Postdoctoral Fellowship Research – Simons Center for the Social Brain

Autism spectrum disorders (ASD) are a diverse family of neurodevelopmental conditions that lack any consistent biomarkers to date. The enzyme acetylcholinesterase, which degrades acetylcholine at cholinergic synapses, has been emerging as potential therapeutic target in ASDs, and could serve as synapse-specific biomarker for these disorders. However, probe technologies to correlate AChE activity and ASD remained elusive. This fellowship proposal therefore seeks to design and validate novel AChE-sensitive MRI contrast agents to probe cholinergic phenotypes in ASD models, facilitate therapy development, and ultimately establish a non-invasive diagnostic tool for clinical evaluation of autistic patients. Our approach will use a previously validated molecular mechanism developed in the Jasanoff lab to image brain enzyme activity in animal models. Furthermore, these new contrast agents will be designed to facilitate probing AChE activity via multimodal imaging in addition to MRI. This added feature will permit valuable integration of readouts obtained over a range of spatial scales, both in living subjects and postmortem tissue. In concert, this proposed work promises to yield an innovative and important tool for autism research, with the potential for future extension to evaluation of cholinergic function in human subjects.

Observational learning is the ability to learn about hidden states of the environment through observing others’ experiences. Although behavioral and neural signatures of observational learning have been reported, a mechanistic understanding of its underlying neural computations is lacking. Here, I formulate a computational hypothesis for the problem of observational learning based on the notion of prediction error and test this hypothesis in the non-human primate model by recording from multiple higher-order brain areas in a novel two-player decision-making task. I will use the behavioral and neural data to develop neural network models of observational learning and use model perturbations to characterize potential failure mechanisms that may underlie behavioral impairments in neuropsychiatric diseases such as autism.

Figuring out the desires of others is a crucial, yet complicated act of interpretation. Even seemingly straight-forward utterances like “Can you pass the salt?” can have different possible interpretations (hand the salt to you or am I physically able?). What’s more, our goals and desires factor into how we interpret the ambiguous utterances of others: If I don’t want to pass the salt, I might choose to interpret the question in an unintended way. Misunderstandings and social conflicts crop up when we have the wrong space of possible interpretations, or when the most likely interpretation conflicts with our own goals. Neurotypical children and individuals with autism may face particular challenges in these contexts; they may even be considered non-compliant or unhelpful, when they inadvertently interpreted someone’s request differently than what was expected. My project aims to better understand how we reason about other people’s goals and trade-off between our own and others’ needs to decide whether or how to comply with others’ requests. The insights derived from the models and experiments in this proposal will deepen our understanding and potentially provide avenues for intervention on both those with autism and their social partners to improve communication and social connection.

Individuals with autism can experience sensory overload, a state of panic induced by excessive sensory inputs such as repetitive sounds, light, and touch. In neurotypicals, the brain suppresses constant or repetitive stimuli. Sensory overload may result from a lack of this habituation. Our model of brain function suggests sensory input is carried by brain rhythms know as gamma, which are primarily found in the upper layers of the cortex. In contrast, alpha/beta rhythms are predominantly found in deeper layers and can suppress gamma rhythms. Deficient alpha/beta rhythms have been reported in autism. We hypothesize this deficient alpha/beta may be the cause of disrupted habituation and therefore sensory overload in autism.
These theories of brain function are based on observed correlations and lack tests of
causality that directly manipulate brain circuitry. We have developed a technique to selectively shut down neurons in upper or deep layers of cortex. We believe we can simulate sensory overload in rhesus monkeys by suppressing neurons in deep layers of rhesus monkeys. This is predicted to decrease alpha/beta activity and thus increase gamma activity and processing of sensory inputs. This will directly test a hypothesized mechanism of sensory overload, perhaps leading research towards improved symptom management.

Human Accelerated Regions (HAR) are recently identified DNA sequences that underwent unique changes in the human evolution. HARs can control gene expression and mutations in HARs are associated to the risk of neurodevelopmental disorders including autism. Despite of their importance, the function of HARs have remained largely uncharted. Here, I propose to develop a new method to screen the gene regulatory functions of hundreds of HARs simultaneously by assigning each HAR with unique barcodes, which can be read by sequencing. Using the platform of human brain organoids, human stem cell-derived 3D tissue cultures that resemble the embryonic brain, I will characterize the regulatory roles of HARs in brain development.
Finally, for candidate HARs with strong association to autism risk, I will use genomic editing to introduce specific mutation or delete the HAR sequence, and generate brain organoids to analyze the changes caused by the editing. Together, my proposed study will be a substantial technological advance for the field, and provide instrumental knowledge for better understanding human brain development and the etiology of autism.

