitive Appraisal in the Relationship between Personality and Emotional Reactivity

Emotion is defined as a rapid psychological process involving experiential, expressive and physiological responses. These emerge following an appraisal process that involves cognitive evaluations of the environment assessing its relevance, implication, coping potential, and normative significance. It has been suggested that changes in appraisal processes lead to changes in the resulting emotional nature. Simultaneously, it was demonstrated that personality can be seen as a predisposition to feel more frequently certain emotions, but the personality-appraisal-emotional response chain is rarely fully investigated. The present project thus sought to investigate the extent to which personality traits influence certain appraisals, which in turn influence the subsequent emotional reactions via a systematic analysis of the link between personality traits of different current models, specific appraisals, and emotional response patterns at the experiential, expressive, and physiological levels. Major results include the coherence of emotion components clustering, and the centrality of the pleasantness, coping potential and consequences appraisals, in context; and the differentiated mediating role of cognitive appraisal in the relation between personality and the intensity and duration of an emotional state, and autonomic arousal, such as Extraversion-pleasantness-experience, and Neuroticism-powerlessness-arousal. Elucidating these relationships deepens our understanding of individual differences in emotional reactivity and spot routes of action on appraisal processes to modify upcoming adverse emotional responses, with a broader societal impact on clinical and non-clinical populations.

Learning produces a hippocampal cognitive map in the form of an orthogonalized state machine

Cognitive maps confer animals with flexible intelligence by representing spatial, temporal, and abstract relationships that can be used to shape thought, planning, and behavior. Cognitive maps have been observed in the hippocampus, but their algorithmic form and the processes by which they are learned remain obscure. Here, we employed large-scale, longitudinal two-photon calcium imaging to record activity from thousands of neurons in the CA1 region of the hippocampus while mice learned to efficiently collect rewards from two subtly different versions of linear tracks in virtual reality. The results provide a detailed view of the formation of a cognitive map in the hippocampus. Throughout learning, both the animal behavior and hippocampal neural activity progressed through multiple intermediate stages, gradually revealing improved task representation that mirrored improved behavioral efficiency. The learning process led to progressive decorrelations in initially similar hippocampal neural activity within and across tracks, ultimately resulting in orthogonalized representations resembling a state machine capturing the inherent struture of the task. We show that a Hidden Markov Model (HMM) and a biologically plausible recurrent neural network trained using Hebbian learning can both capture core aspects of the learning dynamics and the orthogonalized representational structure in neural activity. In contrast, we show that gradient-based learning of sequence models such as Long Short-Term Memory networks (LSTMs) and Transformers do not naturally produce such orthogonalized representations. We further demonstrate that mice exhibited adaptive behavior in novel task settings, with neural activity reflecting flexible deployment of the state machine. These findings shed light on the mathematical form of cognitive maps, the learning rules that sculpt them, and the algorithms that promote adaptive behavior in animals. The work thus charts a course toward a deeper understanding of biological intelligence and offers insights toward developing more robust learning algorithms in artificial intelligence.

Neuromodulation of striatal D1 cells shapes BOLD fluctuations in anatomically connected thalamic and cortical regions

Understanding how macroscale brain dynamics are shaped by microscale mechanisms is crucial in neuroscience. We investigate this relationship in animal models by directly manipulating cellular properties and measuring whole-brain responses using resting-state fMRI. Specifically, we explore the impact of chemogenetically neuromodulating D1 medium spiny neurons in the dorsomedial caudate putamen (CPdm) on BOLD dynamics within a striato-thalamo-cortical circuit in mice. Our findings indicate that CPdm neuromodulation alters BOLD dynamics in thalamic subregions projecting to the dorsomedial striatum, influencing both local and inter-regional connectivity in cortical areas. This study contributes to understanding structure–function relationships in shaping inter-regional communication between subcortical and cortical levels.

Perceptions of responsiveness and rejection in romantic relationships. What are the implications for individuals and relationship functioning?

From birth, human beings need to be embedded into social ties to function best, because other individuals can provide us with a sense of belonging, which is a fundamental human need. One of the closest bonds we build throughout our life is with our intimate partners. When the relationship involves intimacy and when both partners accept and support each other’s needs and goals (through perceived responsiveness) individuals experience an increase in relationship satisfaction as well as physical and mental well-being. However, feeling rejected by a partner may impair the feeling of connectedness and belonging, and affect emotional and behavioural responses. When we perceive our partner to be responsive to our needs or desires, in turn we naturally strive to respond positively and adequately to our partner’s needs and desires. This implies that individuals are interdependent, and changes in one partner prompt changes in the other. Evidence suggests that partners regulate themselves and co-regulate each other in their emotional, psychological, and physiological responses. However, such processes may threaten the relationship when partners face stressful situations or interactions, like the transition to parenthood or rejection. Therefore, in this presentation, I will provide evidence for the role of perceptions of being accepted or rejected by a significant other on individual and relationship functioning, while considering the contextual settings. The three studies presented here explore romantic relationships, and how perceptions of rejection and responsiveness from the partner impact both individuals, their physiological and their emotional responses, as well as their relationship dynamics.

