Developmental
developmental
Developmental emergence of personality
The Nature versus Nurture debate has generally been considered from the lens of genome versus experience dichotomy and has dominated our thinking about behavioral individuality and personality traits. In contrast, the role of nonheritable noise during brain development in behavioral variation is understudied. Using the Drosophila melanogaster visual system, I will discuss our efforts to dissect how individuality in circuit wiring emerges during development, and how that helps generate individual behavioral variation.
Alex Pitti
This PhD is funded by the French ANR, under a 4 years' project on Sensorimotor integration of variability during birdsong learning. The applicant will develop an artificial neural model, developmental and brain-inspired, to learn the sound structure in real time and without explicit supervision. Until now, AI models for developmental learning of vocalizations have been solely validated by comparison against a human-annotated corpus and not yet via direct sensorimotor interactions with living animals. We expect to do so with an interactive robot under the framework of active inference and predictive coding.
Cellular Crosstalk in Brain Development, Evolution and Disease
Cellular crosstalk is an essential process during brain development and is influenced by numerous factors, including cell morphology, adhesion, the local extracellular matrix and secreted vesicles. Inspired by mutations associated with neurodevelopmental disorders, we focus on understanding the role of extracellular mechanisms essential for the proper development of the human brain. Therefore, we combine 2D and 3D in vitro human models to better understand the molecular and cellular mechanisms involved in progenitor proliferation and fate, migration and maturation of excitatory and inhibitory neurons during human brain development and tackle the causes of neurodevelopmental disorders.
Understanding reward-guided learning using large-scale datasets
Understanding the neural mechanisms of reward-guided learning is a long-standing goal of computational neuroscience. Recent methodological innovations enable us to collect ever larger neural and behavioral datasets. This presents opportunities to achieve greater understanding of learning in the brain at scale, as well as methodological challenges. In the first part of the talk, I will discuss our recent insights into the mechanisms by which zebra finch songbirds learn to sing. Dopamine has been long thought to guide reward-based trial-and-error learning by encoding reward prediction errors. However, it is unknown whether the learning of natural behaviours, such as developmental vocal learning, occurs through dopamine-based reinforcement. Longitudinal recordings of dopamine and bird songs reveal that dopamine activity is indeed consistent with encoding a reward prediction error during naturalistic learning. In the second part of the talk, I will talk about recent work we are doing at DeepMind to develop tools for automatically discovering interpretable models of behavior directly from animal choice data. Our method, dubbed CogFunSearch, uses LLMs within an evolutionary search process in order to "discover" novel models in the form of Python programs that excel at accurately predicting animal behavior during reward-guided learning. The discovered programs reveal novel patterns of learning and choice behavior that update our understanding of how the brain solves reinforcement learning problems.
Developmental and evolutionary perspectives on thalamic function
Brain organization and function is a complex topic. We are good at establishing correlates of perception and behavior across forebrain circuits, as well as manipulating activity in these circuits to affect behavior. However, we still lack good models for the large-scale organization and function of the forebrain. What are the contributions of the cortex, basal ganglia, and thalamus to behavior? In addressing these questions, we often ascribe function to each area as if it were an independent processing unit. However, we know from the anatomy that the cortex, basal ganglia, and thalamus, are massively interconnected in a large network. One way to generate insight into these questions is to consider the evolution and development of forebrain systems. In this talk, I will discuss the developmental and evolutionary (comparative anatomy) data on the thalamus, and how it fits within forebrain networks. I will address questions including, when did the thalamus appear in evolution, how is the thalamus organized across the vertebrate lineage, and how can the change in the organization of forebrain networks affect behavioral repertoires.
Understanding reward-guided learning using large-scale datasets
Understanding the neural mechanisms of reward-guided learning is a long-standing goal of computational neuroscience. Recent methodological innovations enable us to collect ever larger neural and behavioral datasets. This presents opportunities to achieve greater understanding of learning in the brain at scale, as well as methodological challenges. In the first part of the talk, I will discuss our recent insights into the mechanisms by which zebra finch songbirds learn to sing. Dopamine has been long thought to guide reward-based trial-and-error learning by encoding reward prediction errors. However, it is unknown whether the learning of natural behaviours, such as developmental vocal learning, occurs through dopamine-based reinforcement. Longitudinal recordings of dopamine and bird songs reveal that dopamine activity is indeed consistent with encoding a reward prediction error during naturalistic learning. In the second part of the talk, I will talk about recent work we are doing at DeepMind to develop tools for automatically discovering interpretable models of behavior directly from animal choice data. Our method, dubbed CogFunSearch, uses LLMs within an evolutionary search process in order to "discover" novel models in the form of Python programs that excel at accurately predicting animal behavior during reward-guided learning. The discovered programs reveal novel patterns of learning and choice behavior that update our understanding of how the brain solves reinforcement learning problems.
Gene regulatory mechanisms of neocortex development and evolution
The neocortex is considered to be the seat of higher cognitive functions in humans. During its evolution, most notably in humans, the neocortex has undergone considerable expansion, which is reflected by an increase in the number of neurons. Neocortical neurons are generated during development by neural stem and progenitor cells. Epigenetic mechanisms play a pivotal role in orchestrating the behaviour of stem cells during development. We are interested in the mechanisms that regulate gene expression in neural stem cells, which have implications for our understanding of neocortex development and evolution, neural stem cell regulation and neurodevelopmental disorders.