Autism spectrum disorder is a common neurodevelopmental disorder that is highly heritable; now, via large scale genome sequencing initiatives, we are beginning to gain a clearer understanding for the genetic basis of the disorder. Despite this increase in genetic information, it is too costly and time consuming to validate each purported genetic mutation using traditional transgenic animal models and, even if proven, we have no means of correcting the gene mutation in patients in vivo. Advances in genome engineering have enabled precision gene editing but, to date, there is no tool able to seamlessly replace DNA in the postnatal human. One potential solution is to repurpose retrotransposons, an abundant and diverse class of naturally occurring genetic elements that efficiently insert large amounts of genetic material into their host—retrotransposons are so efficient that these insertion events compose over half of the human genome. My goal is to re-engineer this highly effective gene insertion machinery to mediate large-scale, site-specific genomic rearrangements in mammalian cells. Ultimately, a technology that efficiently inserts DNA into specific genomic loci could be used to rapidly study the effects of autism-associated genomic mutations, and may eventually be harnessed to reverse genomic mutations in patients with the disorder.

Currently, most methods exploring the CRISPR/Cas system for gene therapy are based on correcting genetic mutations in DNA through homology-directed recombination (HDR) or base editing. We chose to focus on RNA-based approaches because these methods do not generate breaks/nicks or changes in the DNA sequences, a significant safety concern for gene therapy. We propose to develop and test the effectiveness of Cas13-based RNA editing as a means of gene therapy targeting Rett Syndrome.

We propose a holistic and multi-scale molecular and structural interrogation of human induced pluripotent stem cell (iPSC)-derived cortical organoids at different stages of differentiation, with a particular interest in the cytoarchitecture of subplate and deep cortical layers, where Rett syndrome (RTT) related protein methyl-CpG-binding protein 2 (MeCP2) is highly expressed during early corticogenesis. Our study will be the first to dissect the neuronal diversity at single-cell resolution in various regions in the whole intact organoid culture, including subplate and deep cortical layers. In addition, we plan to generate cortical organoids from RTT patient-derived iPSC line harboring mutant MECP2 copy (MUT) and the isogenic control iPSC line (WT), respectively. We will employ the multi-scale volumetric phenotyping pipeline to characterize both WT and MUT organoids at different stages of differentiation. We aim to examine the molecular and cellular mechanisms of how the MECP2 mutation may be linked to corticogenesis.

Interacting with others is fundamental to everyday human life, and the importance of successfully perceiving and thinking about the social world is underscored by the devastating effects of impairment of these abilities in disorders such as Autism Spectrum Disorder (ASD). Given the importance of the social world, it is perhaps not surprising then that the brain contains a host of regions dedicated to interpreting social information (i.e., the “social brain”). Although the social brain is increasingly well studied in adults, almost nothing is known about how it develops. My project therefore aims to establish fundamental principles of social brain development using neuroimaging techniques in typically developing children. Understanding the typical development of the social brain is a fundamental step toward understanding how such development goes awry in developmental disorders like ASD.

Autism Spectrum Disorders (ASD) is characterized by impaired social communicational skills and restricted repetitive interests. One fascinating yet understudied phenotype of ASD is a rational, consistent and biasfree evaluation of information compared to healthy controls. While altered social cognition in ASD is typicallyconsidered a deficit, ASD Hyper-Rationality may confer distinctive strengths. A mechanistic understanding of ASD Hyper-Rationality may reveal how neurobiological differences in ASD relate to both difficulties and strengths. Here, I propose to elucidate the neurobiological basis of hyper-rationalism in ASD, by probing a putative reduction of the optimistic bias in ASD. The optimistic bias refers to the underestimation of one’s chances to experience a negative event, and overestimation of one’s chances for a positive event. TD individuals strikingly maintain their optimistic view by rejecting unfavorable future-related information, but ASD individuals integrate information equally, regardless of its favorability, displaying a lack of optimistic bias. I will use neuroimaging to test the hypothesis that differences in reward-related neural systems are related to more rational reasoning in ASD. This would be the first mechanistic link between ASD hyperrationality and altered neural processes.

Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by impaired social interaction and communication, as well as the presence of repetitive behaviors and restricted interests. It has been suggested that individuals with ASD are less able than typically-developing (TD) individuals to predict events and optimize their behavior based on predictions. Here, I propose to test the hypothesis that adults with ASD show reduced neural adaptation across multiple domains. Neural adaptation could be a brain mechanism that supports prediction by differentiating between repeating and novel events. Neural adaptation impairments are thought to contribute to multiple psychiatric and neurodevelopmental disorders, including schizophrenia and dyslexia, and reduced neural adaptation is associated with increased symptom severity in ASD. This research aims to test the scope and limits of the hypothesized deficit in neural adaptation, probe the mechanism of reduced adaptation, and examine the dimensional relation of neural adaptation to ASD traits in both typically-developing adults and adults with autism regardless of diagnosis. This research is of theoretical and practical importance as the prevalence of ASD is estimated at 1:68 and rising, and neural mechanisms underpinning ASD have yet to be identified. Given the pervasiveness of neural adaptation deficits across neurodevelopmental disorders, identifying mechanisms and behavioral correlates of neural adaptation could inform future trans-diagnostic clinical treatments.

Individuals with autism have reduced interest in social engagement. The social motivation hypothesis suggests that decreased motivation to participate in social interactions in infants with ASD causes them to spend less time attending to and learning from social stimuli, resulting in a wide range of social difficulties later in life. Consistent with this idea, successful early behavioral interventions rely on reinforcement of typical social behaviors. Although the neural mechanisms underlying social dysfunction have been studied in mouse models, extending these studies to primate models should further our understanding of human social function and dysfunction due to the similarity in brain structure and function between humans and primates. This project will seek to develop a behavioral paradigm to measure the value of natural social interactions between freely moving marmosets by giving animals the option to interact with a conspecific. Once this paradigm has been developed, we will record neural activity from the midbrain dopamine neurons of these animals, which are known to provide an important motivational signal guiding attention and behavior. Eventually, understanding whether social reward signals are absent or abnormal in ASD model animals will be essential to understanding these disorders as well as to the design of behavioral therapies.

Social brain disorders affect up to 20% of the US population and comprise huge personal, family and economic burdens. The genetic basis for these disorders is complex, making diagnostics unreliable and personalized treatments unavailable. We will address this challenge with a new approach to identify molecular changes in 16p11.2 deletion syndrome patients. In this prevalent syndrome (occurring in 1 in 2000 individuals) part of chromosome 16 is lost, encompassing 25 genes. Deletion leads to severe brain symptoms including autism, intellectual disability and epilepsy. We hypothesize that the biochemistry (‘metabolome’) of brain cells (neurons) is abnormal in people with 16p11.2 deletion syndrome and that this contributes to symptoms observed. Using state-of-the-art metabolite profiling, we will examine the biochemistry of neurons derived from 16p11.2 deletion patient cells compared to unaffected sibling neurons. Neurons will be obtained from stem cells available through the Simons VIP Collection. We will further test whether three enzymes encoded by 16p11.2 genes are key contributors to metabolic changes, and to abnormal behaviors, using an animal model (zebrafish). The groundbreaking novel information obtained will inform treatment of 16p11.2 syndrome and set precedent for new ways to analyze multiple mental health disorders.

Shank3 is a major postsynaptic scaffolding protein of glutamatergic synapses in the central nervous system. It organizes a wide variety of synaptic proteins into a functional assembly called postsynaptic density (PSD), which is critical for synaptic transmission and plasticity. Shank3 dysfunction leads to severe human neurodevelopmental and psychiatric disorders including autism spectrum disorder (ASD), schizophrenia and intellectual disability (ID). However, the underlying pathophysiological mechanisms regarding SHANK3 mutations are largely unknown. In our preliminary studies, we discovered that Shank3 N-terminal domains bind to a major synaptic kinase named CaMKIIα, which is critical for synaptic plasticity regulation and brain’s functions as learning and memory. We also found that a SHANK3 N-terminal mutation identified in human ASD patients largely compromises Shank3-CaMKIIα interaction. In this proposed project, we will characterize the functional impact of Shank3-CaMKIIα interaction in mouse brain. We will examine the cellular, electrophysiological and behavioral consequences after disrupting Shank3-CaMKIIα interaction in genetically engineered mouse models. Our study will provide a comprehensive understanding of Shank3-CaMKIIα interaction from the molecular mechanism to physiological function. It will help us to understand why and how mutations impairing Shank3 N-terminus will lead to brain dysfunctions in human ASD patients.

