The Laboratory for Computational Neuroscience (Coen-Cagli lab) invites applications for a postdoctoral position at Albert Einstein College of Medicine (Einstein) in the Bronx, New York City. The position is available immediately, it is funded for two years through a NIH training grant to the Rose F. Kennedy IDDRC at Einstein, and targets eligible candidates interested in careers in the biomedical sciences focused on the neurobiological underpinnings of neurodevelopmental disorders associated with intellectual disability and autism. The candidate will have the opportunity learn and apply an integrated approach that leverages innovative experiments and computational modeling of perceptual grouping and segmentation developed by the Coen-Cagli lab, to test theories of sensory processing in autism, in collaboration with the Cognitive Neurophysiology Laboratory (Molholm lab) at Einstein.

The Osterweil lab is recruiting a motivated individual to fill a Wellcome Trust funded postdoctoral position in the Centre for Discovery Brain Sciences at the University of Edinburgh. We are studying mRNA translation in specific neural circuits, and investigating how disruptions lead to autism and intellectual disability. Our work uses cutting-edge molecular techniques, including cell type-specific TRAP-seq, ribosome profiling and single-cell RNA-seq, and combines them with electrophysiology and behavior to assess how circuit-specific changes in translation alter learning in autism models. This approach continues to identify novel therapeutic strategies. The post requires relevant experience in Neuroscience research, with a PhD either obtained or expected within 6 months of the start of the contract. The applicant must have experience with molecular biology and a working knowledge of RNA-seq analysis and/or related bioinformatics processing. This is a full-time post. Interested applicants should send a CV and letters of reference to Emily.osterweil@ed.ac.uk. Lab website: https://www.osterlab.org/

We are looking for a highly motivated individual to join the Neurophotonics lab, University of Florence, as an early postdoctoral researcher. For this position, we aim to investigate common patterns of resting state functional connectivity in two mouse models of autism. The laboratory uses in vivo imaging techniques (including two-photon microscopy, wide-field fluorescence imaging and optogenetics) in mice. The successful candidate will investigate plasticity dynamics in cerebral cortex in genetically modified mice expressing fluorescent indicators of neuronal activity. The approach will be interdisciplinary and will make use of advanced optical imaging methods, like multiphoton microscopy of cortical neurons, behavioural tests, electrophysiology and immunohistochemistry.

The Osterweil lab is recruiting a motivated individual to fill a Wellcome Trust funded postdoctoral position in the Centre for Discovery Brain Sciences at the University of Edinburgh. We are studying mRNA translation in specific neural circuits, and investigating how disruptions lead to autism and intellectual disability. Our work uses cutting-edge molecular techniques, including cell type-specific TRAP-seq, ribosome profiling and single-cell RNA-seq, and combines them with electrophysiology and behavior to assess how circuit-specific changes in translation alter learning in autism models. This approach continues to identify novel therapeutic strategies.

