sensorimotor control, mouvement, touch, EEG

Traditionally, touch is associated with exteroception and is rarely considered a relevant sensory cue for controlling movements in space, unlike vision. We developed a technique to isolate and measure tactile involvement in controlling sliding finger movements over a surface. Young adults traced a 2D shape with their index finger under direct or mirror-reversed visual feedback to create a conflict between visual and somatosensory inputs. In this context, increased reliance on somatosensory input compromises movement accuracy. Based on the hypothesis that tactile cues contribute to guiding hand movements when in contact with a surface, we predicted poorer performance when the participants traced with their bare finger compared to when their tactile sensation was dampened by a smooth, rigid finger splint. The results supported this prediction. EEG source analyses revealed smaller current in the source-localized somatosensory cortex during sensory conflict when the finger directly touched the surface. This finding supports the hypothesis that, in response to mirror-reversed visual feedback, the central nervous system selectively gated task-irrelevant somatosensory inputs, thereby mitigating, though not entirely resolving, the visuo-somatosensory conflict. Together, our results emphasize touch’s involvement in movement control over a surface, challenging the notion that vision predominantly governs goal-directed hand or finger movements.

Memory Decoding Journal Club: "Connectomic traces of Hebbian plasticity in the entorhinalhippocampal system

Connectomic traces of Hebbian plasticity in the entorhinalhippocampal system

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.

A personal journey on understanding intelligence

The focus of this talk is not about my research in AI or Robotics but my own journey on trying to do research and understand intelligence in a rapidly evolving research landscape. I will trace my path from conducting early-stage research during graduate school, to working on practical solutions within a startup environment, and finally to my current role where I participate in more structured research at a major tech company. Through these varied experiences, I will provide different perspectives on research and talk about how my core beliefs on intelligence have changed and sometimes even been compromised. There are no lessons to be learned from my stories, but hopefully they will be entertaining.

Digital Traces of Human Behaviour: From Political Mobilisation to Conspiracy Narratives

Digital platforms generate unprecedented traces of human behaviour, offering new methodological approaches to understanding collective action, polarisation, and social dynamics. Through analysis of millions of digital traces across multiple studies, we demonstrate how online behaviours predict offline action: Brexit-related tribal discourse responds to real-world events, machine learning models achieve 80% accuracy in predicting real-world protest attendance from digital signals, and social validation through "likes" emerges as a key driver of mobilization. Extending this approach to conspiracy narratives reveals how digital traces illuminate psychological mechanisms of belief and community formation. Longitudinal analysis of YouTube conspiracy content demonstrates how narratives systematically address existential, epistemic, and social needs, while examination of alt-tech platforms shows how emotions of anger, contempt, and disgust correlate with violence-legitimating discourse, with significant differences between narratives associated with offline violence versus peaceful communities. This work establishes digital traces as both methodological innovation and theoretical lens, demonstrating that computational social science can illuminate fundamental questions about polarisation, mobilisation, and collective behaviour across contexts from electoral politics to conspiracy communities.

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.

Cognitive maps as expectations learned across episodes – a model of the two dentate gyrus blades

How can the hippocampal system transition from episodic one-shot learning to a multi-shot learning regime and what is the utility of the resultant neural representations? This talk will explore the role of the dentate gyrus (DG) anatomy in this context. The canonical DG model suggests it performs pattern separation. More recent experimental results challenge this standard model, suggesting DG function is more complex and also supports the precise binding of objects and events to space and the integration of information across episodes. Very recent studies attribute pattern separation and pattern integration to anatomically distinct parts of the DG (the suprapyramidal blade vs the infrapyramidal blade). We propose a computational model that investigates this distinction. In the model the two processing streams (potentially localized in separate blades) contribute to the storage of distinct episodic memories, and the integration of information across episodes, respectively. The latter forms generalized expectations across episodes, eventually forming a cognitive map. We train the model with two data sets, MNIST and plausible entorhinal cortex inputs. The comparison between the two streams allows for the calculation of a prediction error, which can drive the storage of poorly predicted memories and the forgetting of well-predicted memories. We suggest that differential processing across the DG aids in the iterative construction of spatial cognitive maps to serve the generation of location-dependent expectations, while at the same time preserving episodic memory traces of idiosyncratic events.

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.

Characterizing hormone sensitivity along the menstrual cycle and during hormonal contraceptive use

Learning representations of specifics and generalities over time

There is a fundamental tension between storing discrete traces of individual experiences, which allows recall of particular moments in our past without interference, and extracting regularities across these experiences, which supports generalization and prediction in similar situations in the future. One influential proposal for how the brain resolves this tension is that it separates the processes anatomically into Complementary Learning Systems, with the hippocampus rapidly encoding individual episodes and the neocortex slowly extracting regularities over days, months, and years. But this does not explain our ability to learn and generalize from new regularities in our environment quickly, often within minutes. We have put forward a neural network model of the hippocampus that suggests that the hippocampus itself may contain complementary learning systems, with one pathway specializing in the rapid learning of regularities and a separate pathway handling the region’s classic episodic memory functions. This proposal has broad implications for how we learn and represent novel information of specific and generalized types, which we test across statistical learning, inference, and category learning paradigms. We also explore how this system interacts with slower-learning neocortical memory systems, with empirical and modeling investigations into how the hippocampus shapes neocortical representations during sleep. Together, the work helps us understand how structured information in our environment is initially encoded and how it then transforms over time.

Blood-brain barrier dysfunction in epilepsy: Time for translation

The neurovascular unit (NVU) consists of cerebral blood vessels, neurons, astrocytes, microglia, and pericytes. It plays a vital role in regulating blood flow and ensuring the proper functioning of neural circuits. Among other, this is made possible by the blood-brain barrier (BBB), which acts as both a physical and functional barrier. Previous studies have shown that dysfunction of the BBB is common in most neurological disorders and is associated with neural dysfunction. Our studies have demonstrated that BBB dysfunction results in the transformation of astrocytes through transforming growth factor beta (TGFβ) signaling. This leads to activation of the innate neuroinflammatory system, changes in the extracellular matrix, and pathological plasticity. These changes ultimately result in dysfunction of the cortical circuit, lower seizure threshold, and spontaneous seizures. Blocking TGFβ signaling and its associated pro-inflammatory pathway can prevent this cascade of events, reduces neuroinflammation, repairs BBB dysfunction, and prevents post-injury epilepsy, as shown in experimental rodents. To further understand and assess BBB integrity in human epilepsy, we developed a novel imaging technique that quantitatively measures BBB permeability. Our findings have confirmed that BBB dysfunction is common in patients with drug-resistant epilepsy and can assist in identifying the ictal-onset zone prior to surgery. Current clinical studies are ongoing to explore the potential of targeting BBB dysfunction as a novel treatment approach and investigate its role in drug resistance, the spread of seizures, and comorbidities associated with epilepsy.

The role of extracellular vesicles in sickness and in health

State-of-the-Art Spike Sorting with SpikeInterface

This webinar will focus on spike sorting analysis with SpikeInterface, an open-source framework for the analysis of extracellular electrophysiology data. After a brief introduction of the project (~30 mins) highlighting the basics of the SpikeInterface software and advanced features (e.g., data compression, quality metrics, drift correction, cloud visualization), we will have an extensive hands-on tutorial (~90 mins) showing how to use SpikeInterface in a real-world scenario. After attending the webinar, you will: (1) have a global overview of the different steps involved in a processing pipeline; (2) know how to write a complete analysis pipeline with SpikeInterface.

Cellular crosstalk in Neurodevelopmental Disorders

Cellular crosstalk is an essential process during brain development and it is influenced by numerous factors, including the morphology of the cells, their adhesion molecules, the local extracellular matrix and the secreted vesicles. Inspired by mutations associated with neurodevelopmental disorders, we focus on understanding the role of extracellular mechanisms essential for the correct development of the human brain. Hence, we combine the in vivo mouse model and the in vitro human-derived neurons, cerebral organoids, and dorso-ventral assembloids in order to better comprehend the molecular and cellular mechanisms involved in ventral progenitors’ proliferation and fate as well as migration and maturation of inhibitory neurons during human brain development and tackle the causes of neurodevelopmental disorders. We particularly focus on mutations in genes influencing cell-cell contacts, extracellular matrix, and secretion of vesicles and therefore study intrinsic and extrinsic mechanisms contributing to the formation of the brain. Our data reveal an important contribution of cell non-autonomous mechanisms in the development of neurodevelopmental disorders.