Screen Savers : Protecting adolescent mental health in a digital world
In our rapidly evolving digital world, there is increasing concern about the impact of digital technologies and social media on the mental health of young people. Policymakers and the public are nervous. Psychologists are facing mounting pressures to deliver evidence that can inform policies and practices to safeguard both young people and society at large. However, research progress is slow while technological change is accelerating.My talk will reflect on this, both as a question of psychological science and metascience. Digital companies have designed highly popular environments that differ in important ways from traditional offline spaces. By revisiting the foundations of psychology (e.g. development and cognition) and considering digital changes' impact on theories and findings, we gain deeper insights into questions such as the following. (1) How do digital environments exacerbate developmental vulnerabilities that predispose young people to mental health conditions? (2) How do digital designs interact with cognitive and learning processes, formalised through computational approaches such as reinforcement learning or Bayesian modelling?However, we also need to face deeper questions about what it means to do science about new technologies and the challenge of keeping pace with technological advancements. Therefore, I discuss the concept of ‘fast science’, where, during crises, scientists might lower their standards of evidence to come to conclusions quicker. Might psychologists want to take this approach in the face of technological change and looming concerns? The talk concludes with a discussion of such strategies for 21st-century psychology research in the era of digitalization.
Virtual and experimental approaches to the pathogenicity of SynGAP1 missense mutations
Targeting gamma oscillations to improve cognition
Optogenetic control of Nodal signaling patterns
Embryos issue instructions to their cells in the form of patterns of signaling activity. Within these patterns, the distribution of signaling in time and space directs the fate of embryonic cells. Tools to perturb developmental signaling with high resolution in space and time can help reveal how these patterns are decoded to make appropriate fate decisions. In this talk, I will present new optogenetic reagents and an experimental pipeline for creating designer Nodal signaling patterns in live zebrafish embryos. Our improved optoNodal reagents eliminate dark activity and improve response kinetics, without sacrificing dynamic range. We adapted an ultra-widefield microscopy platform for parallel light patterning in up to 36 embryos and demonstrated precise spatial control over Nodal signaling activity and downstream gene expression. Using this system, we demonstrate that patterned Nodal activation can initiate specification and internalization movements of endodermal precursors. Further, we used patterned illumination to generate synthetic signaling patterns in Nodal signaling mutants, rescuing several characteristic developmental defects. This study establishes an experimental toolkit for systematic exploration of Nodal signaling patterns in live embryos.
SYNGAP1 Natural History Study/ Multidisciplinary Clinic at Children’s Hospital Colorado
Beyond the synapse: SYNGAP1 in primary and motile cilia
The Roles of Distinct Functions of SynGAP1 in SYNGAP1-Related Disorders
The multi-phase plasticity supporting winner effect
Aggression is an innate behavior across animal species. It is essential for competing for food, defending territory, securing mates, and protecting families and oneself. Since initiating an attack requires no explicit learning, the neural circuit underlying aggression is believed to be genetically and developmentally hardwired. Despite being innate, aggression is highly plastic. It is influenced by a wide variety of experiences, particularly winning and losing previous encounters. Numerous studies have shown that winning leads to an increased tendency to fight while losing leads to flight in future encounters. In the talk, I will present our recent findings regarding the neural mechanisms underlying the behavioral changes caused by winning.
Modeling human brain development and disease: the role of primary cilia
Neurodevelopmental disorders (NDDs) impose a global burden, affecting an increasing number of individuals. While some causative genes have been identified, understanding the human-specific mechanisms involved in these disorders remains limited. Traditional gene-driven approaches for modeling brain diseases have failed to capture the diverse and convergent mechanisms at play. Centrosomes and cilia act as intermediaries between environmental and intrinsic signals, regulating cellular behavior. Mutations or dosage variations disrupting their function have been linked to brain formation deficits, highlighting their importance, yet their precise contributions remain largely unknown. Hence, we aim to investigate whether the centrosome/cilia axis is crucial for brain development and serves as a hub for human-specific mechanisms disrupted in NDDs. Towards this direction, we first demonstrated species-specific and cell-type-specific differences in the cilia-genes expression during mouse and human corticogenesis. Then, to dissect their role, we provoked their ectopic overexpression or silencing in the developing mouse cortex or in human brain organoids. Our findings suggest that cilia genes manipulation alters both the numbers and the position of NPCs and neurons in the developing cortex. Interestingly, primary cilium morphology is disrupted, as we find changes in their length, orientation and number that lead to disruption of the apical belt and altered delamination profiles during development. Our results give insight into the role of primary cilia in human cortical development and address fundamental questions regarding the diversity and convergence of gene function in development and disease manifestation. It has the potential to uncover novel pharmacological targets, facilitate personalized medicine, and improve the lives of individuals affected by NDDs through targeted cilia-based therapies.
Contrasting developmental principles of human brain development and their relevance to neurodevelopmental disorders
Cortical interneurons from brain development to disease
Dyslexia, Rhythm, Language and the Developing Brain
Recent insights from auditory neuroscience provide a new perspective on how the brain encodes speech. Using these recent insights, I will provide an overview of key factors underpinning individual differences in children’s development of language and phonology, providing a context for exploring atypical reading development (dyslexia). Children with dyslexia are relatively insensitive to acoustic cues related to speech rhythm patterns. This lack of rhythmic sensitivity is related to the atypical neural encoding of rhythm patterns in speech by the brain. I will describe our recent data from infants as well as children, demonstrating developmental continuity in the key neural variables.