The Osterweil lab is recruiting a motivated individual to fill a postdoctoral position in cellular neuroscience and bioinformatics. You will be joining the exceptional group of scientists in the Centre for Discovery Brain Sciences and the Simons Centre for the Developing Brain at the University of Edinburgh, recently ranked as the 16th best university in the world. You will be working in Edinburgh, one of the world’s most liveable cities with access to world-class cultural activities, UNESCO Heritage sites and unparalleled outdoor experiences. The laboratory’s research sits at the interface of cellular neuroscience and disease, seeking to address the role of mRNA translation in autism-related neurodevelopmental disorders. You will use cutting edge approaches such as TRAP-seq, Ribo-seq and scRNA-seq to discover how alterations in specific neural circuits contribute to disruptions in circuit function and behavior in animal models of autism. This Wellcome Trust funded position will use these approaches to answer critical questions about how ribosome expression changes mRNA translation in hippocampal and cortical circuits, and how this process may be targeted for therapeutic intervention in mouse models of autism. The post requires relevant experience in bioinformatics analysis of RNA-seq datasets, and experience with scRNA-seq datasets is desired. Candidates must have a PhD in cell biology, neuroscience or a related topic either obtained or expected within 6 months of the start of the contract. This is a full-time post, and start date is flexible. Applications will be reviewed on a rolling basis with a soft deadline of Aug 21. Interested applicants should send a CV and letters of reference to Emily.osterweil@ed.ac.uk. Lab website: https://www.osterlab.org/ University of Edinburgh: https://www.ed.ac.uk/ Simons Centre for the Developing Brain: https://www.sidb.org.uk/ Centre for Discovery Brain Sciences: https://www.ed.ac.uk/discovery-brain-sciences Further Reading 1) Thomson SR*, Seo SS*, Barnes SA✝, Louros SR✝, Muscas M, Dando O, Kirby C, Hardingham GE, Wyllie DJA, Kind PC, and Osterweil EK. Cell type-specific translation profiling reveals a novel strategy for treating fragile X syndrome. Neuron. 2017 Aug 2; 95(3):550-563.e5. doi: 10.1016/j.neuron.2017.07.013. 2) Stoppel LJ, Osterweil EK, and Bear MF. The mGluR Theory of fragile X syndrome. Fragile X Syndrome: From Genetics to Targeted Treatment. Willemsen, R. & Kooy, F. (Eds.). Academic Press, 2017. ISBN: 0128045078, 9780128045077. 3) Asiminas A*, Jackson AD*, Louros S†, Till SM†, Spano T, Dando O, Bear MF, Chattarji S, Hardingham GE, Osterweil EK, Wyllie DJA, Wood ER, and Kind PC. Sustained correction of associative learning deficits following brief, early treatment in a rat model of Fragile X Syndrome. Science Translational Medicine. 2019 May 29;11(494). pii: eaao0498. doi: 10.1126/scitranslmed.aao0498.

The laboratory of Silvia De Rubeis, PhD, at the Seaver Autism Center for Research and Treatment in the Department of Psychiatry at the Icahn School of Medicine at Mount Sinai in New York, is seeking an ambitious, creative, and motivated postdoctoral fellow with expertise in neuroscience to study the mechanisms underlying intellectual disability (ID) and autism spectrum disorder (ASD). Dr. De Rubeis’ laboratory aims at translating emerging genetic findings from large-scale genomic studies into functional analyses in cellular and mouse models with the goal of understanding the pathogenic underpinnings of ID and ASD. The laboratory focuses on DDX3X syndrome, a rare genetic disorder associated with ID and ASD, using cellular and animal models. Our team currently includes two postdoctoral fellows, a PhD student, three research associates, one undergraduate student, and three high-school students.

Towards an inclusive enterprise: Development of neuropsychological tools for competence mapping in persons with autism in business contexts. Supervisor SISSA Prof Raffaella Rumiati (rumiati@sissa.it) Co-supervisors Roma Tor Vergata Dr. Maria Rosaria Nappa (maria.rosaria.nappa@uniroma2.it) Dr. Elisa Cavicchiolo (elisa.cavicchiolo@uniroma2.it) Introduction: Most people with an autism spectrum disorder are unemployed or have a low level of employment, often of short duration and underpaid. The literature dedicated to this topic (e.g. Wehman et al., 2017) points out that these people have difficulties in finding a job suited to their skills and keeping it, mainly due to problems associated with their relational functioning and the type of support offered by employment settings. On the other hand, it has been shown that the effectiveness of employment pathways for people with autism is fostered by the presence of individualized plans that take into account the characteristics of these people, including their motivations, preferences and expectations, those of their caregivers and the configuration of the work group. Therefore, as also suggested by the Recommendations published by Autism Europe (2016) and by the Istituto Superiore di Sanità (2023), in order to foster the insertion and inclusion of persons with autism in the world of work, it is necessary, first of all, to develop standardized assessment and monitoring tools that can be referred to all levels of support needs. Objectives: The main objective of the project is to develop and validate tools for the assessment and monitoring of skills useful for the insertion and inclusion of people with autism in the corporate environment. These tools will concern the assessment of task-specific skills (e.g. IT and digital skills) and of executive, transversal and motivational dimensions in persons with autism spectrum disorder. Furthermore, it is planned to record event-related potential (ERP) components that account for differences between persons with autism along the above-mentioned dimensions. Method: The project is based on a multi-informant and multi-method approach. In addition to persons with autism spectrum disorder, caregivers and company contact persons will be involved. A qualitative and quantitative research methodology will be adopted. In particular, interviews and/or focus groups will be conducted with caregivers and company contact persons and psychometric approaches will be used to validate instruments useful for the initial assessment and monitoring of competences. ERPs will be recorded individually and will help to define the cognitive endophenotypes of the persons with autism in the study. Expected results: The results of this project will form the basis for the development of evidence-based best practices oriented towards the creation of inclusive work environments in which the 'autistic brain' can represent an opportunity for the growth and integration of persons with autism with caregivers and company contact persons.