Internal representation of musical rhythm: transformation from sound to periodic beat

When listening to music, humans readily perceive and move along with a periodic beat. Critically, perception of a periodic beat is commonly elicited by rhythmic stimuli with physical features arranged in a way that is not strictly periodic. Hence, beat perception must capitalize on mechanisms that transform stimulus features into a temporally recurrent format with emphasized beat periodicity. Here, I will present a line of work that aims to clarify the nature and neural basis of this transformation. In these studies, electrophysiological activity was recorded as participants listened to rhythms known to induce perception of a consistent beat across healthy Western adults. The results show that the human brain selectively emphasizes beat representation when it is not acoustically prominent in the stimulus, and this transformation (i) can be captured non-invasively using surface EEG in adult participants, (ii) is already in place in 5- to 6-month-old infants, and (iii) cannot be fully explained by subcortical auditory nonlinearities. Moreover, as revealed by human intracerebral recordings, a prominent beat representation emerges already in the primary auditory cortex. Finally, electrophysiological recordings from the auditory cortex of a rhesus monkey show a significant enhancement of beat periodicities in this area, similar to humans. Taken together, these findings indicate an early, general auditory cortical stage of processing by which rhythmic inputs are rendered more temporally recurrent than they are in reality. Already present in non-human primates and human infants, this "periodized" default format could then be shaped by higher-level associative sensory-motor areas and guide movement in individuals with strongly coupled auditory and motor systems. Together, this highlights the multiplicity of neural processes supporting coordinated musical behaviors widely observed across human cultures.The experiments herein include: a motor timing task comparing the effects of movement vs non-movement with and without feedback (Exp. 1A & 1B), a transcranial magnetic stimulation (TMS) study on the role of the supplementary motor area (SMA) in transforming temporal information (Exp. 2), and a perceptual timing task investigating the effect of noisy movement on time perception with both visual and auditory modalities (Exp. 3A & 3B). Together, the results of these studies support the Bayesian cue combination framework, in that: movement improves the precision of time perception not only in perceptual timing tasks but also motor timing tasks (Exp. 1A & 1B), stimulating the SMA appears to disrupt the transformation of temporal information (Exp. 2), and when movement becomes unreliable or noisy there is no longer an improvement in precision of time perception (Exp. 3A & 3B). Although there is support for the proposed framework, more studies (i.e., fMRI, TMS, EEG, etc.) need to be conducted in order to better understand where and how this may be instantiated in the brain; however, this work provides a starting point to better understanding the intrinsic connection between time and movement

How AI is advancing Clinical Neuropsychology and Cognitive Neuroscience

This talk aims to highlight the immense potential of Artificial Intelligence (AI) in advancing the field of psychology and cognitive neuroscience. Through the integration of machine learning algorithms, big data analytics, and neuroimaging techniques, AI has the potential to revolutionize the way we study human cognition and brain characteristics. In this talk, I will highlight our latest scientific advancements in utilizing AI to gain deeper insights into variations in cognitive performance across the lifespan and along the continuum from healthy to pathological functioning. The presentation will showcase cutting-edge examples of AI-driven applications, such as deep learning for automated scoring of neuropsychological tests, natural language processing to characeterize semantic coherence of patients with psychosis, and other application to diagnose and treat psychiatric and neurological disorders. Furthermore, the talk will address the challenges and ethical considerations associated with using AI in psychological research, such as data privacy, bias, and interpretability. Finally, the talk will discuss future directions and opportunities for further advancements in this dynamic field.

Assigning credit through the "other” connectome

Learning in neural networks requires assigning the right values to thousands to trillions or more of individual connections, so that the network as a whole produces the desired behavior. Neuroscientists have gained insights into this “credit assignment” problem through decades of experimental, modeling, and theoretical studies. This has suggested key roles for synaptic eligibility traces and top-down feedback signals, among other factors. Here we study the potential contribution of another type of signaling that is being revealed in greater and greater fidelity by ongoing molecular and genomics studies. This is the set of modulatory pathways local to a given circuit, which form an intriguing second type of connectome overlayed on top of synaptic connectivity. We will share ongoing modeling and theoretical work that explores the possible roles of this local modulatory connectome in network learning.

Autopoiesis and Enaction in the Game of Life

Enaction plays a central role in the broader fabric of so-called 4E (embodied, embedded, extended, enactive) cognition. Although the origin of the enactive approach is widely dated to the 1991 publication of the book "The Embodied Mind" by Varela, Thompson and Rosch, many of the central ideas trace to much earlier work. Over 40 years ago, the Chilean biologists Humberto Maturana and Francisco Varela put forward the notion of autopoiesis as a way to understand living systems and the phenomena that they generate, including cognition. Varela and others subsequently extended this framework to an enactive approach that places biological autonomy at the foundation of situated and embodied behavior and cognition. I will describe an attempt to place Maturana and Varela's original ideas on a firmer foundation by studying them within the context of a toy model universe, John Conway's Game of Life (GoL) cellular automata. This work has both pedagogical and theoretical goals. Simple concrete models provide an excellent vehicle for introducing some of the core concepts of autopoiesis and enaction and explaining how these concepts fit together into a broader whole. In addition, a careful analysis of such toy models can hone our intuitions about these concepts, probe their strengths and weaknesses, and move the entire enterprise in the direction of a more mathematically rigorous theory. In particular, I will identify the primitive processes that can occur in GoL, show how these can be linked together into mutually-supporting networks that underlie persistent bounded entities, map the responses of such entities to environmental perturbations, and investigate the paths of mutual perturbation that these entities and their environments can undergo.

Brain mosaicism in epileptogenic cortical malformations

Focal Cortical Dysplasia (FCD) is the most common focal cortical malformation leading to intractable childhood focal epilepsy. In recent years, we and others have shown that FCD type II is caused by mosaic mutations in genes within the PI3K-AKT-mTOR-signaling pathway. Hyperactivation of the mTOR pathway accounts for neuropathological abnormalities and seizure occurrence in FCD. We further showed from human surgical FCDII tissue that epileptiform activity correlates with the density of mutated dysmorphic neurons, supporting their pro-epileptogenic role. The level of mosaicism, as defined by variant allele frequency (VAF) is thought to correlate with the size and regional brain distribution of the lesion such that when a somatic mutation occurs early during the cortical development, the dysplastic area is smaller than if it occurs later. Novel approaches based on the detection of cell-free DNA from the CSF and from trace tissue adherent to SEEG electrodes promise future opportunities for genetic testing during the presurgical evaluation of refractory epilepsy patients or in those that are not eligible for surgery. In utero-based electroporation mouse models allow to express somatic mutation during neurodevelopment and recapitulate most neuropathological and clinical features of FCDII, establishing relevant preclinical mouse models for developing precision medicine strategies.