Mathematical and computational modelling of ocular hemodynamics: from theory to applications

Changes in ocular hemodynamics may be indicative of pathological conditions in the eye (e.g. glaucoma, age-related macular degeneration), but also elsewhere in the body (e.g. systemic hypertension, diabetes, neurodegenerative disorders). Thanks to its transparent fluids and structures that allow the light to go through, the eye offers a unique window on the circulation from large to small vessels, and from arteries to veins. Deciphering the causes that lead to changes in ocular hemodynamics in a specific individual could help prevent vision loss as well as aid in the diagnosis and management of diseases beyond the eye. In this talk, we will discuss how mathematical and computational modelling can help in this regard. We will focus on two main factors, namely blood pressure (BP), which drives the blood flow through the vessels, and intraocular pressure (IOP), which compresses the vessels and may impede the flow. Mechanism-driven models translates fundamental principles of physics and physiology into computable equations that allow for identification of cause-to-effect relationships among interplaying factors (e.g. BP, IOP, blood flow). While invaluable for causality, mechanism-driven models are often based on simplifying assumptions to make them tractable for analysis and simulation; however, this often brings into question their relevance beyond theoretical explorations. Data-driven models offer a natural remedy to address these short-comings. Data-driven methods may be supervised (based on labelled training data) or unsupervised (clustering and other data analytics) and they include models based on statistics, machine learning, deep learning and neural networks. Data-driven models naturally thrive on large datasets, making them scalable to a plethora of applications. While invaluable for scalability, data-driven models are often perceived as black- boxes, as their outcomes are difficult to explain in terms of fundamental principles of physics and physiology and this limits the delivery of actionable insights. The combination of mechanism-driven and data-driven models allows us to harness the advantages of both, as mechanism-driven models excel at interpretability but suffer from a lack of scalability, while data-driven models are excellent at scale but suffer in terms of generalizability and insights for hypothesis generation. This combined, integrative approach represents the pillar of the interdisciplinary approach to data science that will be discussed in this talk, with application to ocular hemodynamics and specific examples in glaucoma research.

Movements and engagement during decision-making

When experts are immersed in a task, a natural assumption is that their brains prioritize task-related activity. Accordingly, most efforts to understand neural activity during well-learned tasks focus on cognitive computations and task-related movements. Surprisingly, we observed that during decision-making, the cortex-wide activity of multiple cell types is dominated by movements, especially “uninstructed movements”, that are spontaneously expressed. These observations argue that animals execute expert decisions while performing richly varied, uninstructed movements that profoundly shape neural activity. To understand the relationship between these movements and decision-making, we examined the movements more closely. We tested whether the magnitude or the timing of the movements was correlated with decision-making performance. To do this, we partitioned movements into two groups: task-aligned movements that were well predicted by task events (such as the onset of the sensory stimulus or choice) and task independent movement (TIM) that occurred independently of task events. TIM had a reliable, inverse correlation with performance in head-restrained mice and freely moving rats. This hinted that the timing of spontaneous movements could indicate periods of disengagement. To confirm this, we compared TIM to the latent behavioral states recovered by a hidden Markov model with Bernoulli generalized linear model observations (GLM-HMM) and found these, again, to be inversely correlated. Finally, we examined the impact of these behavioral states on neural activity. Surprisingly, we found that the same movement impacts neural activity more strongly when animals are disengaged. An intriguing possibility is that these larger movement signals disrupt cognitive computations, leading to poor decision-making performance. Taken together, these observations argue that movements and cognitionare closely intertwined, even during expert decision-making.

Metabolic Remodelling in the Developing Forebrain in Health and Disease

Little is known about the critical metabolic changes that neural cells have to undergo during development and how temporary shifts in this program can influence brain circuitries and behavior. Motivated by the identification of autism-associated mutations in SLC7A5, a transporter for metabolically essential large neutral amino acids (LNAAs), we utilized metabolomic profiling to investigate the metabolic states of the cerebral cortex across various developmental stages. Our findings reveal significant metabolic restructuring occurring in the forebrain throughout development, with specific groups of metabolites exhibiting stage-specific changes. Through the manipulation of Slc7a5 expression in neural cells, we discovered an interconnected relationship between the metabolism of LNAAs and lipids within the cortex. Neuronal deletion of Slc7a5 influences the postnatal metabolic state, resulting in a shift in lipid metabolism and a cell-type-specific modification in neuronal activity patterns. This ultimately gives rise to enduring circuit dysfunction.