The laboratory of Silvia De Rubeis, PhD, at the Seaver Autism Center for Research and Treatment in the Department of Psychiatry at the Icahn School of Medicine at Mount Sinai in New York, is seeking a postdoctoral fellow with expertise in RNA biology interested in applying their skillset to neuroscience and advance the field of autism and related neurodevelopmental disorders. Dr. De Rubeis’ laboratory aims at translating emerging genetic findings from large-scale genomic studies into functional analyses in cellular and mouse models with the goal of understanding the pathogenic underpinnings of ID and ASD. The laboratory focuses on DDX3X syndrome, a rare genetic neurodevelopmental disorder, using cellular and animal models. Our team currently includes one instructor, two postdoctoral fellows, two PhD students, and one undergraduate student.

We are pleased to announce the opening of a PhD position at INMED (Aix-Marseille University) through the SCHADOC program, focused on the neural coding of social interactions and memory in the cortex of behaving mice. The project will investigate how social behaviors essential for cooperation, mating, and group dynamics are encoded in the brain, and how these processes are disrupted in neurodevelopmental disorders such as autism. This project uses longitudinal calcium imaging and population-level data analysis to study how cortical circuits encode social interactions in mice. Recordings from mPFC and S1 in wild-type and Neurod2 KO mice will be used to extract neural representations of social memory. The candidate will develop and apply computational models of neural dynamics and representational geometry to uncover how these codes evolve over time and are disrupted in social amnesia.

We are looking for a motivated PhD student to join our project "Social Cognition In Silico and In Vivo" (SCIVIS), with proficiency in Dutch of at least B2 level. The research is embedded in a vibrant and interdisciplinary research network. The Center Neuropsychiatry at KU Leuven (Belgium) operates at the crossroads of neurology, psychiatry, and cognitive neuroscience. Through an integrated, interdisciplinary approach, we investigate how brain networks support behavior, emotions, and social interaction, both in neurotypical individuals and in people with neuropsychiatric conditions. The project is conducted in close collaboration with the Research Unit Brain & Cognition at KU Leuven, known for its expertise in experimental psychology and cognitive neuroscience, and the AI Lab of VUB university, Brussels, a leading center in artificial intelligence research. Together, these partners bring complementary strengths to the study of social cognition, linking brain, behavior, and computation. As part of the SCIVIS project, we are looking for a PhD candidate to investigate the neural underpinnings of social cognition using functional brain imaging (fMRI/fNIRS). This cutting-edge initiative bridges neuroscience and artificial intelligence to advance our understanding of social cognition in both neurotypical individuals and those with atypical development, with a particular focus on autism and frontotemporal dementia. The position offers the opportunity to design and carry out behavioral and neuroimaging experiments, and to collaborate closely with computational scientists and experimental psychologists. You will join a dynamic research team and contribute to high-impact science at the interface of neuroscience and AI, with real potential to advance our understanding of the social brain. As a PhD student, you will contribute mostly to the in vivo research package, including: Designing and conducting behavioral and neuroimaging experiments (fMRI and fNIRS) to explore social cognitive functions. Collecting and analyzing imaging data to investigate the brain mechanisms underlying social cognition. Collaborating with a multidisciplinary team and integrating findings with computational modeling efforts. Preparing publications for leading scientific journals and presenting at international conferences.