Protective microglial signaling in Alzheimer's Disease

Recent studies have begun to reveal critical roles for the brain’s professional phagocytes, microglia, and their receptors in the control of neurotoxic amyloid beta (Aβ) and myelin debris accumulation in neurodegenerative disease. However, the critical intracellular molecules that orchestrate neuroprotective functions of microglia remain poorly understood. In our studies, we find that targeted deletion of SYK in microglia leads to exacerbated Aβ deposition, aggravated neuropathology, and cognitive defects in the 5xFAD mouse model of Alzheimer’s disease (AD). Disruption of SYK signaling in this AD model was further shown to impede the development of disease-associated microglia (DAM), alter AKT/GSK3β-signaling, and restrict Aβ phagocytosis by microglia. Conversely, receptor-mediated activation of SYK limits Aβ load. We also found that SYK critically regulates microglial phagocytosis and DAM acquisition in demyelinating disease. Collectively, these results broaden our understanding of the key innate immune signaling molecules that instruct beneficial microglial functions in response to neurotoxic material." https://doi.org/10.1016/j.cell.2022.09.030

Cholesterol and matrisome pathways dysregulated in Alzheimer’s disease brain astrocytes and microglia

The impact of apolipoprotein E ε4 (APOE4), the strongest genetic risk factor for Alzheimer’s disease (AD), on human brain cellular function remains unclear. Here, we investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotent stem cells, post-mortem brain, and APOE targeted replacement mice. Population and isogenic models demonstrate that APOE4 local haplotype, rather than a single risk allele, contributes to risk. Global transcriptomic analyses reveal human-specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia. APOE4 enhances de novo cholesterol synthesis despite elevated intracellular cholesterol due to lysosomal cholesterol sequestration in astrocytes. Further, matrisome dysregulation is associated with upregulated chemotaxis, glial activation, and lipid biosynthesis in astrocytes co-cultured with neurons, which recapitulates altered astrocyte matrisome signaling in human brain. Thus, APOE4 initiates glia-specific cell and non-cell autonomous dysregulation that may contribute to increased AD risk." https://doi.org/10.1016/j.cell.2022.05.017

Flexible selection of task-relevant features through population gating

Brains can gracefully weed out irrelevant stimuli to guide behavior. This feat is believed to rely on a progressive selection of task-relevant stimuli across the cortical hierarchy, but the specific across-area interactions enabling stimulus selection are still unclear. Here, we propose that population gating, occurring within A1 but controlled by top-down inputs from mPFC, can support across-area stimulus selection. Examining single-unit activity recorded while rats performed an auditory context-dependent task, we found that A1 encoded relevant and irrelevant stimuli along a common dimension of its neural space. Yet, the relevant stimulus encoding was enhanced along an extra dimension. In turn, mPFC encoded only the stimulus relevant to the ongoing context. To identify candidate mechanisms for stimulus selection within A1, we reverse-engineered low-rank RNNs trained on a similar task. Our analyses predicted that two context-modulated neural populations gated their preferred stimulus in opposite contexts, which we confirmed in further analyses of A1. Finally, we show in a two-region RNN how population gating within A1 could be controlled by top-down inputs from PFC, enabling flexible across-area communication despite fixed inter-areal connectivity.

The future of neuropsychology will be open, transdiagnostic, and FAIR - why it matters and how we can get there

Cognitive neuroscience has witnessed great progress since modern neuroimaging embraced an open science framework, with the adoption of shared principles (Wilkinson et al., 2016), standards (Gorgolewski et al., 2016), and ontologies (Poldrack et al., 2011), as well as practices of meta-analysis (Yarkoni et al., 2011; Dockès et al., 2020) and data sharing (Gorgolewski et al., 2015). However, while functional neuroimaging data provide correlational maps between cognitive functions and activated brain regions, its usefulness in determining causal link between specific brain regions and given behaviors or functions is disputed (Weber et al., 2010; Siddiqiet al 2022). On the contrary, neuropsychological data enable causal inference, highlighting critical neural substrates and opening a unique window into the inner workings of the brain (Price, 2018). Unfortunately, the adoption of Open Science practices in clinical settings is hampered by several ethical, technical, economic, and political barriers, and as a result, open platforms enabling access to and sharing clinical (meta)data are scarce (e.g., Larivière et al., 2021). We are working with clinicians, neuroimagers, and software developers to develop an open source platform for the storage, sharing, synthesis and meta-analysis of human clinical data to the service of the clinical and cognitive neuroscience community so that the future of neuropsychology can be transdiagnostic, open, and FAIR. We call it neurocausal (https://neurocausal.github.io).

Setting network states via the dynamics of action potential generation

To understand neural computation and the dynamics in the brain, we usually focus on the connectivity among neurons. In contrast, the properties of single neurons are often thought to be negligible, at least as far as the activity of networks is concerned. In this talk, I will contradict this notion and demonstrate how the biophysics of action-potential generation can have a decisive impact on network behaviour. Our recent theoretical work shows that, among regularly firing neurons, the somewhat unattended homoclinic type (characterized by a spike onset via a saddle homoclinic orbit bifurcation) particularly stands out: First, spikes of this type foster specific network states - synchronization in inhibitory and splayed-out/frustrated states in excitatory networks. Second, homoclinic spikes can easily be induced by changes in a variety of physiological parameters (like temperature, extracellular potassium, or dendritic morphology). As a consequence, such parameter changes can even induce switches in network states, solely based on a modification of cellular voltage dynamics. I will provide first experimental evidence and discuss functional consequences of homoclinic spikes for the design of efficient pattern-generating motor circuits in insects as well as for mammalian pathologies like febrile seizures. Our analysis predicts an interesting role for homoclinic action potentials as an integral part of brain dynamics in both health and disease.

Extrinsic control and intrinsic computation in the hippocampal CA1 network

A key issue in understanding circuit operations is the extent to which neuronal spiking reflects local computation or responses to upstream inputs. Several studies have lesioned or silenced inputs to area CA1 of the hippocampus - either area CA3 or the entorhinal cortex and examined the effect on CA1 pyramidal cells. However, the types of the reported physiological impairments vary widely, primarily because simultaneous manipulations of these redundant inputs have never been performed. In this study, I combined optogenetic silencing of unilateral and bilateral mEC, of the local CA1 region, and performed bilateral pharmacogenetic silencing of CA3. I combined this with high spatial resolution extracellular recordings along the CA1-dentate axis. Silencing the medial entorhinal largely abolished extracellular theta and gamma currents in CA1, without affecting firing rates. In contrast, CA3 and local CA1 silencing strongly decreased firing of CA1 neurons without affecting theta currents. Each perturbation reconfigured the CA1 spatial map. Yet, the ability of the CA1 circuit to support place field activity persisted, maintaining the same fraction of spatially tuned place fields. In contrast to these results, unilateral mEC manipulations that were ineffective in impacting place cells during awake behavior were found to alter sharp-wave ripple sequences activated during sleep. Thus, intrinsic excitatory-inhibitory circuits within CA1 can generate neuronal assemblies in the absence of external inputs, although external synaptic inputs are critical to reconfigure (remap) neuronal assemblies in a brain-state dependent manner.

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.

Where do problem spaces come from? On metaphors and representational change

The challenges of problem solving do not exclusively lie in how to perform heuristic search, but they begin with how we understand a given task: How to cognitively represent the task domain and its components can determine how quickly someone is able to progress towards a solution, whether advanced strategies can be discovered, or even whether a solution is found at all. While this challenge of constructing and changing representations has been acknowledged early on in problem solving research, for the most part it has been sidestepped by focussing on simple, well-defined problems whose representation is almost fully determined by the task instructions. Thus, the established theory of problem solving as heuristic search in problem spaces has little to say on this. In this talk, I will present a study designed to explore this issue, by virtue of finding and refining an adequate problem representation being its main challenge. In this exploratory case study, it was investigated how pairs of participants acquaint themselves with a complex spatial transformation task in the domain of iterated mental paper folding over the course of several days. Participants have to understand the geometry of edges which occurs when repeatedly mentally folding a sheet of paper in alternating directions without the use of external aids. Faced with the difficulty of handling increasingly complex folds in light of limited cognitive capacity, participants are forced to look for ways in which to represent folds more efficiently. In a qualitative analysis of video recordings of the participants' behaviour, the development of their conceptualisation of the task domain was traced over the course of the study, focussing especially on their use of gesture and the spontaneous occurrence and use of metaphors in the construction of new representations. Based on these observations, I will conclude the talk with several theoretical speculations regarding the roles of metaphor and cognitive capacity in representational change.

Perception during visual disruptions

Visual perception is perceived as continuous despite frequent disruptions in our visual environment. For example, internal events, such as saccadic eye-movements, and external events, such as object occlusion temporarily prevent visual information from reaching the brain. Combining evidence from these two models of visual disruption (occlusion and saccades), we will describe what information is maintained and how it is updated across the sensory interruption.   Lina Teichmann will focus on dynamic occlusion and demonstrate how object motion is processed through perceptual gaps. Grace Edwards will then describe what pre-saccadic information is maintained across a saccade and how it interacts with post-saccadic processing in retinotopically relevant areas of the early visual cortex. Both occlusion and saccades provide a window into how the brain bridges perceptual disruptions. Our evidence thus far suggests a role for extrapolation, integration, and potentially suppression in both models. Combining evidence from these typically separate fields enables us to determine if there is a set of mechanisms which support visual processing during visual disruptions in general.