A recurrent network model of planning predicts hippocampal replay and human behavior

When interacting with complex environments, humans can rapidly adapt their behavior to changes in task or context. To facilitate this adaptation, we often spend substantial periods of time contemplating possible futures before acting. For such planning to be rational, the benefits of planning to future behavior must at least compensate for the time spent thinking. Here we capture these features of human behavior by developing a neural network model where not only actions, but also planning, are controlled by prefrontal cortex. This model consists of a meta-reinforcement learning agent augmented with the ability to plan by sampling imagined action sequences drawn from its own policy, which we refer to as `rollouts'. Our results demonstrate that this agent learns to plan when planning is beneficial, explaining the empirical variability in human thinking times. Additionally, the patterns of policy rollouts employed by the artificial agent closely resemble patterns of rodent hippocampal replays recently recorded in a spatial navigation task, in terms of both their spatial statistics and their relationship to subsequent behavior. Our work provides a new theory of how the brain could implement planning through prefrontal-hippocampal interactions, where hippocampal replays are triggered by -- and in turn adaptively affect -- prefrontal dynamics.

Location, time and type of epileptic activity influence how sleep modulates epilepsy

Sleep and epilepsy are tightly interconnected: On the one hand disturbed sleep is known to negatively affect epilepsy, whereas on the other hand epilepsy negatively impacts sleep. In this talk, we leverage on the unique opportunity provided by simultaneous stereo-EEG and sleep recordings to disentangle these relationships. We will discuss latest evidence on if anatomy (temporal vs. extratemporal), time (early vs. late sleep), and type of epileptic activity (ictal vs. interictal) influence how epileptic activity is modulated by sleep. After this talk, attendees will have a more nuanced understanding of the contributions of location, time and type of epileptic activity in the relationship between sleep and epilepsy.

Touch in romantic relationships

Responsive behavior is crucial to relationship quality and well-being across a variety of interpersonal domains. In this talk I will share research from studies in which we investigate how responsiveness is conveyed nonverbally in the context of male friendships and in heterosexual romantic relationships, largely focusing on affectionate touch as a nonverbal signal of understanding, validation, and care

Brain Connectivity Workshop

Founded in 2002, the Brain Connectivity Workshop (BCW) is an annual international meeting for in-depth discussions of all aspects of brain connectivity research. By bringing together experts in computational neuroscience, neuroscience methodology and experimental neuroscience, it aims to improve the understanding of the relationship between anatomical connectivity, brain dynamics and cognitive function. These workshops have a unique format, featuring only short presentations followed by intense discussion. This year’s workshop is co-organised by Wellcome, putting the spotlight on brain connectivity in mental health disorders. We look forward to having you join us for this exciting, thought-provoking and inclusive event.

The contribution of mental face representations to individual face processing abilities

People largely differ with respect to how well they can learn, memorize, and perceive faces. In this talk, I address two potential sources of variation. One factor might be people’s ability to adapt their perception to the kind of faces they are currently exposed to. For instance, some studies report that those who show larger adaptation effects are also better at performing face learning and memory tasks. Another factor might be people’s sensitivity to perceive fine differences between similar-looking faces. In fact, one study shows that the brain of good performers in a face memory task shows larger neural differences between similar-looking faces. Capitalizing on this body of evidence, I present a behavioural study where I explore the relationship between people’s perceptual adaptability and sensitivity and their individual face processing performance.

In vivo direct imaging of neuronal activity at high temporospatial resolution

Advanced noninvasive neuroimaging methods provide valuable information on the brain function, but they have obvious pros and cons in terms of temporal and spatial resolution. Functional magnetic resonance imaging (fMRI) using blood-oxygenation-level-dependent (BOLD) effect provides good spatial resolution in the order of millimeters, but has a poor temporal resolution in the order of seconds due to slow hemodynamic responses to neuronal activation, providing indirect information on neuronal activity. In contrast, electroencephalography (EEG) and magnetoencephalography (MEG) provide excellent temporal resolution in the millisecond range, but spatial information is limited to centimeter scales. Therefore, there has been a longstanding demand for noninvasive brain imaging methods capable of detecting neuronal activity at both high temporal and spatial resolution. In this talk, I will introduce a novel approach that enables Direct Imaging of Neuronal Activity (DIANA) using MRI that can dynamically image neuronal spiking activity in milliseconds precision, achieved by data acquisition scheme of rapid 2D line scan synchronized with periodically applied functional stimuli. DIANA was demonstrated through in vivo mouse brain imaging on a 9.4T animal scanner during electrical whisker-pad stimulation. DIANA with milliseconds temporal resolution had high correlations with neuronal spike activities, which could also be applied in capturing the sequential propagation of neuronal activity along the thalamocortical pathway of brain networks. In terms of the contrast mechanism, DIANA was almost unaffected by hemodynamic responses, but was subject to changes in membrane potential-associated tissue relaxation times such as T2 relaxation time. DIANA is expected to break new ground in brain science by providing an in-depth understanding of the hierarchical functional organization of the brain, including the spatiotemporal dynamics of neural networks.