Studies of sensory systems in genetic models of autism have paved the way for understanding the effects of genetic changes on synaptic transmission and single neuron responses. But how these neuronal-level changes produce network-level disruptions in the cognitive processes associated with autism remains largely unexplored. A key component for linking these levels is the integration of different synaptic inputs in the elaborate dendrites of individual neurons. Here, I will examine the contributions of these dendritic computations to network function in a complex associative behaviour. I have developed a novel virtual-reality method that allows us to precisely measure and perturb dendritic activity in mice in an easily trained, yet computationally complex 2d navigation task that provides the complexity required to engage associative cortical circuits, while maintaining all the advantages of head-fixed sensory tasks. By relating dendritic gating mechanisms at the single cell level to a tractable associative computation in mice, the study will bridge cellular-level and network-level mechanisms, providing fundamental new insights into how cellular-level effects of genetic changes in autism spectrum disorders can lead to network level and behavioural phenotypes.

Most animals live in groups organized by social hierarchies. By acting according to their social rank, animals decrease unnecessary aggression and save energy. Although hierarchies are central to successful group dynamics, the neural basis of dominance behaviors remains unknown. Autism spectrum disorders (ASDs) include debilitating social deficits. Many studies have provided evidence linking genes to ASDs behavioral deficits. However, there has been little progress in elucidating the neural circuits that underlie normal social behaviors. Identifying these circuits is crucial for developing targeted molecular therapies for ASDs patients. Mouse models of ASDs show deficits in ultrasonic vocalizations and other social behaviors. Mice, like humans in modern societies, have flexible hierarchies in which social rank is not inherited, but earned. These similarities – combined with the vast number of tools for circuit dissection–make mice a good model to investigate the neural dynamics of social hierarchy. Crossn species evidence suggests that the medial prefrontal cortex (mPFC) is crucial for social dominance behaviors. Given the role of the lateral hypothalamus (LH) in social behaviors, and its connectivity with the mPFC, it is well positioned to modulate social behaviors in a rankn dependent manner. By combining freely moving calcium imaging, optogenetic manipulations, and novel social assays, I will investigate the role of the mPFC to LH pathway in the appropriate expression of dominance behavior.

A neuromodulator, oxytocin, has been implicated in multiple social behaviors and social deficits. In particular, our lab has previously shown that the disruption of oxytocin receptor signaling impairs the formation of social memory. Pharmacological or genetic disruption of oxytocin signaling selectively impaired the social learning both with appetitive and aversive social cues, but not with non-social cues, such as food, sucrose, or aversive footshock. These results provided the behavioral evidence for the critical role of oxytocin in social learning. Nevertheless, the neural substrates and physiological mechanisms behind oxytocin-mediated social learning remain unknown. Here, I propose that the piriform inputs delivering the neutral olfactory information converge on accessory olfactory bulbal inputs conveying the US pheromonal information in the medial amygdala (MeA) and the plasticity at this locus during social learning is gated by oxytocin signaling. These studies will not only delineate a novel
neural circuitry mediating social learning, but also will provide new insights into the regulatory role of the oxytocin neuromodulatory system in social behavior and memory formation.

In addition to core symptoms of social communication deficits and repetitive behavior/restricted interest, individuals with autism spectrum disorder (ASD) experience a wide range of other symptoms including aggression, an extremely challenging social disruption. Unfortunately aggression in the context of ASD is poorly understood due to a lack of good models. To address this gap, we will use a mouse model based on a mutation that contributes to 1% of ASD cases and leads to hyper-aggression in these people. Importantly, this increased aggression is also seen in the mutant mouse model. We will test where in the brain this gene is required for normal levels of aggression. We will also remove and restore expression of this gene at different timepoints to determine when it is possible to rescue aggressive behaviors. Together our results will for the first time identify a target brain region and a target time window for designing and testing therapies for aggression in ASD and other disorders.

As is consistent with the pathology observed in autism spectrum disorder (ASD) human patients, ASD rodent models frequently exhibit compulsive/repetitive behaviors, which hinder neuromodulation approaches that rely on invasive implantable devices. Since these models (e.g. Shank3-/- mice) are unusually sensitive to foreign implant objects, the behavioral observation and ASD circuitry investigation in these models may be altered by the implantation of optogenetic and electrical neuromodulation devices. In this proposed study, we will develop a minimally invasive neuromodulation tool for magnetothermal deep brain interrogation of neural circuitry in freely moving rodents. This approach will enable temporally and spatially precise chemical manipulation of neural activity by local release of designer drugs in response to remote exposure to alternating magnetic fields. We will achieve the implant -free convenience of magnetothermal neuromodulation together with the genetic prec ision of chemogenetics, and thus enable spatial and temporal modulation for behavioral investigation in ASD rodent models. We anticipate the magnetochemogenetics tool developed in this study will prove a powerful method for localized neural modulation and facilitate the investigation of circuits contributing to ASD-like phenotypes.