Perception during visual disruptions

Visual perception is perceived as continuous despite frequent disruptions in our visual environment. For example, internal events, such as saccadic eye-movements, and external events, such as object occlusion temporarily prevent visual information from reaching the brain. Combining evidence from these two models of visual disruption (occlusion and saccades), we will describe what information is maintained and how it is updated across the sensory interruption. Lina Teichmann will focus on dynamic occlusion and demonstrate how object motion is processed through perceptual gaps. Grace Edwards will then describe what pre-saccadic information is maintained across a saccade and how it interacts with post-saccadic processing in retinotopically relevant areas of the early visual cortex. Both occlusion and saccades provide a window into how the brain bridges perceptual disruptions. Our evidence thus far suggests a role for extrapolation, integration, and potentially suppression in both models. Combining evidence from these typically separate fields enables us to determine if there is a set of mechanisms which support visual processing during visual disruptions in general.

Multi-muscle TMS mapping assessment of the motor cortex reorganization after finger dexterity training

It is widely known that motor learning leads to reorganization changes in the motor cortex. Recently, we have shown that using navigated transcranial magnetic stimulation (TMS) allows us to reliably trace interactions among motor cortical representations (MCRs) of different upper limb muscles. Using this approach, we investigate changes in the MCRs after fine finger movement training. Our preliminary results demonstrated that areas of the APB and ADM and their overlaps tended to increase after finger independence training. Considering the behavioral data, hand dexterity increased for both hands, but the amplitudes of voluntary contraction of the muscles for the APB and ADM did not change significantly. The behavioral results correspond with a previously described suggestion that hand strength and hand dexterity are not directly related as well as an increase in overlaps between MCRs of the trained muscles supports the idea that voluntary muscle relaxation is an active physiological process.

PET imaging in brain diseases

Talk 1. PET based biomarkers of treatment efficacy in temporal lobe epilepsy A critical aspect of drug development involves identifying robust biomarkers of treatment response for use as surrogate endpoints in clinical trials. However, these biomarkers also have the capacity to inform mechanisms of disease pathogenesis and therapeutic efficacy. In this webinar, Dr Bianca Jupp will report on a series of studies using the GABAA PET ligand, [18F]-Flumazenil, to establish biomarkers of treatment response to a novel therapeutic for temporal lobe epilepsy, identifying affinity at this receptor as a key predictor of treatment outcome. Dr Bianca Jupp is a Research Fellow in the Department of Neuroscience, Monash University and Lead PET/CT Scientist at the Alfred Research Alliance–Monash Biomedical Imaging facility. Her research focuses on neuroimaging and its capacity to inform the neurobiology underlying neurological and neuropsychiatric disorders. Talk 2. The development of a PET radiotracer for reparative microglia Imaging of neuroinflammation is currently hindered by the technical limitations associated with TSPO imaging. In this webinar, Dr Lucy Vivash will discuss the development of PET radiotracers that specifically image reparative microglia through targeting the receptor kinase MerTK. This includes medicinal chemistry design and testing, radiochemistry, and in vitro and in vivo testing of lead tracers. Dr Lucy Vivash is a Research Fellow in the Department of Neuroscience, Monash University. Her research focuses on the preclinical development and clinical translation of novel PET radiotracers for the imaging of neurodegenerative diseases.

Malignant synaptic plasticity in pediatric high-grade gliomas

Pediatric high-grade gliomas (pHGG) are a devastating group of diseases that urgently require novel therapeutic options. We have previously demonstrated that pHGGs directly synapse onto neurons and the subsequent tumor cell depolarization, mediated by calcium-permeable AMPA channels, promotes their proliferation. The regulatory mechanisms governing these postsynaptic connections are unknown. Here, we investigated the role of BDNF-TrkB signaling in modulating the plasticity of the malignant synapse. BDNF ligand activation of its canonical receptor, TrkB (which is encoded for by the gene NTRK2), has been shown to be one important modulator of synaptic regulation in the normal setting. Electrophysiological recordings of glioma cell membrane properties, in response to acute neurotransmitter stimulation, demonstrate in an inward current resembling AMPA receptor (AMPAR) mediated excitatory neurotransmission. Extracellular BDNF increases the amplitude of this glutamate-induced tumor cell depolarization and this effect is abrogated in NTRK2 knockout glioma cells. Upon examining tumor cell excitability using in situ calcium imaging, we found that BDNF increases the intensity of glutamate-evoked calcium transients in GCaMP6s expressing glioma cells. Western blot analysis indicates the tumors AMPAR properties are altered downstream of BDNF induced TrkB activation in glioma. Cell membrane protein capture (via biotinylation) and live imaging of pH sensitive GFP-tagged AMPAR subunits demonstrate an increase of calcium permeable channels at the tumors postsynaptic membrane in response to BDNF. We find that BDNF-TrkB signaling promotes neuron-to-glioma synaptogenesis as measured by high-resolution confocal and electron microscopy in culture and tumor xenografts. Our analysis of published pHGG transcriptomic datasets, together with brain slice conditioned medium experiments in culture, indicates the tumor microenvironment as the chief source of BDNF ligand. Disruption of the BDNF-TrkB pathway in patient-derived orthotopic glioma xenograft models, both genetically and pharmacologically, results in an increased overall survival and reduced tumor proliferation rate. These findings suggest that gliomas leverage normal mechanisms of plasticity to modulate the excitatory channels involved in synaptic neurotransmission and they reveal the potential to target the regulatory components of glioma circuit dynamics as a therapeutic strategy for these lethal cancers.

The neural basis of flexible semantic cognition (BACN Mid-career Prize Lecture 2022)

Semantic cognition brings meaning to our world – it allows us to make sense of what we see and hear, and to produce adaptive thoughts and behaviour. Since we have a wealth of information about any given concept, our store of knowledge is not sufficient for successful semantic cognition; we also need mechanisms that can steer the information that we retrieve so it suits the context or our current goals. This talk traces the neural networks that underpin this flexibility in semantic cognition. It draws on evidence from multiple methods (neuropsychology, neuroimaging, neural stimulation) to show that two interacting heteromodal networks underpin different aspects of flexibility. Regions including anterior temporal cortex and left angular gyrus respond more strongly when semantic retrieval follows highly-related concepts or multiple convergent cues; the multivariate responses in these regions correspond to context-dependent aspects of meaning. A second network centred on left inferior frontal gyrus and left posterior middle temporal gyrus is associated with controlled semantic retrieval, responding more strongly when weak associations are required or there is more competition between concepts. This semantic control network is linked to creativity and also captures context-dependent aspects of meaning; however, this network specifically shows more similar multivariate responses across trials when association strength is weak, reflecting a common controlled retrieval state when more unusual associations are the focus. Evidence from neuropsychology, fMRI and TMS suggests that this semantic control network is distinct from multiple-demand cortex which supports executive control across domains, although challenging semantic tasks recruit both networks. The semantic control network is juxtaposed between regions of default mode network that might be sufficient for the retrieval of strong semantic relationships and multiple-demand regions in the left hemisphere, suggesting that the large-scale organisation of flexible semantic cognition can be understood in terms of cortical gradients that capture systematic functional transitions that are repeated in temporal, parietal and frontal cortex.

Learning in/about/from the basal ganglia

The basal ganglia are a collection of brain areas that are connected by a variety of synaptic pathways and are a site of significant reward-related dopamine release. These properties suggest a possible role for the basal ganglia in action selection, guided by reinforcement learning. In this talk, I will discuss a framework for how this function might be performed and computational results using an upward mapping to identify putative low-dimensional control ensembles that may be involved in tuning decision policy. I will also present some recent experimental results and theory – related to effects of extracellular ion dynamics -- that run counter to the classical view of basal ganglia pathways and suggest a new interpretation of certain aspects of this framework. For those not so interested in the basal ganglia, I hope that the upward mapping approach and impact of extracellular ion dynamics will nonetheless be of interest!