Diverse applications of artificial intelligence and mathematical approaches in ophthalmology

Ophthalmology is ideally placed to benefit from recent advances in artificial intelligence. It is a highly image-based specialty and provides unique access to the microvascular circulation and the central nervous system. This talk will demonstrate diverse applications of machine learning and deep learning techniques in ophthalmology, including in age-related macular degeneration (AMD), the leading cause of blindness in industrialized countries, and cataract, the leading cause of blindness worldwide. This will include deep learning approaches to automated diagnosis, quantitative severity classification, and prognostic prediction of disease progression, both from images alone and accompanied by demographic and genetic information. The approaches discussed will include deep feature extraction, label transfer, and multi-modal, multi-task training. Cluster analysis, an unsupervised machine learning approach to data classification, will be demonstrated by its application to geographic atrophy in AMD, including exploration of genotype-phenotype relationships. Finally, mediation analysis will be discussed, with the aim of dissecting complex relationships between AMD disease features, genotype, and progression.

A recurrent network model of planning explains hippocampal replay and human behavior

When interacting with complex environments, humans can rapidly adapt their behavior to changes in task or context. To facilitate this adaptation, we often spend substantial periods of time contemplating possible futures before acting. For such planning to be rational, the benefits of planning to future behavior must at least compensate for the time spent thinking. Here we capture these features of human behavior by developing a neural network model where not only actions, but also planning, are controlled by prefrontal cortex. This model consists of a meta-reinforcement learning agent augmented with the ability to plan by sampling imagined action sequences drawn from its own policy, which we refer to as 'rollouts'. Our results demonstrate that this agent learns to plan when planning is beneficial, explaining the empirical variability in human thinking times. Additionally, the patterns of policy rollouts employed by the artificial agent closely resemble patterns of rodent hippocampal replays recently recorded in a spatial navigation task, in terms of both their spatial statistics and their relationship to subsequent behavior. Our work provides a new theory of how the brain could implement planning through prefrontal-hippocampal interactions, where hippocampal replays are triggered by - and in turn adaptively affect - prefrontal dynamics.

Consciousness in the age of mechanical minds

We are now clearly entering a new age in our relationship with machines. The power of AI natural language processors and image generators has rapidly exceeded the expectations of even those who developed them. Serious questions are now being asked about the extent to which machines could become — or perhaps already are — sentient or conscious. Do AI machines understand the instructions they are given and the answers they provide? In this talk I will consider the prospects for conscious machines, by which I mean machines that have feelings, know about their own existence, and about ours. I will suggest that the recent focus on information processing in models of consciousness, in which the brain is treated as a kind of digital computer, have mislead us about the nature of consciousness and how it is produced in biological systems. Treating the brain as an energy processing system is more likely to yield answers to these fundamental questions and help us understand how and when machines might become minds.

Brain and Behavior: Employing Frequency Tagging as a Tool for Measuring Cognitive Abilities

Frequency tagging based on fast periodic visual stimulation (FPVS) provides a window into ongoing visual and cognitive processing and can be leveraged to measure rule learning and high-level categorization. In this talk, I will present data demonstrating highly proficient categorization as living and non-living in preschool children, and characterize the development of this ability during infancy. In addition to associating cognitive functions with development, an intriguing question is whether frequency tagging also captures enduring individual differences, e.g. in general cognitive abilities. First studies indicate high psychometric quality of FPVS categorization responses (XU et al., Dzhelyova), providing a basis for research on individual differences. I will present results from a pilot study demonstrating high correlations between FPVS categorization responses and behavioral measures of processing speed and fluid intelligences. Drawing upon this first evidence, I will discuss the potential of frequency tagging for diagnosing cognitive functions across development.

Manipulating single-unit theta phase-locking with PhaSER: An open-source tool for real-time phase estimation and manipulation

Zoe has developed an open-source tool PhaSER, which allows her to perform real-time oscillatory phase estimation and apply optogenetic manipulations at precise phases of hippocampal theta during high-density electrophysiological recordings in head-fixed mice while they navigate a virtual environment. The precise timing of single-unit spiking relative to network-wide oscillations (i.e., phase locking) has long been thought to maintain excitatory-inhibitory homeostasis and coordinate cognitive processes, but due to intense experimental demands, the causal influence of this phenomenon has never been determined. Thus, we developed PhaSER (Phase-locked Stimulation to Endogenous Rhythms), a tool which allows the user to explore the temporal relationship between single-unit spiking and ongoing oscillatory activity.

The centrality of population-level factors to network computation is demonstrated by a versatile approach for training spiking networks

Neural activity is often described in terms of population-level factors extracted from the responses of many neurons. Factors provide a lower-dimensional description with the aim of shedding light on network computations. Yet, mechanistically, computations are performed not by continuously valued factors but by interactions among neurons that spike discretely and variably. Models provide a means of bridging these levels of description. We developed a general method for training model networks of spiking neurons by leveraging factors extracted from either data or firing-rate-based networks. In addition to providing a useful model-building framework, this formalism illustrates how reliable and continuously valued factors can arise from seemingly stochastic spiking. Our framework establishes procedures for embedding this property in network models with different levels of realism. The relationship between spikes and factors in such networks provides a foundation for interpreting (and subtly redefining) commonly used quantities such as firing rates.