Rett Syndrome (RTT) is a devastating neurodevelopmental disease with motor, developmental, and social dysfunctions. RTT is caused by mutations to a single X-linked gene that encodes the protein methyl CpG binding protein 2 (MeCP2). Because MeCP2 functions to both activate and repress many target genes, loss of function of this single protein has broad effects on neural circuitry. While structural and neural specific features induced by MeCP2 mutations have been linked to behavioral abnormalities, detailed molecular understanding is lacking by our inability to identify substrates of MeCP2 in specific neurons. My proposed research goal is to use novel mapping techniques developed in our lab—which can provide comprehensive structural and molecular profiling of the whole brain—to gain detailed molecular insight into the function of MeCP2 and its effects on RTT pathogenesis. Instead of traditional rodent models, I plan to use brain-like tissue, called brain organoids, derived directly from RTT patients to more faithfully recapitulate disease phenotypes and to increase throughput due to its facile scalability. Furthermore, I plan to grow brain organoids on a dish to screen for therapeutic compounds while monitoring disease progression over space and time.

Individuals with Autism Spectrum Disorder (ASD) often have great difficulty interpreting and using nonverbal communication, understanding and navigating social relationships, and making sense of their own and others’ emotions. Many of these impairments can be understood in terms of deficits in social reciprocity – the ability to attend to, predict, and respond appropriately to the mental states of others – and are present in both more severely affected as well as “higher-functioning” individuals with ASD who have little or no cognitive impairment. A key challenge to studying the development of social reciprocity in ASD is that social interactions are fundamentally transactional, taking place within a system rather than in isolation, and that people affect and are affected by their interactions with others. A growing body of work in interpersonal physiology – the study of psychophysiological signals across two or more people – offers a powerful new means for non-invasive ambulatory assessment of affective synchrony and socio-affective dynamics in children with ASD. This proposal aims to further develop, validate, and disseminate tools and methods to enable the use of interpersonal physiological synchrony measures by researchers conducting both basic and translational research into social and affective functioning in ASD.

The optogenetics and genomic engineering revolutions have transformed neuroscience and are empowering major discoveries in neuroscience, but their translational potential is severely limited by the lack of any system capable of causing targeted expression of the required opsins and nucleases in specific types of neurons in human patients. We will use high throughput techniques to produce a set of viral vectors that will allow selective expression of transgenes in specific populations of neurons in the brains of wild-type animals. Along with many other applications, this will allow optogenetic control, recording, and targeted genomic modification of targeted neuronal populations in any species, with no need for production of transgenic or knock-in lines. This will have two transformative results. First, it will provide neuroscience with a versatile and powerful set of tools that will make possible a broad set of new experimental designs that are likely to yield major insights into the organization of the brain. Second, because the new tools are also designed to work in humans, it will allow the direct implementation in human patients of the powerful genetic techniques that are currently used almost entirely only in rodents. This is likely to result in important new therapies for disorders of social cognition and many other mental and neurological diseases.

Social deficits observed in humans with autism spectrum disorder (ASD) are hypothesized to be related to both genes and environment. It has been shown that ASD can be induced by maternal immune activation (MIA) during pregnancy. A recently developed MIA-driven rodent model is a promising research platform, considering that offspring exhibits disorder in social communication, repetitive behaviors, and characteristic phenotypical abnormalities at specific layers of the cortex as is commonly observed in ASD. The correlation between observed social deficits, phenotypical abnormalities at the different layers of cortex, and altered communication between cortical layers and down-stream structures require in vivo electrophysiological measurements and neuromodulation approaches for a better understanding of developmental reasons for ASD. In the proposed study, we will employ a multifunctional fiber-based neural probe design with fine spatial resolution that will allow us to execute optogenetic, electrophysiological and pharmacological experiments at different layers of the cortex simultaneously in freely moving mice. We aim to apply these tools to the development of a dynamic electrophysiological map of the disordered patch structure in a cytokine interleukin- 17a (IL-17a) dependent MIA-driven mouse model of ASD and compare it to the cortex of healthy controls. We anticipate that the optical and electrophysiological approaches identified within this study will find applications in a range of rodent models of ASD thus facilitating the basic study of this heterogeneous group of neurological disorders.