A draft connectome for ganglion cell types of the mouse retina

The visual system of the brain is highly parallel in its architecture. This is clearly evident in the outputs of the retina, which arise from neurons called ganglion cells. Work in our lab has shown that mammalian retinas contain more than a dozen distinct types of ganglion cells. Each type appears to filter the retinal image in a unique way and to relay this processed signal to a specific set of targets in the brain. My students and I are working to understand the meaning of this parallel organization through electrophysiological and anatomical studies. We record from light-responsive ganglion cells in vitro using the whole-cell patch method. This allows us to correlate directly the visual response properties, intrinsic electrical behavior, synaptic pharmacology, dendritic morphology and axonal projections of single neurons. Other methods used in the lab include neuroanatomical tracing techniques, single-unit recording and immunohistochemistry. We seek to specify the total number of ganglion cell types, the distinguishing characteristics of each type, and the intraretinal mechanisms (structural, electrical, and synaptic) that shape their stimulus selectivities. Recent work in the lab has identified a bizarre new ganglion cell type that is also a photoreceptor, capable of responding to light even when it is synaptically uncoupled from conventional (rod and cone) photoreceptors. These ganglion cells appear to play a key role in resetting the biological clock. It is just this sort of link, between a specific cell type and a well-defined behavioral or perceptual function, that we seek to establish for the full range of ganglion cell types. My research concerns the structural and functional organization of retinal ganglion cells, the output cells of the retina whose axons make up the optic nerve. Ganglion cells exhibit great diversity both in their morphology and in their responses to light stimuli. On this basis, they are divisible into a large number of types (>15). Each ganglion-cell type appears to send its outputs to a specific set of central visual nuclei. This suggests that ganglion cell heterogeneity has evolved to provide each visual center in the brain with pre-processed representations of the visual scene tailored to its specific functional requirements. Though the outline of this story has been appreciated for some time, it has received little systematic exploration. My laboratory is addressing in parallel three sets of related questions: 1) How many types of ganglion cells are there in a typical mammalian retina and what are their structural and functional characteristics? 2) What combination of synaptic networks and intrinsic membrane properties are responsible for the characteristic light responses of individual types? 3) What do the functional specializations of individual classes contribute to perceptual function or to visually mediated behavior? To pursue these questions, we label retinal ganglion cells by retrograde transport from the brain; analyze in vitro their light responses, intrinsic membrane properties and synaptic pharmacology using the whole-cell patch clamp method; and reveal their morphology with intracellular dyes. Recently, we have discovered a novel ganglion cell in rat retina that is intrinsically photosensitive. These ganglion cells exhibit robust light responses even when all influences from classical photoreceptors (rods and cones) are blocked, either by applying pharmacological agents or by dissociating the ganglion cell from the retina. These photosensitive ganglion cells seem likely to serve as photoreceptors for the photic synchronization of circadian rhythms, the mechanism that allows us to overcome jet lag. They project to the circadian pacemaker of the brain, the suprachiasmatic nucleus of the hypothalamus. Their temporal kinetics, threshold, dynamic range, and spectral tuning all match known properties of the synchronization or "entrainment" mechanism. These photosensitive ganglion cells innervate various other brain targets, such as the midbrain pupillary control center, and apparently contribute to a host of behavioral responses to ambient lighting conditions. These findings help to explain why circadian and pupillary light responses persist in mammals, including humans, with profound disruption of rod and cone function. Ongoing experiments are designed to elucidate the phototransduction mechanism, including the identity of the photopigment and the nature of downstream signaling pathways. In other studies, we seek to provide a more detailed characterization of the photic responsiveness and both morphological and functional evidence concerning possible interactions with conventional rod- and cone-driven retinal circuits. These studies are of potential value in understanding and designing appropriate therapies for jet lag, the negative consequences of shift work, and seasonal affective disorder.

Timescales of neural activity: their inference, control, and relevance

Timescales characterize how fast the observables change in time. In neuroscience, they can be estimated from the measured activity and can be used, for example, as a signature of the memory trace in the network. I will first discuss the inference of the timescales from the neuroscience data comprised of the short trials and introduce a new unbiased method. Then, I will apply the method to the data recorded from a local population of cortical neurons from the visual area V4. I will demonstrate that the ongoing spiking activity unfolds across at least two distinct timescales - fast and slow - and the slow timescale increases when monkeys attend to the location of the receptive field. Which models can give rise to such behavior? Random balanced networks are known for their fast timescales; thus, a change in the neurons or network properties is required to mimic the data. I will propose a set of models that can control effective timescales and demonstrate that only the model with strong recurrent interactions fits the neural data. Finally, I will discuss the timescales' relevance for behavior and cortical computations.

From a by-stander to an influencer: How microglia adapt to altered environments and influence neuronal activity

Microglia, traditionally classified as immune-responsive, adjust synaptic connections during development and disease. However, their role in the adult nervous system has been mostly diminished to an observer. In my research group, we are interested in how microglia are involved in establishing and maintaining accurate neuronal circuit function in the retina and in the visual cortex. In my talk, I will introduce our strategies how to decipher the microglia’s functional identity and how this information guided us to microglia enabled extracellular matrix remodeling and reinstatment of juvenile-like plasticity in the adult brain.

Extrinsic control and autonomous computation in the hippocampal CA1 circuit

In understanding circuit operations, a key issue is the extent to which neuronal spiking reflects local computation or responses to upstream inputs. Because pyramidal cells in CA1 do not have local recurrent projections, it is currently assumed that firing in CA1 is inherited from its inputs – thus, entorhinal inputs provide communication with the rest of the neocortex and the outside world, whereas CA3 inputs provide internal and past memory representations. Several studies have attempted to prove this hypothesis, by lesioning or silencing either area CA3 or the entorhinal cortex and examining the effect of firing on CA1 pyramidal cells. Despite the intense and careful work in this research area, the magnitudes and types of the reported physiological impairments vary widely across experiments. At least part of the existing variability and conflicts is due to the different behavioral paradigms, designs and evaluation methods used by different investigators. Simultaneous manipulations in the same animal or even separate manipulations of the different inputs to the hippocampal circuits in the same experiment are rare. To address these issues, I used optogenetic silencing of unilateral and bilateral mEC, of the local CA1 region, and performed bilateral pharmacogenetic silencing of the entire CA3 region. I combined this with high spatial resolution recording of local field potentials (LFP) in the CA1-dentate axis and simultaneously collected firing pattern data from thousands of single neurons. Each experimental animal had up to two of these manipulations being performed simultaneously. Silencing the medial entorhinal (mEC) largely abolished extracellular theta and gamma currents in CA1, without affecting firing rates. In contrast, CA3 and local CA1 silencing strongly decreased firing of CA1 neurons without affecting theta currents. Each perturbation reconfigured the CA1 spatial map. Yet, the ability of the CA1 circuit to support place field activity persisted, maintaining the same fraction of spatially tuned place fields, and reliable assembly expression as in the intact mouse. Thus, the CA1 network can maintain autonomous computation to support coordinated place cell assemblies without reliance on its inputs, yet these inputs can effectively reconfigure and assist in maintaining stability of the CA1 map.

Distributed and stable memory representations may lead to serial dependence

Perception and action are biased by our recent experiences. Even when a sequence of stimuli are randomly presented, responses are sometimes attracted toward the past. The mechanism of such bias, recently termed serial dependence, is still under investigation. Currently, there is mixed evidence indicating that such bias could be either from a sensory and perceptual origin or occurring only at decisional stages. In this talk, I will present recent findings from our group showing that biases are decreased when disrupting the memory trace in a premotor region in a simple visuomotor task. In addition, we have shown that this bias is stable over periods of up to 8 s. At the end, I will show ongoing analysis of a recent experiment and argue that serial dependence may rely on distributed memory representations of stimuli and task relevant features.

Forensic use of face recognition systems for investigation

With the increasing development of automatic systems and artificial intelligence, face recognition is becoming increasingly important in forensic and civil contexts. However, face recognition has yet to be thoroughly empirically studied to provide an adequate scientific and legal framework for investigative and court purposes. This observation sets the foundation for the research. We focus on issues related to face images and the use of automatic systems. Our objective is to validate a likelihood ratio computation methodology for interpreting comparison scores from automatic face recognition systems (score-based likelihood ratio, SLR). We collected three types of traces: portraits (ID), video surveillance footage recorded by ATM and by a wide-angle camera (CCTV). The performance of two automatic face recognition systems is compared: the commercial IDEMIA Morphoface (MFE) system and the open source FaceNet algorithm.