Divergent Recruitment of Developmentally-Defined Neuronal Ensembles Supports Memory Dynamics
Investigating face processing impairments in Developmental Prosopagnosia: Insights from behavioural tasks and lived experience
The defining characteristic of development prosopagnosia is severe difficulty recognising familiar faces in everyday life. Numerous studies have reported that the condition is highly heterogeneous in terms of both presentation and severity with many mixed findings in the literature. I will present behavioural data from a large face processing test battery (n = 24 DPs) as well as some early findings from a larger survey of the lived experience of individuals with DP and discuss how insights from individuals' real-world experience can help to understand and interpret lab-based data.
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.
The role of CNS microglia in health and disease
Microglia are the resident CNS macrophages of the brain parenchyma. They have many and opposing roles in health and disease, ranging from inflammatory to anti-inflammatory and protective functions, depending on the developmental stage and the disease context. In Multiple Sclerosis, microglia are involved to important hallmarks of the disease, such as inflammation, demyelination, axonal damage and remyelination, however the exact mechanisms controlling their transformation towards a protective or devastating phenotype during the disease progression remains largely unknown until now. We wish to understand how brain microglia respond to demyelinating insults and how their behaviour changes in recovery. To do so we developed a novel histopathological analysis approach in 3D and a cell-based analysis tool that when applied in the cuprizone model of demyelination revealed region- and disease- dependent changes in microglial dynamics in the brain grey matter during demyelination and remyelination. We now use similar approaches with the aim to unravel sensitive changes in microglial dynamics during neuroinflammation in the EAE model. Furthermore, we employ constitutive knockout and tamoxifen-inducible gene-targeting approaches, immunological techniques, genetics and bioinformatics and currently seek to clarify the specific role of the brain resident microglial NF-κB molecular pathway versus other tissue macrophages in EAE.
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.
Vision Unveiled: Understanding Face Perception in Children Treated for Congenital Blindness
Despite her still poor visual acuity and minimal visual experience, a 2-3 month old baby will reliably respond to facial expressions, smiling back at her caretaker or older sibling. But what if that same baby had been deprived of her early visual experience? Will she be able to appropriately respond to seemingly mundane interactions, such as a peer’s facial expression, if she begins seeing at the age of 10? My work is part of Project Prakash, a dual humanitarian/scientific mission to identify and treat curably blind children in India and then study how their brain learns to make sense of the visual world when their visual journey begins late in life. In my talk, I will give a brief overview of Project Prakash, and present findings from one of my primary lines of research: plasticity of face perception with late sight onset. Specifically, I will discuss a mixed methods effort to probe and explain the differential windows of plasticity that we find across different aspects of distributed face recognition, from distinguishing a face from a nonface early in the developmental trajectory, to recognizing facial expressions, identifying individuals, and even identifying one’s own caretaker. I will draw connections between our empirical findings and our recent theoretical work hypothesizing that children with late sight onset may suffer persistent face identification difficulties because of the unusual acuity progression they experience relative to typically developing infants. Finally, time permitting, I will point to potential implications of our findings in supporting newly-sighted children as they transition back into society and school, given that their needs and possibilities significantly change upon the introduction of vision into their lives.
Quantifying perturbed SynGAP1 function caused by coding mutations
Movement planning as a window into hierarchical motor control
The ability to organise one's body for action without having to think about it is taken for granted, whether it is handwriting, typing on a smartphone or computer keyboard, tying a shoelace or playing the piano. When compromised, e.g. in stroke, neurodegenerative and developmental disorders, the individuals’ study, work and day-to-day living are impacted with high societal costs. Until recently, indirect methods such as invasive recordings in animal models, computer simulations, and behavioural markers during sequence execution have been used to study covert motor sequence planning in humans. In this talk, I will demonstrate how multivariate pattern analyses of non-invasive neurophysiological recordings (MEG/EEG), fMRI, and muscular recordings, combined with a new behavioural paradigm, can help us investigate the structure and dynamics of motor sequence control before and after movement execution. Across paradigms, participants learned to retrieve and produce sequences of finger presses from long-term memory. Our findings suggest that sequence planning involves parallel pre-ordering of serial elements of the upcoming sequence, rather than a preparation of a serial trajectory of activation states. Additionally, we observed that the human neocortex automatically reorganizes the order and timing of well-trained movement sequences retrieved from memory into lower and higher-level representations on a trial-by-trial basis. This echoes behavioural transfer across task contexts and flexibility in the final hundreds of milliseconds before movement execution. These findings strongly support a hierarchical and dynamic model of skilled sequence control across the peri-movement phase, which may have implications for clinical interventions.
Therapeutic Strategies for Autism: Targeting Three Levels of the Central Dogma of Molecular Biology with a Focus on SYNGAP1
The development of visual experience
Vision and visual cognition is experience-dependent with likely multiple sensitive periods, but we know very little about statistics of visual experience at the scale of everyday life and how they might change with development. By traditional assumptions, the world at the massive scale of daily life presents pretty much the same visual statistics to all perceivers. I will present an overview our work on ego-centric vision showing that this is not the case. The momentary image received at the eye is spatially selective, dependent on the location, posture and behavior of the perceiver. If a perceiver’s location, possible postures and/or preferences for looking at some kinds of scenes over others are constrained, then their sampling of images from the world and thus the visual statistics at the scale of daily life could be biased. I will present evidence with respect to both low-level and higher level visual statistics about the developmental changes in the visual input over the first 18 months post-birth.