Perceiving relational structure

The Neural Race Reduction: Dynamics of nonlinear representation learning in deep architectures

What is the relationship between task, network architecture, and population activity in nonlinear deep networks? I will describe the Gated Deep Linear Network framework, which schematizes how pathways of information flow impact learning dynamics within an architecture. Because of the gating, these networks can compute nonlinear functions of their input. We derive an exact reduction and, for certain cases, exact solutions to the dynamics of learning. The reduction takes the form of a neural race with an implicit bias towards shared representations, which then govern the model’s ability to systematically generalize, multi-task, and transfer. We show how appropriate network architectures can help factorize and abstract knowledge. Together, these results begin to shed light on the links between architecture, learning dynamics and network performance.

Relations and Predictions in Brains and Machines

Humans and animals learn and plan with flexibility and efficiency well beyond that of modern Machine Learning methods. This is hypothesized to owe in part to the ability of animals to build structured representations of their environments, and modulate these representations to rapidly adapt to new settings. In the first part of this talk, I will discuss theoretical work describing how learned representations in hippocampus enable rapid adaptation to new goals by learning predictive representations, while entorhinal cortex compresses these predictive representations with spectral methods that support smooth generalization among related states. I will also cover recent work extending this account, in which we show how the predictive model can be adapted to the probabilistic setting to describe a broader array of generalization results in humans and animals, and how entorhinal representations can be modulated to support sample generation optimized for different behavioral states. In the second part of the talk, I will overview some of the ways in which we have combined many of the same mathematical concepts with state-of-the-art deep learning methods to improve efficiency and performance in machine learning applications like physical simulation, relational reasoning, and design.

Are place cells just memory cells? Probably yes

Neurons in the rodent hippocampus appear to encode the position of the animal in physical space during movement. Individual ``place cells'' fire in restricted sub-regions of an environment, a feature often taken as evidence that the hippocampus encodes a map of space that subserves navigation. But these same neurons exhibit complex responses to many other variables that defy explanation by position alone, and the hippocampus is known to be more broadly critical for memory formation. Here we elaborate and test a theory of hippocampal coding which produces place cells as a general consequence of efficient memory coding. We constructed neural networks that actively exploit the correlations between memories in order to learn compressed representations of experience. Place cells readily emerged in the trained model, due to the correlations in sensory input between experiences at nearby locations. Notably, these properties were highly sensitive to the compressibility of the sensory environment, with place field size and population coding level in dynamic opposition to optimally encode the correlations between experiences. The effects of learning were also strongly biphasic: nearby locations are represented more similarly following training, while locations with intermediate similarity become increasingly decorrelated, both distance-dependent effects that scaled with the compressibility of the input features. Using virtual reality and 2-photon functional calcium imaging in head-fixed mice, we recorded the simultaneous activity of thousands of hippocampal neurons during virtual exploration to test these predictions. Varying the compressibility of sensory information in the environment produced systematic changes in place cell properties that reflected the changing input statistics, consistent with the theory. We similarly identified representational plasticity during learning, which produced a distance-dependent exchange between compression and pattern separation. These results motivate a more domain-general interpretation of hippocampal computation, one that is naturally compatible with earlier theories on the circuit's importance for episodic memory formation. Work done in collaboration with James Priestley, Lorenzo Posani, Marcus Benna, Attila Losonczy.

How Children Design by Analogy: The Role of Spatial Thinking

Analogical reasoning is a common reasoning tool for learning and problem-solving. Existing research has extensively studied children’s reasoning when comparing, or choosing from ready-made analogies. Relatively less is known about how children come up with analogies in authentic learning environments. Design education provides a suitable context to investigate how children generate analogies for creative learning purposes. Meanwhile, the frequent use of visual analogies in design provides an additional opportunity to understand the role of spatial reasoning in design-by-analogy. Spatial reasoning is one of the most studied human cognitive factors and is critical to the learning of science, technology, engineering, arts, and mathematics (STEAM). There is growing interest in exploring the interplay between analogical reasoning and spatial reasoning. In this talk, I will share qualitative findings from a case study, where a class of 11-to-12-year-olds in the Netherlands participated in a biomimicry design project. These findings illustrate (1) practical ways to support children’s analogical reasoning in the ideation process and (2) the potential role of spatial reasoning as seen in children mapping form-function relationships in nature analogically and adaptively to those in human designs.

Central place foraging: how insects anchor spatial information

Many insect species maintain a nest around which their foraging behaviour is centered, and can use path integration to maintain an accurate estimate of their distance and direction (a vector) to their nest. Some species, such as bees and ants, can also store the vector information for multiple salient locations in the world, such as food sources, in a common coordinate system. They can also use remembered views of the terrain around salient locations or along travelled routes to guide return. Recent modelling of these abilities shows convergence on a small set of algorithms and assumptions that appear sufficient to account for a wide range of behavioural data, and which can be mapped to specific insect brain circuits. Notably, this does not include any significant topological knowledge: the insect does not need to recover the information (implicit in their vector memory) about the relationships between salient places; nor to maintain any connectedness or ordering information between view memories; nor to form any associations between views and vectors. However, there remains some experimental evidence not fully explained by these algorithms that may point towards the existence of a more complex or integrated mental map in insects.