K+/Cl- cotransporter-2 (KCC2) is an essential gene for proper brain function. Rett syndrome (RTT) is a form of autism spectrum disorder that show severe deficits in neuronal function. My previous work has demonstrated that restoration of the decreased KCC2 expression level in RTT neurons lead to recovery of impaired neuronal functions. In this study, we have developed a novel screening platform that utilize gene-targeted KCC2 reporter human neurons to identify compounds that increase the expression of KCC2. We will further test the effectiveness of candidate KCC2 enhancer compounds for treating symptoms in RTT animal models. The results from my proposed study will potentially lead to novel therapeutic strategies that target KCC2 to halt or even reverse the progression of RTT. Furthermore, the KCC2 enhancer compounds identified from human reporter neuron screening and further validated in animal model of RTT may be readily applicable to treating other types of autism spectrum disorders.

I am developing a new super-resolution imaging technique that can image protein architectures over a large volume. I will use this technique to map multiple synaptic proteins over the whole brain in autism-model mice to comprehend the molecular mechanisms underlying ASDs.

Human studies suggest that maternal viral infections early in pregnancy correlate with an increased frequency of ASD in the offspring. However, the neural basis of ASD-like behavioral deficits induced by MIA remains unknown. Currently, I am investigating the role of IL17Ra during brain development in autistic model mice.

Each cell in our body contains approximately two meters of DNA. In order to accommodate such a large amount of genetic information, DNA wraps around histone proteins to form chromatin. Chromatin is folded in a precise way to partition the genome into domains, and within those domains genetic elements called enhancers physically contact gene promoters to control gene expression. The CCCTC-binding factor (CTCF) is a critical protein that mediates DNA contacts. Autism spectrum disorder (ASD) is a complex and heterogeneous group of developmental brain disorders. While ASD affects upwards of 2% of the population, we have a very limited understanding of its underlying causes. Genetic studies of ASD patients indicate that genes encoding proteins involved in DNA packaging and the regulation of gene expression, such as CTCF, are mutated in patients. This suggests that the way the DNA is folded in the nucleus to control gene expression has a profound effect on brain development and susceptibility to ASD, yet our knowledge of how abnormalities in this process contribute to ASD is lacking. Therefore, the purpose of this proposal is to obtain a better understanding of how the genome is folded in human neural progenitor cells to regulate gene expression control and brain development. Moreover, ASD-associated genetic mutations will be introduced into human neural cells using cutting-edge genome editing tools to investigate how specific mutations in CTCF
influence chromatin folding, gene expression, and brain development.

Each cognitive process is the result of computations performed simultaneously and interactively by multiple brain regions. In order to understand the neural mechanisms underlying cognition we need to study 1) how information is processed within individual brain regions and 2) how information flows between regions. I am currently investigating the human ability to acquire knowledge about other people, including recognition of person identity (from faces and voices) and recognition of emotional expressions, in neurotypical and ASD participants. I use fMRI and a combination of multi-voxel pattern analysis (MVPA) and connectivity methods to address questions 1) and 2) above.

My research is focused on a mouse model (Flailer) that shows early birth seizures and ASD-like behaviors caused by a spontaneous recombination event producing an extra gene. The goal of my research is to identify specific brain regions and pathways that are involved in the abnormal behaviors displayed by Flailer. To address this I will make use of CRISPR technology in order to specifically remove this gene in the different brain areas.

Ian is developing and utilizing genome-engineering techniques to study the genetic causes of autism.

To understand the synaptic underpinnings of autism, one must be able to address and read out biological processes at synapses. We are developing a class of optogenetic activators and reporters that can be targeted so as to enable control and readout of individual synapses between identified neurons. These tools will hopefully enable new frontiers in neuroscience and autism research to be addressed, enabling a synapse by synapse comparison of autistic and wild-type brain circuits in model animals.

I am interested in the relation between autism spectrum disorders, aberrant neural circuit development, and neural circuit dysfunction underlying autism-associated behavioral symptoms. To shed light on this relation, I am applying and developing tools for monitoring and manipulating neural activity in larval zebrafish models of autism. Ultimately, my goal is to design high-throughput technologies that will allow characterizing neural circuit deficits in different disease models to identify neural targets for treatment as well as facilitate drug screening.