Why robots? A brief introduction to the use of robots in psychological research
Why should psychologists be interested in robots? This talk aims to illustrate how social robots – machines with human-like features and behaviors – can offer interesting insights into the human mind. I will first provide a brief overview of how robots have been used in psychology and cognitive science research focusing on two approaches - Developmental Robotics and Human-Robot Interaction (HRI). We will then delve into recent works in HRI, including my own, in greater detail. We will also address the limitations of research thus far, such as the lack of proper controlled experiments, and discuss how the scientific community should evaluate the use of technology in educational and other social settings.
Mechanisms Underlying the Persistence of Cancer-Related Fatigue
Cancer-related fatigue is a prominent and debilitating side effect of cancer and its treatment. It can develop prior to diagnosis, generally peaks during cancer treatment, and can persist long after treatment completion. Its mechanisms are multifactorial, and its expression is highly variable. Unfortunately, treatment options are limited. Our research uses syngeneic murine models of cancer and cisplatin-based chemotherapy to better understand these mechanisms. Our data indicate that both peripherally and centrally processes may contribute to the developmental of fatigue. These processes include metabolic alterations, mitochondrial dysfunction, pre-cachexia, and inflammation. However, our data has revealed that behavioral fatigue can persist even after the toxicity associated with cancer and its treatment recover. For example, running during cancer treatment attenuates kidney toxicity while also delaying recovery from fatigue-like behavior. Additionally, administration of anesthetics known to disrupt memory consolidation at the time treatment can promote recovery, and treatment-related cues can re-instate fatigue after recovery. Cancer-related fatigue can also promote habitual behavioral patterns, as observed using a devaluation task. We interpret this data to suggest that limit metabolic resources during cancer promote the utilization of habit-based behavioral strategies that serve to maintain fatigue behavior into survivorship. This line of work is exciting as it points us toward novel interventional targets for the treatment of persistent cancer-related fatigue.
Involvement of the brain endothelium in neurodevelopmental disorders
Circuit mechanisms of attention dysfunction in Scn8a+/- mice: implications for epilepsy and neurodevelopmental disorders
Microbial modulation of zebrafish behavior and brain development
There is growing recognition that host-associated microbiotas modulate intrinsic neurodevelopmental programs including those underlying human social behavior. Despite this awareness, the fundamental processes are generally not understood. We discovered that the zebrafish microbiota is necessary for normal social behavior. By examining neuronal correlates of behavior, we found that the microbiota restrains neurite complexity and targeting of key forebrain neurons within the social behavior circuitry. The microbiota is also necessary for both localization and molecular functions of forebrain microglia, brain-resident phagocytes that remodel neuronal arbors. In particular, the microbiota promotes expression of complement signaling pathway components important for synapse remodeling. Our work provides evidence that the microbiota modulates zebrafish social behavior by stimulating microglial remodeling of forebrain circuits during early neurodevelopment and suggests molecular pathways for therapeutic interventions during atypical neurodevelopment.
Catatonia in Neurodevelopmental Conditions
The balanced brain: two-photon microscopy of inhibitory synapse formation
Coordination between excitatory and inhibitory synapses (providing positive and negative signals respectively) is required to ensure proper information processing in the brain. Many brain disorders, especially neurodevelopental disorders, are rooted in a specific disturbance of this coordination. In my research group we use a combination of two-photon microscopy and electrophisiology to examine how inhibitory synapses are fromed and how this formation is coordinated with nearby excitatroy synapses.
Why are we consistently inconsistent? On the neural mechanisms of behavioural inconsistency
Epigenetic rewiring in Schinzel-Giedion syndrome
During life, a variety of specialized cells arise to grant the right and timely corrected functions of tissues and organs. Regulation of chromatin in defining specialized genomic regions (e.g. enhancers) plays a key role in developmental transitions from progenitors into cell lineages. These enhancers, properly topologically positioned in 3D space, ultimately guide the transcriptional programs. It is becoming clear that several pathologies converge in differential enhancer usage with respect to physiological situations. However, why some regulatory regions are physiologically preferred, while some others can emerge in certain conditions, including other fate decisions or diseases, remains obscure. Schinzel-Giedion syndrome (SGS) is a rare disease with symptoms such as severe developmental delay, congenital malformations, progressive brain atrophy, intractable seizures, and infantile death. SGS is caused by mutations in the SETBP1 gene that results in its accumulation further leading to the downstream accumulation of SET. The oncoprotein SET has been found as part of the histone chaperone complex INHAT that blocks the activity of histone acetyltransferases suggesting that SGS may (i) represent a natural model of alternative chromatin regulation and (ii) offer chances to study downstream (mal)adaptive mechanisms. I will present our work on the characterization of SGS in appropriate experimental models including iPSC-derived cultures and mouse.