Retinotopic maps and their relationship to white matter tracts in the human brain

The speaker identification ability of blind and sighted listeners

Previous studies have shown that blind individuals outperform sighted controls in a variety of auditory tasks; however, only few studies have investigated blind listeners’ speaker identification abilities. In addition, existing studies in the area show conflicting results. The presented empirical investigation with 153 blind (74 of them congenitally blind) and 153 sighted listeners is the first of its kind and scale in which long-term memory effects of blind listeners’ speaker identification abilities are examined. For the empirical investigation, all listeners were evenly assigned to one of nine subgroups (3 x 3 design) in order to investigate the influence of two parameters with three levels, respectively, on blind and sighted listeners’ speaker identification performance. The parameters were a) time interval; i.e. a time interval of 1, 3 or 6 weeks between the first exposure to the voice to be recognised (familiarisation) and the speaker identification task (voice lineup); and b) signal quality; i.e. voice recordings were presented in either studio-quality, mobile phone-quality or as recordings of whispered speech. Half of the presented voice lineups were target-present lineups in which the previously heard target voice was included. The other half consisted of target-absent lineups which contained solely distractor voices. Blind individuals outperformed sighted listeners only under studio quality conditions. Furthermore, for blind and sighted listeners no significant performance differences were found with regard to the three investigated time intervals of 1, 3 and 6 weeks. Blind as well as sighted listeners were significantly better at picking the target voice from target-present lineups than at indicating that the target voice was absent in target-absent lineups. Within the blind group, no significant correlations were found between identification performance and onset or duration of blindness. Implications for the field of forensic phonetics are discussed.

Exploring the Potential of High-Density Data for Neuropsychological Testing with Coregraph

Coregraph is a tool under development that allows us to collect high-density data patterns during the administration of classic neuropsychological tests such as the Trail Making Test and Clock Drawing Test. These tests are widely used to evaluate cognitive function and screen for neurodegenerative disorders, but traditional methods of data collection only yield sparse information, such as test completion time or error types. By contrast, the high-density data collected with Coregraph may contribute to a better understanding of the cognitive processes involved in executing these tests. In addition, Coregraph may potentially revolutionize the field of cognitive evaluation by aiding in the prediction of cognitive deficits and in the identification of early signs of neurodegenerative disorders such as Alzheimer's dementia. By analyzing high-density graphomotor data through techniques like manual feature engineering and machine learning, we can uncover patterns and relationships that would be otherwise hidden with traditional methods of data analysis. We are currently in the process of determining the most effective methods of feature extraction and feature analysis to develop Coregraph to its full potential.

Does subjective time interact with the heart rate?

Decades of research have investigated the relationship between perception of time and heart rate with often mixed results. In search of such a relationship, I will present my far journey between two projects: from time perception in the realistic VR experience of crowded subway trips in the order of minutes (project 1); to the perceived duration of sub-second white noise tones (project 2). Heart rate had multiple concurrent relationships with subjective temporal distortions for the sub-second tones, while the effects were lacking or weak for the supra-minute subway trips. What does the heart have to do with sub-second time perception? We addressed this question with a cardiac drift-diffusion model, demonstrating the sensory accumulation of temporal evidence as a function of heart rate.

How do visual abilities relate to each other?

In vision, there is, surprisingly, very little evidence of common factors. Most studies have found only weak correlations between performance in different visual tests; meaning that, a participant performing better in one test is not more likely to perform also better in another test. Likewise in ageing, cross-sectional studies have repeatedly shown that older adults show deteriorated performance in most visual tests compared to young adults. However, within the older population, there is no evidence for a common factor underlying visual abilities. To investigate further the decline of visual abilities, we performed a longitudinal study with a battery of nine visual tasks three times, with two re-tests after about 4 and 7 years. Most visual abilities are rather stable across 7 years, but not visual acuity. I will discuss possible causes of these paradoxical outcomes.

Modelling metaphor comprehension as a form of analogizing

What do people do when they comprehend language in discourse? According to many psychologists, they build and maintain cognitive representations of utterances in four complementary mental models for discourse that interact with each other: the surface text, the text base, the situation model, and the context model. When people encounter metaphors in these utterances, they need to incorporate them into each of these mental representations for the discourse. Since influential metaphor theories define metaphor as a form of (figurative) analogy, involving cross-domain mapping of a smaller or greater extent, the general expectation has been that metaphor comprehension is also based on analogizing. This expectation, however, has been partly borne out by the data, but not completely. There is no one-to-one relationship between metaphor as (conceptual) structure (analogy) and metaphor as (psychological) process (analogizing). According to Deliberate Metaphor Theory (DMT), only some metaphors are handled by analogy. Instead, most metaphors are presumably handled by lexical disambiguation. This is a hypothesis that brings together most metaphor research in a provocatively new way: it means that most metaphors are not processed metaphorically, which produces a paradox of metaphor. In this talk I will sketch out how this paradox arises and how it can be resolved by a new version of DMT, which I have described in my forthcoming book Slowing metaphor down: Updating Deliberate Metaphor Theory (currently under review). In this theory, the distinction between, but also the relation between, analogy in metaphorical structure versus analogy in metaphorical process is of central importance.