Deception, ExoNETs, SmushWare & Organic Data: Tech-facilitated neurorehabilitation & human-machine training

Making use of visual display technology and human-robotic interfaces, many researchers have illustrated various opportunities to distort visual and physical realities. We have had success with interventions such as error augmentation, sensory crossover, and negative viscosity.  Judicial application of these techniques leads to training situations that enhance the learning process and can restore movement ability after neural injury. I will trace out clinical studies that have employed such technologies to improve the health and function, as well as share some leading-edge insights that include deceiving the patient, moving the "smarts" of software into the hardware, and examining clinical effectiveness

From single cell to population coding during defensive behaviors in prefrontal circuits

Coping with threatening situations requires both identifying stimuli predicting danger and selecting adaptive behavioral responses in order to survive. The dorso medial prefrontal cortex (dmPFC) is a critical structure involved in the regulation of threat-related behaviour, yet it is still largely unclear how threat-predicting stimuli and defensive behaviours are associated within prefrontal networks in order to successfully drive adaptive responses. Over the past years, we used a combination we used a combination of extracellular recordings, neuronal decoding approaches, and state of the art optogenetic manipulations to identify key neuronal elements and mechanisms controlling defensive fear responses. I will present an overview of our recent work ranging from analyses of dedicated neuronal types and oscillatory and synchronization mechanisms to artificial intelligence approaches used to decode the activity or large population of neurons. Ultimately these analyses allowed the identification of high dimensional representations of defensive behavior unfolding within prefrontal networks.

Online "From Bench to Bedside" Neurosciences Symposium

2 Keynote lectures :“Homeostatic control of sleep in the fly"and “Management of Intracerebral Haemorrhage – where is the evidence?” and 2 sessions: "Cortical top-down information processing” and “Virtual/augmented reality and its implications for the clinic”

New Mechanisms of Extracellular Matrix Remodeling

In the adult brain, synapses are tightly enwrapped by lattices of extracellular matrix that consist of extremely long-lived molecules. These lattices are deemed to stabilize synapses, restrict the reorganization of their transmission machinery, and prevent them from undergoing structural or morphological changes. At the same time, they are expected to retain some degree of flexibility to permit occasional events of synaptic plasticity. The recent understanding that structural changes to synapses are significantly more frequent than previously assumed (occurring even on a timescale of minutes) has called for a mechanism that allows continual and energy-efficient remodeling of the ECM at synapses. I review in the talk our recent work showcasing such a process, based on the constitutive recycling of synaptic ECM molecules. I discuss the key characteristics of this mechanism, focusing on its roles in mediating synaptic transmission and plasticity, and speculate on additional potential functions in neuronal signaling.

A Flash of Darkness within Dusk: Crossover inhibition in the mouse retina

To survive in the wild small rodents evolved specialized retinas. To escape predators, looming shadows need to be detected with speed and precision. To evade starvation, small seeds, grass, nuts and insects need to also be detected quickly. Some of these succulent seeds and insects may be camouflaged offering only low contrast targets.Moreover, these challenging tasks need to be accomplished continuously at dusk, night, dawn and daytime. Crossover inhibition is thought to be involved in enhancing contrast detectionin the microcircuits of the inner plexiform layer of the mammalian retina. The AII amacrine cells are narrow field cells that play a key role in crossover inhibition. Our lab studies the synaptic physiology that regulates glycine release from AII amacrine cellsin mouse retina. These interneurons receive excitation from rod and conebipolar cells and transmit excitation to ON-type bipolar cell terminals via gap junctions. They also transmit inhibition via multiple glycinergic synapses onto OFF bipolar cell terminals.AII amacrine cells are thus a central hub of synaptic information processing that cross links the ON and the OFF pathways. What are the functions of crossover inhibition? How does it enhance contrast detection at different ambient light levels? How is the dynamicrange, frequency response and synaptic gain of glycine release modulated by luminance levels and circadian rhythms? How is synaptic gain changed by different extracellular neuromodulators, like dopamine, and by intracellular messengers like cAMP, phosphateand Ca2+ ions from Ca2+ channels and Ca2+ stores? My talk will try to answer some of these questions and will pose additional ones. It will end with further hypothesis and speculations on the multiple roles of crossover inhibition.

A nonlinear shot noise model for calcium-based synaptic plasticity

Activity dependent synaptic plasticity is considered to be a primary mechanism underlying learning and memory. Yet it is unclear whether plasticity rules such as STDP measured in vitro apply in vivo. Network models with STDP predict that activity patterns (e.g., place-cell spatial selectivity) should change much faster than observed experimentally. We address this gap by investigating a nonlinear calcium-based plasticity rule fit to experiments done in physiological conditions. In this model, LTP and LTD result from intracellular calcium transients arising almost exclusively from synchronous coactivation of pre- and postsynaptic neurons. We analytically approximate the full distribution of nonlinear calcium transients as a function of pre- and postsynaptic firing rates, and temporal correlations. This analysis directly relates activity statistics that can be measured in vivo to the changes in synaptic efficacy they cause. Our results highlight that both high-firing rates and temporal correlations can lead to significant changes to synaptic efficacy. Using a mean-field theory, we show that the nonlinear plasticity rule, without any fine-tuning, gives a stable, unimodal synaptic weight distribution characterized by many strong synapses which remain stable over long periods of time, consistent with electrophysiological and behavioral studies. Moreover, our theory explains how memories encoded by strong synapses can be preferentially stabilized by the plasticity rule. We confirmed our analytical results in a spiking recurrent network. Interestingly, although most synapses are weak and undergo rapid turnover, the fraction of strong synapses are sufficient for supporting realistic spiking dynamics and serve to maintain the network’s cluster structure. Our results provide a mechanistic understanding of how stable memories may emerge on the behavioral level from an STDP rule measured in physiological conditions. Furthermore, the plasticity rule we investigate is mathematically equivalent to other learning rules which rely on the statistics of coincidences, so we expect that our formalism will be useful to study other learning processes beyond the calcium-based plasticity rule.

NMC4 Short Talk: Directly interfacing brain and deep networks exposes non-hierarchical visual processing

A recent approach to understanding the mammalian visual system is to show correspondence between the sequential stages of processing in the ventral stream with layers in a deep convolutional neural network (DCNN), providing evidence that visual information is processed hierarchically, with successive stages containing ever higher-level information. However, correspondence is usually defined as shared variance between brain region and model layer. We propose that task-relevant variance is a stricter test: If a DCNN layer corresponds to a brain region, then substituting the model’s activity with brain activity should successfully drive the model’s object recognition decision. Using this approach on three datasets (human fMRI and macaque neuron firing rates) we found that in contrast to the hierarchical view, all ventral stream regions corresponded best to later model layers. That is, all regions contain high-level information about object category. We hypothesised that this is due to recurrent connections propagating high-level visual information from later regions back to early regions, in contrast to the exclusively feed-forward connectivity of DCNNs. Using task-relevant correspondence with a late DCNN layer akin to a tracer, we used Granger causal modelling to show late-DCNN correspondence in IT drives correspondence in V4. Our analysis suggests, effectively, that no ventral stream region can be appropriately characterised as ‘early’ beyond 70ms after stimulus presentation, challenging hierarchical models. More broadly, we ask what it means for a model component and brain region to correspond: beyond quantifying shared variance, we must consider the functional role in the computation. We also demonstrate that using a DCNN to decode high-level conceptual information from ventral stream produces a general mapping from brain to model activation space, which generalises to novel classes held-out from training data. This suggests future possibilities for brain-machine interface with high-level conceptual information, beyond current designs that interface with the sensorimotor periphery.