Precision Genomics in Neurodevelopmental Disorders
A Data-Driven Approach to Reconstructing Disease Trajectories in SYNGAP1-Related Disorders
Nature over Nurture: Functional neuronal circuits emerge in the absence of developmental activity
During development, the complex neuronal circuitry of the brain arises from limited information contained in the genome. After the genetic code instructs the birth of neurons, the emergence of brain regions, and the formation of axon tracts, it is believed that neuronal activity plays a critical role in shaping circuits for behavior. Current AI technologies are modeled after the same principle: connections in an initial weight matrix are pruned and strengthened by activity-dependent signals until the network can sufficiently generalize a set of inputs into outputs. Here, we challenge these learning-dominated assumptions by quantifying the contribution of neuronal activity to the development of visually guided swimming behavior in larval zebrafish. Intriguingly, dark-rearing zebrafish revealed that visual experience has no effect on the emergence of the optomotor response (OMR). We then raised animals under conditions where neuronal activity was pharmacologically silenced from organogenesis onward using the sodium-channel blocker tricaine. Strikingly, after washout of the anesthetic, animals performed swim bouts and responded to visual stimuli with 75% accuracy in the OMR paradigm. After shorter periods of silenced activity OMR performance stayed above 90% accuracy, calling into question the importance and impact of classical critical periods for visual development. Detailed quantification of the emergence of functional circuit properties by brain-wide imaging experiments confirmed that neuronal circuits came ‘online’ fully tuned and without the requirement for activity-dependent plasticity. Thus, contrary to what you learned on your mother's knee, complex sensory guided behaviors can be wired up innately by activity-independent developmental mechanisms.
Developmentally structured coactivity in the hippocampal trisynaptic loop
The hippocampus is a key player in learning and memory. Research into this brain structure has long emphasized its plasticity and flexibility, though recent reports have come to appreciate its remarkably stable firing patterns. How novel information incorporates itself into networks that maintain their ongoing dynamics remains an open question, largely due to a lack of experimental access points into network stability. Development may provide one such access point. To explore this hypothesis, we birthdated CA1 pyramidal neurons using in-utero electroporation and examined their functional features in freely moving, adult mice. We show that CA1 pyramidal neurons of the same embryonic birthdate exhibit prominent cofiring across different brain states, including behavior in the form of overlapping place fields. Spatial representations remapped across different environments in a manner that preserves the biased correlation patterns between same birthdate neurons. These features of CA1 activity could partially be explained by structured connectivity between pyramidal cells and local interneurons. These observations suggest the existence of developmentally installed circuit motifs that impose powerful constraints on the statistics of hippocampal output.
Harnessing mRNA metabolism for the development of precision gene therapy
Integration of 3D human stem cell models derived from post-mortem tissue and statistical genomics to guide schizophrenia therapeutic development
Schizophrenia is a neuropsychiatric disorder characterized by positive symptoms (such as hallucinations and delusions), negative symptoms (such as avolition and withdrawal) and cognitive dysfunction1. Schizophrenia is highly heritable, and genetic studies are playing a pivotal role in identifying potential biomarkers and causal disease mechanisms with the hope of informing new treatments. Genome-wide association studies (GWAS) identified nearly 270 loci with a high statistical association with schizophrenia risk; however each locus confers only a small increase in risk therefore it is difficult to translate these findings into understanding disease biology that can lead to treatments. Induced pluripotent stem cell (iPSC) models are a tractable system to translate genetic findings and interrogate mechanisms of pathogenesis. Mounting research with patient-derived iPSCs has proposed several neurodevelopmental pathways altered in SCZ, such as neural progenitor cell (NPC) proliferation, imbalanced differentiation of excitatory and inhibitory cortical neurons. However, it is unclear what exactly these iPS models recapitulate, how potential perturbations of early brain development translates into illness in adults and how iPS models that represent fetal stages can be utilized to further drug development efforts to treat adult illness. I will present the largest transcriptome analysis of post-mortem caudate nucleus in schizophrenia where we discovered that decreased presynaptic DRD2 autoregulation is the causal dopamine risk factor for schizophrenia (Benjamin et al, Nature Neuroscience 2022 https://doi.org/10.1038/s41593-022-01182-7). We developed stem cell models from a subset of the postmortem cohort to better understand the molecular underpinnings of human psychiatric disorders (Sawada et al, Stem Cell Research 2020). We established a method for the differentiation of iPS cells into ventral forebrain organoids and performed single cell RNAseq and cellular phenotyping. To our knowledge, this is the first study to evaluate iPSC models of SZ from the same individuals with postmortem tissue. Our study establishes that striatal neurons in the patients with SCZ carry abnormalities that originated during early brain development. Differentiation of inhibitory neurons is accelerated whereas excitatory neuronal development is delayed, implicating an excitation and inhibition (E-I) imbalance during early brain development in SCZ. We found a significant overlap of genes upregulated in the inhibitory neurons in SCZ organoids with upregulated genes in postmortem caudate tissues from patients with SCZ compared with control individuals, including the donors of our iPS cell cohort. Altogether, we demonstrate that ventral forebrain organoids derived from postmortem tissue of individuals with schizophrenia recapitulate perturbed striatal gene expression dynamics of the donors’ brains (Sawada et al, biorxiv 2022 https://doi.org/10.1101/2022.05.26.493589).