Thalamic networks, at the core of thalamocortical and thalamosubcortical communications, underlie processes of perception, attention, memory, emotions, and the sleep-wake cycle, and are disrupted in mental disorders, including schizophrenia and autism. However, the underlying mechanisms of pathology are unknown. I will present novel evidence on key organizational principles, structural, and molecular features of thalamocortical networks, as well as critical thalamic pathway interactions that are likely affected in disorders. This data can facilitate modeling typical and abnormal brain function and can provide the foundation to understand heterogeneous disruption of these networks in sleep disorders, attention deficits, and cognitive and affective impairments in schizophrenia and autism, with important implications for the design of targeted therapeutic interventions

Pluripotent cells, including embryonic stem (ES) and induced pluripotent stem (iPS) cells, are used to investigate the genetic and epigenetic underpinnings of human diseases such as Parkinson’s, Alzheimer’s, autism, and cancer. Mechanisms of somatic cell reprogramming to an embryonic pluripotent state are explored, utilizing patient-specific pluripotent cells to model and analyze neurodegenerative diseases.

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

Electroencephalography (EEG) has been thoroughly studied for decades in psychiatry research. Yet its integration into clinical practice as a diagnostic/prognostic tool remains unachieved. We hypothesize that a key reason is the underlying patient's heterogeneity, overlooked in psychiatric EEG research relying on a case-control approach. We combine HD-EEG with normative modeling to quantify this heterogeneity using two well-established and extensively investigated EEG characteristics -spectral power and functional connectivity- across a cohort of 1674 patients with attention-deficit/hyperactivity disorder, autism spectrum disorder, learning disorder, or anxiety, and 560 matched controls. Normative models showed that deviations from population norms among patients were highly heterogeneous and frequency-dependent. Deviation spatial overlap across patients did not exceed 40% and 24% for spectral and connectivity, respectively. Considering individual deviations in patients has significantly enhanced comparative analysis, and the identification of patient-specific markers has demonstrated a correlation with clinical assessments, representing a crucial step towards attaining precision psychiatry through EEG.

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.

Individuals afflicted with certain types of autism spectrum disorder often exhibit impaired cognitive function alongside enhanced emotional symptoms and mood lability. However, current understanding of the pathogenesis of autism and intellectual disabilities is based primarily on studies in the hippocampus and cortex, brain areas involved in cognitive function. But, these disorders are also associated with strong emotional symptoms, which are likely to involve changes in the amygdala and other brain areas. In this talk I will highlight these issues by presenting analyses in rat models of ASD/ID lacking Nlgn3 and Frm1 (causing Fragile X Syndrome). In addition to identifying new circuit and cellular alterations underlying divergent patterns of fear expression, these findings also suggest novel therapeutic strategies.

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.

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.

In the lecture Yvette Roke and Jamie Hoefakker will discuss the positive and negative effects of daily stress on mental health. They will also highlight which characteristics are likely to cause more stress related issues, and why recovery time is very important. They will give an understanding of autism spectrum disorder (ASD) in relation to daily stress and they will discuss the app, SAM the stress autism mate, developed and investigated (SCED design) in co-creation with their patients with ASD.

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.

Proper development of the nervous system depends not only on the inherited DNA sequence, but also on proper regulation of gene expression, as controlled in part by epigenetic mechanisms present in the parental gametes. In this presentation an internationally recognized research advocate explains why researchers concerned about the origins of increasingly prevalent neurodevelopmental disorders such as autism and attention deficit hyperactivity disorder should look beyond genetics in probing the origins of dysregulated transcription of brain-related genes. The culprit for a subset of cases, she contends, may lie in the exposure history of the parents, and thus their germ cells. To illustrate how environmentally informed, nongenetic dysfunction may occur, she focuses on the example of parents' histories of exposure to common agents of modern inhalational anesthesia, a highly toxic exposure that in mammalian models has been seen to induce heritable neurodevelopmental abnormality in offspring born of exposed germline.