The wonders and complexities of brain microstructure: Enabling biomedical engineering studies combining imaging and models

Brain microstructure plays a key role in driving the transport of drug molecules directly administered to the brain tissue as in Convection-Enhanced Delivery procedures. This study reports the first systematic attempt to characterize the cytoarchitecture of commissural, long association and projection fiber, namely: the corpus callosum, the fornix and the corona radiata. Ovine samples from three different subjects have been imaged using scanning electron microscope combined with focused ion beam milling. Particular focus has been given to the axons. For each tract, a 3D reconstruction of relatively large volumes (including a significant number of axons) has been performed. Namely, outer axonal ellipticity, outer axonal cross-sectional area and its relative perimeter have been measured. This study [1] provides useful insight into the fibrous organization of the tissue that can be described as composite material presenting elliptical tortuous tubular fibers, leading to a workflow to enable accurate simulations of drug delivery which include well-resolved microstructural features.  As a demonstration of the use of these imaging and reconstruction techniques, our research analyses the hydraulic permeability of two white matter (WM) areas (corpus callosum and fornix) whose three-dimensional microstructure was reconstructed starting from the acquisition of the electron microscopy images. Considering that the white matter structure is mainly composed of elongated and parallel axons we computed the permeability along the parallel and perpendicular directions using computational fluid dynamics [2]. The results show a statistically significant difference between parallel and perpendicular permeability, with a ratio about 2 in both the white matter structures analysed, thus demonstrating their anisotropic behaviour. This is in line with the experimental results obtained using perfusion of brain matter [3]. Moreover, we find a significant difference between permeability in corpus callosum and fornix, which suggests that also the white matter heterogeneity should be considered when modelling drug transport in the brain. Our findings, that demonstrate and quantify the anisotropic and heterogeneous character of the white matter, represent a fundamental contribution not only for drug delivery modelling but also for shedding light on the interstitial transport mechanisms in the extracellular space. These and many other discoveries will be discussed during the talk." "1. https://www.researchsquare.com/article/rs-686577/v1, 2. https://www.pnas.org/content/118/36/e2105328118, 3. https://ieeexplore.ieee.org/abstract/document/9198110

Mechano-adaptation in a large protein complex

Macromolecular protein complexes perform essential biological functions across life forms. A fundamental, though yet unsolved question in biology is how the function of such complexes is regulated by intracellular or extracellular signals. For instance, we have little understanding of how forces affect multi-protein machines whose function is often mechanical in nature. We address this question by studying the bacterial flagellar motor, a large complex that powers swimming motility in many bacteria. This rotary motor autonomously adapts to changes in mechanical load by adding or removing force-generating ‘stator’ units that power rotation. In the bacterium Escherichia coli, up to 11 units drive the motor at high load while all the units are released at low load. We manipulate motor load using electrorotation, a technique in which a rapidly rotating electric field applies an external torque on the motor. This allows us to change motor load at will and measure the resulting stator dynamics at single-unit resolution. We found that the force generated by the stator units controls their unbinding, forming a feedback loop that leads to autoregulation of the assembly. We complemented our experiments with theoretical models that provide insight into the underlying molecular interactions. Torque-dependent remodeling takes place within seconds, making it a highly responsive control mechanism, one that is mediated by the mechano-chemical tuning of protein interactions.

Adaptive bottleneck to pallium for sequence memory, path integration and mixed selectivity representation

Spike-driven adaptation involves intracellular mechanisms that are initiated by neural firing and lead to the subsequent reduction of spiking rate followed by a recovery back to baseline. We report on long (>0.5 second) recovery times from adaptation in a thalamic-like structure in weakly electric fish. This adaptation process is shown via modeling and experiment to encode in a spatially invariant manner the time intervals between event encounters, e.g. with landmarks as the animal learns the location of food. These cells also come in two varieties, ones that care only about the time since the last encounter, and others that care about the history of encounters. We discuss how the two populations can share in the task of representing sequences of events, supporting path integration and converting from ego-to-allocentric representations. The heterogeneity of the population parameters enables the representation and Bayesian decoding of time sequences of events which may be put to good use in path integration and hilus neuron function in hippocampus. Finally we discuss how all the cells of this gateway to the pallium exhibit mixed selectivity of social features of their environment. The data and computational modeling further reveal that, in contrast to a long-held belief, these gymnotiform fish are endowed with a corollary discharge, albeit only for social signalling.

Making connections: how epithelial tissues guarantee folding

Tissue folding is a ubiquitous shape change event during development whereby a cell sheet bends into a curved 3D structure. This mechanical process is remarkably robust, and the correct final form is almost always achieved despite internal fluctuations and external perturbations inherent in living systems. While many genetic and molecular strategies that lead to robust development have been established, much less is known about how mechanical patterns and movements are ensured at the population level. I will describe how quantitative imaging, physical modeling and concepts from network science can uncover collective interactions that govern tissue patterning and shape change. Actin and myosin are two important cytoskeletal proteins involved in the force generation and movement of cells. Both parts of this talk will be about the spontaneous organization of actomyosin networks and their role in collective tissue dynamics. First, I will present how out-of-plane curvature can trigger the global alignment of actin fibers and a novel transition from collective to individual cell migration in culture. I will then describe how tissue-scale cytoskeletal patterns can guide tissue folding in the early fruit fly embryo. I will show that actin and myosin organize into a network that spans a domain of the embryo that will fold. Redundancy in this supracellular network encodes the tissue’s intrinsic robustness to mechanical and molecular perturbations during folding.

Dancing to a Different Tune: TANGO Gives Hope for Dravet Syndrome

The long-term goal of our research is to understand the mechanisms of SUDEP, defined as Sudden, Unexpected, witnessed or unwitnessed, nontraumatic and non-drowning Death in patients with EPilepsy, excluding cases of documented status epilepticus. The majority of SUDEP patients die during sleep. SUDEP is the most devastating consequence of epilepsy, yet little is understood about its causes and no biomarkers exist to identify at risk patients. While SUDEP accounts for 7.5-20% of all epilepsy deaths, SUDEP risk in the genetic epilepsies varies with affected genes. Patients with ion channel gene variants have the highest SUDEP risk. Indirect evidence variably links SUDEP to seizure-induced apnea, pulmonary edema, dysregulation of cerebral circulation, autonomic dysfunction, and cardiac arrhythmias. Arrhythmias may be primary or secondary to hormonal or metabolic changes, or autonomic discharges. When SUDEP is compared to Sudden Cardiac Death secondary to Long QT Syndrome, especially to LQT3 linked to variants in the voltage-gated sodium channel (VGSC) gene SCN5A, there are parallels in the circumstances of death. To gain insight into SUDEP mechanisms, our approach has focused on channelopathies with high SUDEP incidence. One such disorder is Dravet syndrome (DS), a devastating form of developmental and epileptic encephalopathy (DEE) characterized by multiple pharmacoresistant seizure types, intellectual disability, ataxia, and increased mortality. While all patients with epilepsy are at risk for SUDEP, DS patients may have the highest risk, up to 20%, with a mean age at SUDEP of 4.6 years. Over 80% of DS is caused by de novo heterozygous loss-of-function (LOF) variants in SCN1A, encoding the VGSC Nav1.1  subunit, resulting in haploinsufficiency. A smaller cohort of patients with DS or a more severe DEE have inherited, homozygous LOF variants in SCN1B, encoding the VGSC 1/1B non-pore-forming subunits. A related DEE, Early Infantile EE (EIEE) type 13, is linked to de novo heterozygous gain-of-function variants in SCN8A, encoding the VGSC Nav1.6. VGSCs underlie the rising phase and propagation of action potentials in neurons and cardiac myocytes. SCN1A, SCN8A, and SCN1B are expressed in both the heart and brain of humans and mice. Because of this, we proposed that cardiac arrhythmias contribute to the mechanism of SUDEP in DEE. We have taken a novel approach to the development of therapeutics for DS in collaboration with Stoke Therapeutics. We employed Targeted Augmentation of Nuclear Gene Output (TANGO) technology, which modulates naturally occurring, non-productive splicing events to increase target gene and protein expression and ameliorate disease phenotype in a mouse model. We identified antisense oligonucleotides (ASOs) that specifically increase the expression of productive Scn1a transcript in human and mouse cell lines, as well as in mouse brain. We showed that a single intracerebroventricular dose of a lead ASO at postnatal day 2 or 14 reduced the incidence of electrographic seizures and SUDEP in the F1:129S-Scn1a+/- x C57BL/6J mouse model of DS. Increased expression of productive Scn1a transcript and NaV1.1 protein were confirmed in brains of treated mice. Our results suggest that TANGO may provide a unique, gene-specific approach for the treatment of DS.