Linking SYNGAP1 with Human-Specific Mechanisms of Neuronal Development
SYNGAP1 and Epilepsy SurgerySYNGAP1 and Epilepsy Surgery
Myelin Formation and Oligodendrocyte Biology in Epilepsy
Epilepsy is one of the most common neurological diseases according to the World Health Organization (WHO) affecting around 70 million people worldwide [WHO]. Patients who suffer from epilepsy also suffer from a variety of neuro-psychiatric co-morbidities, which they can experience as crippling as the seizure condition itself. Adequate organization of cerebral white matter is utterly important for cognitive development. The failure of integration of neurologic function with cognition is reflected in neuro-psychiatric disease, such as autism spectrum disorder (ASD). However, in epilepsy we know little about the importance of white matter abnormalities in epilepsy-associated co-morbidities. Epilepsy surgery is an important therapy strategy in patients where conventional anti-epileptic drug treatment fails . On histology of the resected brain samples, malformations of cortical development (MCD) are common among the epilepsy surgery population, especially focal cortical dysplasia (FCD) and tuberous sclerosis complex (TSC). Both pathologies are associated with constitutive activation of the mTOR pathway. Interestingly, some type of FCD is morphological similar to TSC cortical tubers including the abnormalities of the white matter. Hypomyelination with lack of myelin-producing cells, the oligodendrocytes, within the lesional area is a striking phenomenon. Impairment of the complex myelination process can have a major impact on brain function. In the worst case leading to distorted or interrupted neurotransmissions. It is still unclear whether the observed myelin pathology in epilepsy surgical specimens is primarily related to the underlying malformation process or is just a secondary phenomenon of recurrent epileptic seizures creating a toxic micro-environment which hampers myelin formation. Interestingly, mTORC1 has been implicated as key signal for myelination, thus, promoting the maturation of oligodendrocytes . These results, however, remain controversial. Regardless of the underlying pathophysiologic mechanism, alterations of myelin dynamics, depending on their severity, are known to be linked to various kinds of developmental disorders or neuropsychiatric manifestations.
Cell-type specific alterations underpinning convergent ASD phenotypes in PACS1 neurodevelopmental disorder
Children-Agent Interaction For Assessment and Rehabilitation: From Linguistic Skills To Mental Well-being
Socially Assistive Robots (SARs) have shown great potential to help children in therapeutic and healthcare contexts. SARs have been used for companionship, learning enhancement, social and communication skills rehabilitation for children with special needs (e.g., autism), and mood improvement. Robots can be used as novel tools to assess and rehabilitate children’s communication skills and mental well-being by providing affordable and accessible therapeutic and mental health services. In this talk, I will present the various studies I have conducted during my PhD and at the Cambridge Affective Intelligence and Robotics Lab to explore how robots can help assess and rehabilitate children’s communication skills and mental well-being. More specifically, I will provide both quantitative and qualitative results and findings from (i) an exploratory study with children with autism and global developmental disorders to investigate the use of intelligent personal assistants in therapy; (ii) an empirical study involving children with and without language disorders interacting with a physical robot, a virtual agent, and a human counterpart to assess their linguistic skills; (iii) an 8-week longitudinal study involving children with autism and language disorders who interacted either with a physical or a virtual robot to rehabilitate their linguistic skills; and (iv) an empirical study to aid the assessment of mental well-being in children. These findings can inform and help the child-robot interaction community design and develop new adaptive robots to help assess and rehabilitate linguistic skills and mental well-being in children.
What's wrong with the prosopagnosia literature? A new approach to diagnosing and researching the condition
Developmental prosopagnosia is characterised by severe, lifelong difficulties when recognising facial identity. Most researchers require prosopagnosia cases exhibit ultra-conservative levels of impairment on the Cambridge Face Memory Test before they include them in their experiments. This results in the majority of people who believe that they have this condition being excluded from the scientific literature. In this talk I outline the many issues that will afflict prosopagnosia research if this continues, and show that these excluded cases do exhibit impairments on all commonly used diagnostic tests when a group-based method of assessment is utilised. I propose a paradigm shift away from cognitive task-based approaches to diagnosing prosopagnosia, and outline a new way that researchers can investigate this condition.
How can we shift research culture to drive Credibility in Neuroscience?
This webinar will demonstrate changes that are already happening at individual, institutional and funder level to shift research culture toward supporting credible research, and will allow attendees working in neuroscience to ask further questions to our speakers. Our panel of speakers, chaired by Ana Dorrego-Rivas: Emily Farran, Professor in Developmental Psychology and Academic Lead Research Culture and Integrity at the University of Surrey Rosa Sancho, Head of Research at Alzheimer's Research UK Sepideh Keshavarzi, Senior Research Fellow at the Sainsbury Wellcome Centre
Developmental disorders of presynaptic vesicle cycling - Synaptotagmin-1 and beyond
Post-diagnostic research on rare genetic developmental disorders presents new opportunities (and a few challenges) for discovery neuroscience and translation. In this talk, Kate will describe and discuss neurodevelopmental phenotypes arising from rare, high penetrance genomic variants which directly influence pre-synaptic vesicle cycling (SVC disorders). She will focus on Synaptotagmin-1 Associated Neurodevelopmental Disorder (also known as Baker Gordon Syndrome), first described in 2015 and now diagnosed in more than 50 children and young people worldwide. She will then present work-in-progress by her group on the neurodevelopmental spectrum of SVC disorders more broadly, and discuss opportunities for collaborative neuroscience which can bridge the gaps between genetic cause and complex neurological, cognitive and mental health outcomes.