Neural networks in the replica-mean field limits

In this talk, we propose to decipher the activity of neural networks via a “multiply and conquer” approach. This approach considers limit networks made of infinitely many replicas with the same basic neural structure. The key point is that these so-called replica-mean-field networks are in fact simplified, tractable versions of neural networks that retain important features of the finite network structure of interest. The finite size of neuronal populations and synaptic interactions is a core determinant of neural dynamics, being responsible for non-zero correlation in the spiking activity and for finite transition rates between metastable neural states. Theoretically, we develop our replica framework by expanding on ideas from the theory of communication networks rather than from statistical physics to establish Poissonian mean-field limits for spiking networks. Computationally, we leverage our original replica approach to characterize the stationary spiking activity of various network models via reduction to tractable functional equations. We conclude by discussing perspectives about how to use our replica framework to probe nontrivial regimes of spiking correlations and transition rates between metastable neural states.

Intrinsic Geometry of a Combinatorial Sensory Neural Code for Birdsong

Understanding the nature of neural representation is a central challenge of neuroscience. One common approach to this challenge is to compute receptive fields by correlating neural activity with external variables drawn from sensory signals. But these receptive fields are only meaningful to the experimenter, not the organism, because only the experimenter has access to both the neural activity and knowledge of the external variables. To understand neural representation more directly, recent methodological advances have sought to capture the intrinsic geometry of sensory driven neural responses without external reference. To date, this approach has largely been restricted to low-dimensional stimuli as in spatial navigation. In this talk, I will discuss recent work from my lab examining the intrinsic geometry of sensory representations in a model vocal communication system, songbirds. From the assumption that sensory systems capture invariant relationships among stimulus features, we conceptualized the space of natural birdsongs to lie on the surface of an n-dimensional hypersphere. We computed composite receptive field models for large populations of simultaneously recorded single neurons in the auditory forebrain and show that solutions to these models define convex regions of response probability in the spherical stimulus space. We then define a combinatorial code over the set of receptive fields, realized in the moment-to-moment spiking and non-spiking patterns across the population, and show that this code can be used to reconstruct high-fidelity spectrographic representations of natural songs from evoked neural responses. Notably, we find that topological relationships among combinatorial codewords directly mirror acoustic relationships among songs in the spherical stimulus space. That is, the time-varying pattern of co-activity across the neural population expresses an intrinsic representational geometry that mirrors the natural, extrinsic stimulus space.  Combinatorial patterns across this intrinsic space directly represent complex vocal communication signals, do not require computation of receptive fields, and are in a form, spike time coincidences, amenable to biophysical mechanisms of neural information propagation.

Signal in the Noise: models of inter-trial and inter-subject neural variability

The ability to record large neural populations—hundreds to thousands of cells simultaneously—is a defining feature of modern systems neuroscience. Aside from improved experimental efficiency, what do these technologies fundamentally buy us? I'll argue that they provide an exciting opportunity to move beyond studying the "average" neural response. That is, by providing dense neural circuit measurements in individual subjects and moments in time, these recordings enable us to track changes across repeated behavioral trials and across experimental subjects. These two forms of variability are still poorly understood, despite their obvious importance to understanding the fidelity and flexibility of neural computations. Scientific progress on these points has been impeded by the fact that individual neurons are very noisy and unreliable. My group is investigating a number of customized statistical models to overcome this challenge. I will mention several of these models but focus particularly on a new framework for quantifying across-subject similarity in stochastic trial-by-trial neural responses. By applying this method to noisy representations in deep artificial networks and in mouse visual cortex, we reveal that the geometry of neural noise correlations is a meaningful feature of variation, which is neglected by current methods (e.g. representational similarity analysis).

Internally Organized Abstract Task Maps in the Mouse Medial Frontal Cortex

New tasks are often similar in structure to old ones. Animals that take advantage of such conserved or “abstract” task structures can master new tasks with minimal training. To understand the neural basis of this abstraction, we developed a novel behavioural paradigm for mice: the “ABCD” task, and recorded from their medial frontal neurons as they learned. Animals learned multiple tasks where they had to visit 4 rewarded locations on a spatial maze in sequence, which defined a sequence of four “task states” (ABCD). Tasks shared the same circular transition structure (… ABCDABCD …) but differed in the spatial arrangement of rewards. As well as improving across tasks, mice inferred that A followed D (i.e. completed the loop) on the very first trial of a new task. This “zero-shot inference” is only possible if animals had learned the abstract structure of the task. Across tasks, individual medial Frontal Cortex (mFC) neurons maintained their tuning to the phase of an animal’s trajectory between rewards but not their tuning to task states, even in the absence of spatial tuning. Intriguingly, groups of mFC neurons formed modules of coherently remapping neurons that maintained their tuning relationships across tasks. Such tuning relationships were expressed as replay/preplay during sleep, consistent with an internal organisation of activity into multiple, task-matched ring attractors. Remarkably, these modules were anchored to spatial locations: neurons were tuned to specific task space “distances” from a particular spatial location. These newly discovered “Spatially Anchored Task clocks” (SATs), suggest a novel algorithm for solving abstraction tasks. Using computational modelling, we show that SATs can perform zero-shot inference on new tasks in the absence of plasticity and guide optimal policy in the absence of continual planning. These findings provide novel insights into the Frontal mechanisms mediating abstraction and flexible behaviour.