Connections between nerve cells called synapses are the fundamental units of communication and information processing in the brain. The accurate wiring of neurons through synapses into neural networks or circuits is essential for brain organization. Neuronal networks are sculpted and refined throughout life by constant adjustment of the strength of synaptic communication by neuronal activity, a process known as synaptic plasticity. Deficits in the development or plasticity of synapses underlie various neuropsychiatric disorders, including autism, schizophrenia and intellectual disability. The Siddiqui lab research program comprises three major themes. One, to assess how biochemical switches control the activity of synapse organizing proteins, how these switches act through their binding partners and how these processes are regulated to correct impaired synaptic function in disease. Two, to investigate how synapse organizers regulate the specificity of neuronal circuit development and how defined circuits contribute to cognition and behaviour. Three, to address how synapses are formed in the developing brain and maintained in the mature brain and how microcircuits formed by synapses are refined to fine-tune information processing in the brain. Together, these studies have generated fundamental new knowledge about neuronal circuit development and plasticity and enabled us to identify targets for therapeutic intervention.

Cognitive and emotional processes are shaped by the dynamic integration of brain and body. A major channel of interoceptive information comes from the heart, where phasic signals are conveyed to the brain to indicate how fast and strong the heart is beating. This talk will discuss how interoceptive processes operate across conscious and unconscious levels to influence emotion and memory. The interoceptive channel is disrupted in distinct ways in individuals with autism and anxiety. Selective interoceptive disturbance is related to symptomatology including dissociation and the transdiagnostic expression of anxiety. Interoceptive training can reduce anxiety, with enhanced interoceptive precision associated with greater insula connectivity following targeted interoceptive feedback. The discrete cardiac effects on emotion and cognition have broad relevance to clinical neuroscience, with implications for peripheral treatment targets and behavioural interventions.

Early in development the nervous system is constructed with far too many neurons that make an excessive number of synaptic connections.  Later, a wave of neuronal remodeling radically reshapes nervous system wiring and cell numbers through the selective elimination of excess synapses, axons and dendrites, and even whole neurons.  This remodeling is widespread across the nervous system, extensive in terms of how much individual brain regions can change (e.g. in some cases 50% of neurons integrated into a brain circuit are eliminated), and thought to be essential for optimizing nervous system function.  Perturbations of neuronal remodeling are thought to underlie devastating neurodevelopmental disorders including autism spectrum disorder, schizophrenia, and epilepsy.  This seminar will discuss our efforts to use the relatively simple nervous system of Drosophila to understand the mechanistic basis by which cells, or parts of cells, are specified for removal and eliminated from the nervous system.

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

Three intimately related dimensions of the mammalian genome—linear DNA sequence, gene transcription, and 3D genome architecture—are crucial for the development of nervous systems. Changes in the linear genome (e.g., de novo mutations), transcriptome, and 3D genome structure lead to debilitating neurodevelopmental disorders, such as autism and schizophrenia. However, current technologies and data are severely limited: (1) 3D genome structures of single brain cells have not been solved; (2) little is known about the dynamics of single-cell transcriptome and 3D genome after birth; (3) true de novo mutations are extremely difficult to distinguish from false positives (DNA damage and/or amplification errors). Here, I filled in this longstanding technological and knowledge gap. I recently developed a high-resolution method—diploid chromatin conformation capture (Dip-C)—which resolved the first 3D structure of the human genome, tackling a longstanding problem dating back to the 1880s. Using Dip-C, I obtained the first 3D genome structure of a single brain cell, and created the first transcriptome and 3D genome atlas of the mouse brain during postnatal development. I found that in adults, 3D genome “structure types” delineate all major cell types, with high correlation between chromatin A/B compartments and gene expression. During development, both transcriptome and 3D genome are extensively transformed in the first month of life. In neurons, 3D genome is rewired across scales, correlated with gene expression modules, and independent of sensory experience. Finally, I examined allele-specific structure of imprinted genes, revealing local and chromosome-wide differences. More recently, I expanded my 3D genome atlas to the human and mouse cerebellum—the most consistently affected brain region in autism. I uncovered unique 3D genome rewiring throughout life, providing a structural basis for the cerebellum’s unique mode of development and aging. In addition, to accurately measure de novo mutations in a single cell, I developed a new method—multiplex end-tagging amplification of complementary strands (META-CS), which eliminates nearly all false positives by virtue of DNA complementarity. Using META-CS, I determined the true mutation spectrum of single human brain cells, free from chemical artifacts. Together, my findings uncovered an unknown dimension of neurodevelopment, and open up opportunities for new treatments for autism and other developmental disorders.