Baby steps to breakthroughs in precision health in neurodevelopmental disorders
Myelin Formation and Oligodendrocyte Biology in Epilepsy
Epilepsy is one of the most common neurological diseases according to the World Health Organization (WHO) affecting around 70 million people worldwide [WHO]. Patients who suffer from epilepsy also suffer from a variety of neuro-psychiatric co-morbidities, which they can experience as crippling as the seizure condition itself. Adequate organization of cerebral white matter is utterly important for cognitive development. The failure of integration of neurologic function with cognition is reflected in neuro-psychiatric disease, such as autism spectrum disorder (ASD). However, in epilepsy we know little about the importance of white matter abnormalities in epilepsy-associated co-morbidities. Epilepsy surgery is an important therapy strategy in patients where conventional anti-epileptic drug treatment fails . On histology of the resected brain samples, malformations of cortical development (MCD) are common among the epilepsy surgery population, especially focal cortical dysplasia (FCD) and tuberous sclerosis complex (TSC). Both pathologies are associated with constitutive activation of the mTOR pathway. Interestingly, some type of FCD is morphological similar to TSC cortical tubers including the abnormalities of the white matter. Hypomyelination with lack of myelin-producing cells, the oligodendrocytes, within the lesional area is a striking phenomenon. Impairment of the complex myelination process can have a major impact on brain function. In the worst case leading to distorted or interrupted neurotransmissions. It is still unclear whether the observed myelin pathology in epilepsy surgical specimens is primarily related to the underlying malformation process or is just a secondary phenomenon of recurrent epileptic seizures creating a toxic micro-environment which hampers myelin formation. Interestingly, mTORC1 has been implicated as key signal for myelination, thus, promoting the maturation of oligodendrocytes . These results, however, remain controversial. Regardless of the underlying pathophysiologic mechanism, alterations of myelin dynamics, depending on their severity, are known to be linked to various kinds of developmental disorders or neuropsychiatric manifestations.
Social Curiosity
In this lecture, I would like to share with the broad audience the empirical results gathered and the theoretical advancements made in the framework of the Lendület project entitled ’The cognitive basis of human sociality’. The main objective of this project was to understand the mechanisms that enable the unique sociality of humans, from the angle of cognitive science. In my talk, I will focus on recent empirical evidence in the study of three fundamental social cognitive functions (social categorization, theory of mind and social learning; mainly from the empirical lenses of developmental psychology) in order to outline a theory that emphasizes the need to consider their interconnectedness. The proposal is that the ability to represent the social world along categories and the capacity to read others’ minds are used in an integrated way to efficiently assess the epistemic states of fellow humans by creating a shared representational space. The emergence of this shared representational space is both the result of and a prerequisite to efficient learning about the physical and social environment.
Targeting alternative splicing of SYNGAP1 using antisense oligonucleotides
Development and evolution of neuronal connectivity
In most animal species including humans, commissural axons connect neurons on the left and right side of the nervous system. In humans, abnormal axon midline crossing during development causes a whole range of neurological disorders ranging from congenital mirror movements, horizontal gaze palsy, scoliosis or binocular vision deficits. The mechanisms which guide axons across the CNS midline were thought to be evolutionary conserved but our recent results suggesting that they differ across vertebrates. I will discuss the evolution of visual projection laterality during vertebrate evolution. In most vertebrates, camera-style eyes contain retinal ganglion cell (RGC) neurons projecting to visual centers on both sides of the brain. However, in fish, RGCs are thought to only innervate the contralateral side. Using 3D imaging and tissue clearing we found that bilateral visual projections exist in non-teleost fishes. We also found that the developmental program specifying visual system laterality differs between fishes and mammals. We are currently using various strategies to discover genes controlling the development of visual projections. I will also present ongoing work using 3D imaging techniques to study the development of the visual system in human embryo.
Learning-to-read and dyslexia: a cross-language computational perspective
How do children learn to read in different countries? How do deficits in various components of the reading network affect learning outcomes? What are the consequences of such deficits in different languages? In this talk, I will present a full-blown developmentally plausible computational model of reading acquisition that has been implemented in English, French, Italian and German. The model can simulate individual learning trajectories and intervention outcomes on the basis of three component skills: orthography, phonology, and vocabulary. I will use the model to show how cross-language differences affect the learning-to-read process in different languages and to investigate to what extent similar deficits will produce similar or different manifestations of dyslexia in different languages.
Functional and translational implications of A-to-I editing in brain development and neurodevelopmental disorders
SCN8A (Nav1.6) and DEE: mouse models and pre-clinical therapies
SCN8A encodes a major voltage-gated sodium channel expressed in CNS and PNS neurons. Gain-of-function and loss-of-function mutations contribute to human disorders, most notably Developmental and Epileptic Encephalophy (DEE). More than 600 affected individuals have been reported, with the most common mechanism of de novo, gain-of-function mutations. We have developed constitutive and conditional models of gain- and loss- of function mutations in the mouse and characterized the effects of on neuronal firing and neurological phenotypes. Using CRE lines with cellular and developmental specificity, we have probed the effects of activating mutant alleles in various classes of neurons in the developing and adult mouse. Most recently, we are testing genetic therapies that reduce the expression of gain-of-function mutant alleles. We are comparing the effectiveness of allele specific oligos (ASOs), viral delivery of shRNAs, and allele-specific targeting of mutant alleles using Crispr/Cas9 in mouse models of DEE.
Odd dynamics of living chiral crystals
The emergent dynamics exhibited by collections of living organisms often shows signatures of symmetries that are broken at the single-organism level. At the same time, organism development itself encompasses a well-coordinated sequence of symmetry breaking events that successively transform a single, nearly isotropic cell into an animal with well-defined body axis and various anatomical asymmetries. Combining these key aspects of collective phenomena and embryonic development, we describe here the spontaneous formation of hydrodynamically stabilized active crystals made of hundreds of starfish embryos that gather during early development near fluid surfaces. We describe a minimal hydrodynamic theory that is fully parameterized by experimental measurements of microscopic interactions among embryos. Using this theory, we can quantitatively describe the stability, formation and rotation of crystals and rationalize the emergence of mechanical properties that carry signatures of an odd elastic material. Our work thereby quantitatively connects developmental symmetry breaking events on the single-embryo level with remarkable macroscopic material properties of a novel living chiral crystal system.