A connectome manipulation framework for the systematic and reproducible study of structure-function relationships through simulations

Bernstein Conference 2024

Structure-function relationships and extended critical region in modular spiking model

Bernstein Conference 2024

Exploring behavioral correlations with neuron activity through synaptic plasticity.

Bernstein Conference 2024

Gradient and network~structure of lagged correlations\\in band-limited cortical dynamics

Bernstein Conference 2024

A homeostatic mechanism or statistics can maintain input-output relations of multilayer drifting assemblies

Bernstein Conference 2024

Frontal cortex neural correlations are reduced in the transformation to movement

COSYNE 2022

Frontal cortex neural correlations are reduced in the transformation to movement

COSYNE 2022

Input correlations impede suppression of chaos and learning in balanced rate networks

COSYNE 2022

Inference of the time-varying relationship between spike trains and a latent decision variable

COSYNE 2022

Inference of the time-varying relationship between spike trains and a latent decision variable

COSYNE 2022

Input correlations impede suppression of chaos and learning in balanced rate networks

COSYNE 2022

Information correlations reduce the accuracy of pioneering normative decision makers

COSYNE 2023

Learning beyond the synapse: activity-dependent myelination, neural correlations, and information transfer

COSYNE 2023

Rapid fluctuations in multi-scale correlations of cortical networks encode spontaneous behavior

COSYNE 2023

Reduced correlations in spontaneous activity amongst CA1 engram cells

COSYNE 2023

Tuned inhibition explains strong correlations across segregated excitatory subnetworks

COSYNE 2023

Uncovering relationships between neural network activation changes and parameter dynamics during learning

COSYNE 2023

From Chaos to Coherence: Impact of High-Order Correlations on Neural Dynamics

COSYNE 2025

Glial ensheathment of inhibitory synapses drives hyperactivity and increases correlations

COSYNE 2025

Humans can use positive and negative spectrotemporal correlations to detect rising and falling pitch

COSYNE 2025

Metrics of Task Relations Predict Continual Learning Performance

COSYNE 2025

State-dependent mapping of correlations of subthreshold to spiking activity is expansive in L1 inhibitory circuits

COSYNE 2025

Autistic traits mediate the relationship between occipital GABA and perceptual choice in a target detection task

FENS Forum 2024

Brain activation patterns in patients with autism spectrum disorder in pain-related perspective-taking: Relationship with interoceptive accuracy

FENS Forum 2024

Changes in neurotransmitter activity in septo-hippocampal network in naturally aged rats and a rat model of aging induced by D-galactose administration: Relationship with memory impairment

FENS Forum 2024

Childhood trauma in the adult brain: The relationship between adverse childhood experiences, brain structure, and mental health in late adulthood

FENS Forum 2024

A connectome manipulation framework for the systematic and reproducible study of structure-function relationships through simulations

FENS Forum 2024

Correlations of molecularly defined cortical interneuron populations with morpho-electric properties

FENS Forum 2024

Correlations in neuromodulatory codes during different learning processes

FENS Forum 2024

Corticocerebellar tracts and their relationship to anticipatory control deficits in children with cerebral palsy: A diffusion neuroimaging study

FENS Forum 2024

Criticality explains structure-function relationships in the human brain

FENS Forum 2024

Criticality and generalization in hippocampal subregions reflect relationship predicted by the free-energy principle

FENS Forum 2024

Effectivity of information routing between supragranular and granular neurons in macaque’s area V1 depends on phase relations of their gamma-oscillatory activity

FENS Forum 2024

Exploring the relationship between adipose tissue and Alzheimer's disease pathogenesis

FENS Forum 2024

Exploring relationships between inflammatory mediators and the kynurenine pathway

FENS Forum 2024

Identifying the biological relationship among the stages and patterns of cocaine addiction and behaviors that predict drug abuse

FENS Forum 2024

Investigating the relationship between torpor, sleep, and neural plasticity in Djungarian hamsters (Phodopus sungorus)

FENS Forum 2024

Investigation of GABA transport and the GABA/Na+ relationship in human GAT1 using solid-supported membrane-based electrophysiology

FENS Forum 2024

Novel potential biomarkers for multiple sclerosis: Evaluating the expression levels of miR-141, miR-9, MEG3, IFNG-AS1 and their relationship to different LINC00513 polymorphisms

FENS Forum 2024

Oscillatory waveform shape and temporal spike correlations differ in the bat frontal and auditory cortices

FENS Forum 2024