Executive control processes and flexible behaviors rely on the integrity of, and dynamic interactions between, large-scale functional brain networks. The right insular cortex is a critical component of a salience/midcingulo-insular network that is thought to mediate interactions between brain networks involved in externally oriented (central executive/lateral frontoparietal network) and internally oriented (default mode/medial frontoparietal network) processes. How these brain systems reconfigure with development is a critical question for cognitive neuroscience, with implications for neurodevelopmental pathologies affecting brain connectivity. I will describe studies examining how brain network dynamics support flexible behaviors in typical and atypical development, presenting evidence suggesting a unique role for the dorsal anterior insular from studies of meta-analytic connectivity modeling, dynamic functional connectivity, and structural connectivity. These findings from adults, typically developing children, and children with autism suggest that structural and functional maturation of insular pathways is a critical component of the process by which human brain networks mature to support complex, flexible cognitive processes throughout the lifespan.

Our brains must generate and maintain stable activity patterns over decades of life, despite the dramatic changes in circuit connectivity and function induced by learning and experience-dependent plasticity. How do our brains acheive this balance between opposing need for plasticity and stability? Over the past two decades, we and others have uncovered a family of “homeostatic” negative feedback mechanisms that are theorized to stabilize overall brain activity while allowing specific connections to be reconfigured by experience. Here I discuss recent work in which we demonstrate that individual neocortical neurons in freely behaving animals indeed have a homeostatic activity set-point, to which they return in the face of perturbations. Intriguingly, this firing rate homeostasis is gated by sleep/wake states in a manner that depends on the direction of homeostatic regulation: upward-firing rate homeostasis occurs selectively during periods of active wake, while downward-firing rate homeostasis occurs selectively during periods of sleep, suggesting that an important function of sleep is to temporally segregate bidirectional plasticity. Finally, we show that firing rate homeostasis is compromised in an animal model of autism spectrum disorder. Together our findings suggest that loss of homeostatic plasticity in some neurological disorders may render central circuits unable to compensate for the normal perturbations induced by development and learning.

The Hsieh lab focuses on the mechanisms that promote neural stem cell self-renewal and differentiation in embryonic and adult brain. Using mouse models, video-EEG monitoring, viral techniques, and imaging/electrophysiological approaches, we elucidated many of the key transcriptional/epigenetic regulators of adult neurogenesis and showed aberrant new neuron integration in adult rodent hippocampus contribute to circuit disruption and seizure development. Building on this work, I will present our recent studies describing how GABA-mediated Ca2+ activity regulates the production of aberrant adult-born granule cells. In a new direction of my laboratory, we are using human induced pluripotent stem cells and brain organoid models as approaches to understand brain development and disease. Mutations in one gene, Aristaless-related homeobox (ARX), are of considerable interest since they are known to cause a common spectrum of neurodevelopmental disorders including epilepsy, autism, and intellectual disability. We have generated cortical and subpallial organoids from patients with poly-alanine expansion mutations in ARX. To understand the nature of ARX mutations in the organoid system, we are currently performing cellular, molecular, and physiological analyses. I will present these data to gain a comprehensive picture of the effect of ARX mutations in brain development. Since we do not understand how human brain development is affected by ARX mutations that contribute to epilepsy, we believe these studies will allow us to understand the mechanism of pathogenesis of ARX mutations, which has the potential to impact the diagnosis and care of patients.