Developmental experience of scarcity affects adult responses to negative outcomes and uncertainty
COSYNE 2022
Alignment of ANN Language Models with Humans After a Developmentally Realistic Amount of Training
COSYNE 2023
Complex computation from developmental priors
COSYNE 2023
Developmentally structured coactivity and plasticity in the hippocampal trisynaptic loop
COSYNE 2023
Adenosine and astrocytes determine the developmental dynamics of spike timing-dependent plasticity in the somatosensory cortex
FENS Forum 2024
Adult cortical and hippocampal network dynamics in p.A263V Scn2a mouse model of developmental and epileptic encephalopathy
FENS Forum 2024
The asymmetric brain: Utilizing hyper-gravity to manipulate developmental symmetries
FENS Forum 2024
Is bigger always more? – Investigating developmental changes in non-symbolic number comparison
FENS Forum 2024
Central role of the habenulo-interpeduncular system in the neurodevelopmental basis of susceptibility and resilience to anxiety
FENS Forum 2024
Cerebellar alteration in a mouse model of GRIN2D-related developmental and epileptic encephalopathies
FENS Forum 2024
Characterization of a novel mouse model for CHD2-related neurodevelopmental disorder
FENS Forum 2024
Characterization of the pathophysiological mechanisms of KCNQ2-developmental and epileptic encephalopathy (KCNQ2-DEE) in the KV7.2Thr274Met/+ mouse model
FENS Forum 2024
Characterizing human-derived neuronal network using high-density MEAs and proteomics: In-vitro model for neurodevelopmental disease
FENS Forum 2024
Chronic exposure to glucocorticoids during critical neurodevelopmental periods leads to lasting shifts in neuronal type distribution and overall brain architecture
FENS Forum 2024
Chronodisruption during early developmental stages affects clock in the SCN in a sex-dependent manner via melatonin-independent signaling pathways
FENS Forum 2024
Clinical features of SYT1-associated neurodevelopmental disorder correlate with functional defects in evoked neurotransmitter release
FENS Forum 2024
Combined bulk transcriptomics reveals a neurodevelopmental signature in the Alzheimer’s disease postmortem brain
FENS Forum 2024
Cracking the code: How early brain asymmetry foretells neurodevelopmental futures
FENS Forum 2024
Critical fear: Developmental trajectories of traumatic life experiences during specific sensitive periods
FENS Forum 2024
Deciphering developmental-aging mechanisms in cell culture: Aberrant ADNP cytoplasmic-nuclear crosstalk and NAP (davunetide) protection
FENS Forum 2024
Deciphering the neurodevelopmental role of the brain secretome in Autism Spectrum Disorder
FENS Forum 2024
Decoding the developmental vulnerability to psychiatric disorders: Investigating the sexual dimorphism and role of perineuronal nets in habenulo-interpeduncular-system-mediated susceptibility to anxiety
FENS Forum 2024
Decreased synaptic GABAergic inhibition in the dentate gyrus of a mouse model of the neurodevelopmental disorder BBSOAS
FENS Forum 2024
Developmental alteration of astrocytic Ca2+ signaling mediated by metabotropic glutamate receptors in the olfactory bulb
FENS Forum 2024
Developmental alteration of social behavior in rat model of autism
FENS Forum 2024
Developmental Cajal-Retzius cell death contributes to the maturation of cortical inhibition and somatosensory processing
FENS Forum 2024
Developmental cell death of interneurons and oligodendroglia is required for cognitive flexibility in mice
FENS Forum 2024
Developmental delay in striatal synaptic pruning in lysosomal storage disorders
FENS Forum 2024
Developmental differences in reward-learning and functional connectivity
FENS Forum 2024
The developmental effects of repeated antenatal dexamethasone treatment on ADP-mediated and adenosinergic signaling system in the auditory brainstem of C57BL/6 mice
FENS Forum 2024
Developmental fine-tuning of medial superior olive neurons mitigates their predisposition to contralateral sound sources
FENS Forum 2024
Developmental perturbation of dopamine pathways as a model for schizophrenia
FENS Forum 2024
Developmental and temporal dynamics in cognitive control engagement during explicit learning
FENS Forum 2024
Developmental trajectories of sleep EEG in neurodevelopmental disorders: Does sex matter?
FENS Forum 2024
Dynamic cortical auditory-motor neuronal projections regulate developmental song learning in zebra finches
FENS Forum 2024
Early life stress & the developmental dynamics of hypothalamic neurogenesis
FENS Forum 2024
Early movement restriction affects the acquisition of neurodevelopmental reflexes in rat pups
FENS Forum 2024
Functional characterization of DPYSL5 gene variants involved in neurodevelopmental disorders with brain malformations
FENS Forum 2024
Heterozygosity for neurodevelopmental disorder-associated TRIO variants leads to distinct deficits in neuronal development and function
FENS Forum 2024
Human iPSC-derived neurons to investigate subtype-specific alterations in neurodevelopmental disorders: Our progress on SSADH deficiency
FENS Forum 2024