Adaptation-driven sensory detection and sequence memory

Spike-driven adaptation involves intracellular mechanisms that are initiated by spiking and lead to the subsequent reduction of spiking rate. One of its consequences is the temporal patterning of spike trains, as it imparts serial correlations between interspike intervals in baseline activity. Surprisingly the hidden adaptation states that lead to these correlations themselves exhibit quasi-independence. This talk will first discuss recent findings about the role of such adaptation in suppressing noise and extending sensory detection to weak stimuli that leave the firing rate unchanged. Further, a matching of the post-synaptic responses to the pre-synaptic adaptation time scale enables a recovery of the quasi-independence property, and can explain observations of correlations between post-synaptic EPSPs and behavioural detection thresholds. We then consider the involvement of spike-driven adaptation in the representation of intervals between sensory events. We discuss the possible link of this time-stamping mechanism to the conversion of egocentric to allocentric coordinates. The heterogeneity of the population parameters enables the representation and Bayesian decoding of time sequences of events which may be put to good use in path integration and hilus neuron function in hippocampus.

Population dynamics of the thalamic head direction system during drift and reorientation

The head direction (HD) system is classically modeled as a ring attractor network which ensures a stable representation of the animal’s head direction. This unidimensional description popularized the view of the HD system as the brain’s internal compass. However, unlike a globally consistent magnetic compass, the orientation of the HD system is dynamic, depends on local cues and exhibits remapping across familiar environments5. Such a system requires mechanisms to remember and align to familiar landmarks, which may not be well described within the classic 1-dimensional framework. To search for these mechanisms, we performed large population recordings of mouse thalamic HD cells using calcium imaging, during controlled manipulations of a visual landmark in a familiar environment. First, we find that realignment of the system was associated with a continuous rotation of the HD network representation. The speed and angular distance of this rotation was predicted by a 2nd dimension to the ring attractor which we refer to as network gain, i.e. the instantaneous population firing rate. Moreover, the 360-degree azimuthal profile of network gain, during darkness, maintained a ‘memory trace’ of a previously displayed visual landmark. In a 2nd experiment, brief presentations of a rotated landmark revealed an attraction of the network back to its initial orientation, suggesting a time-dependent mechanism underlying the formation of these network gain memory traces. Finally, in a 3rd experiment, continuous rotation of a visual landmark induced a similar rotation of the HD representation which persisted following removal of the landmark, demonstrating that HD network orientation is subject to experience-dependent recalibration. Together, these results provide new mechanistic insights into how the neural compass flexibly adapts to environmental cues to maintain a reliable representation of the head direction.

CNStalk: Anatomo-functional organisation of the grasping network in the primate brain

Cortical functions result from the conjoint activity of different, reciprocally connected areas working together as large-scale functionally specialized networks. In the macaque brain, neural tracers and functional data have provided evidence for functionally specialized large-scale cortical networks involving temporal, parietal, and frontal areas. One of these networks, the lateral grasping network, appears to play a primary role in controlling hand action organization and recognition. Available functional and tractograpy data suggest the existence of a human counterpart of this network.

Sequential learning in recurrent neural networks create memory traces of learned tasks

COSYNE 2023

The accumulation of dendritic extracellular Potassium as in vivo model of epilepsy in CA1 pyramidal neurons

COSYNE 2025

Design principles for memory storage and recall in noisy intracellular networks

COSYNE 2025

Activation of Ca2+-permeable AMPARs and intracellular calcium stores are required for structural plasticity induced by sTBS in the mouse hippocampus

FENS Forum 2024

Adeno-associated viral tools to trace neural development and connectivity across amphibians

FENS Forum 2024

Not all-or-nothing: Intracellular action potential waveform varies systematically with extracellular gamma oscillatory state

FENS Forum 2024

Analysis of Gemin3 protein regulation and intracellular pathways in motor neurons in the context of spinal muscular atrophy

FENS Forum 2024

Astrocyte-originated connection mapping of presynaptic neurons using the rabies virus tracer

FENS Forum 2024

Automatic classification of the hippocampal neuronal diversity from large-scale extracellular recordings

FENS Forum 2024

Behavioral performance of mice in open field test (OFT) exposed to the combination of levetiracetam (LEV) and valproic acid (VPA) (1:1) during whole gestation

FENS Forum 2024

Characterizing nerve-derived extracellular vesicles: Potentials and pitfalls

FENS Forum 2024

Crosstalk between AQP4-dependent increase of extracellular adenosine and dopamine neurotransmission during cocaine-induced psychiatric behaviors

FENS Forum 2024

Cuproptosis, copper homeostasis, and management in intracerebral haemorrhage (ICH)

FENS Forum 2024

Deciphering the role of specific membrane transporters in extracellular vesicles

FENS Forum 2024

Deep learning-driven compression of extracellular neural signals

FENS Forum 2024

Dynamic transcellular molecular exchange: A novel view on extracellular matrix remodelling

FENS Forum 2024

Endogenous alpha-Synuclein is essential for the transfer of pathology by exosome-enriched extracellular vesicles, following inoculation with preformed fibrils in vivo

FENS Forum 2024

Evaluation of the effects of taurine treatment on apoptotic processes, miR-34a, oxidative stress, and inflammatory markers in intracerebroventricular Amyloid Beta 1-42 injected rats

FENS Forum 2024

Evaluation of novel object recognition test results of rats injected with intracerebroventricular streptozocin to develop Alzheimer's disease models

FENS Forum 2024

An ex-vivo brain slice model to assess the impact of elevated extracellular glutamate and EAAT blockade on synaptic and extrasynaptic NMDA receptor function

FENS Forum 2024

Extracellular matrix and microglia interactions in stroke recovery

FENS Forum 2024

Extracellular matrix and sharp wave ripple complex changes following treatment with Zuranolone

FENS Forum 2024

Extracellular proteolytic cascade remodels the ECM to promote structural plasticity

FENS Forum 2024

Extracellular vesicles: An exploration into the bi-directional crosstalk of endothelial cells and astrocytes at the blood-brain barrier

FENS Forum 2024

Extracellular vesicles from mesenchymal stem cells alter gut microbiota and improve neuroinflammation and motor impairment in rats with mild liver damage

FENS Forum 2024

Extracellular vesicles from hypothalamic astrocytes modify transcription factors of the leptin signaling pathway in proopiomelanocortin (POMC) neurons

FENS Forum 2024

Extracellular vesicles and transmission of α-synuclein pathology: From cellular models to diagnostic applications

FENS Forum 2024

Extracellular vesicles from poly I:C-infected airway epithelial cells mediate viral signaling in microglia: Implications for neuroinflammation

FENS Forum 2024

Extracellular vesicles from MSCs reverse neuroinflammation in cerebellum and restore motor coordination in hyperammonemic rats

FENS Forum 2024

IL-4-induced microglia-derived small extracellular vesicles exhibit cytoprotective effects against LPS-induced microglial damage through miR-191-5p

FENS Forum 2024

Imaging intracellular chloride changes using the FRET-based SuperClomeleon sensor

FENS Forum 2024

Impact of peripheral glucose and monocarboxylate transporter inhibition on mouse cortical extracellular glucose and lactate

FENS Forum 2024

Impact of ventral hippocampal chondroitinase-ABC infusion on perineuronal nets and diffuse extracellular matrix in male Lister hooded rats

FENS Forum 2024

The importance of high-density microelectrode arrays for recording multi-scale extracellular potential and label-free characterization of network dynamics in iPSC-derived neurons

FENS Forum 2024

Inhibiting DJ-1 oxidation reduces neurofunctional deficits after experimental intracerebral haemorrhage

FENS Forum 2024

Ia inputs are uncoupled from activity-dependent intracellular signaling in motoneurons from SOD1 mice

FENS Forum 2024

Integrity of neural extracellular matrix is required for microglia-mediated synaptic remodeling

FENS Forum 2024

Intracellular Ca2+ signal in hippocampal astrocytes from WT and A7KO mice along aging

FENS Forum 2024

Involvement of glioblastoma-derived extracellular vesicles in promoting endothelial cell remodelling: Implications for glioblastoma tumour progression

FENS Forum 2024

Lavandula angustifolia or astrocytes alleviate nicotine plus high glucose-induced intracellular Ca2+ elevation in neurons and microglia

FENS Forum 2024