Postdoctoral Fellowships


2016

Magnetochemogenetics: wireless temporally and spatially precise chemical neuromodulation in a mouse model of autism

Siyuan Rao, Simons Fellow

Laboratories: Polina Anikeeva, Ph.D., Guoping Feng, Ph.D.

Abstract
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.

 

Structural, molecular, and electrophysiological phenotyping of brain organoid models of Rett syndrome

Ritchie Chen, Simons Fellow

Laboratories: Kwanghun Chung, Ph.D.

Abstract
 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.

 

Quantitative Assessment of Socio-Affective Dynamics in Autism Using Interpersonal Physiology

Oliver Wilder-Smith, Simons Fellow

Laboratories: Rosalind Picard, Sc.D.

Abstract
 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.

 

Engineering systems for cell-type-specific transgene expression in wild-type-animals

Lei Jin, Simons Fellow

Laboratories: Robert Desimone, Ph.D., Ian R. Wickersham, Ph.D.

Abstract
 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.

 

Fiber-Based Probes for Depth Specific Electrophysiological Correlation of Cortical Phenotypical Abnormalities in a Mouse Model of Autism

Mehmet Kanik, Simons Fellow

Laboratories: Polina Anikeeva, Ph.D., Gloria Choi, Ph.D.

Abstract
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.

 

Identify KCC2 Enhancers to treat Rett Syndrome

Xin Tang, Simons Fellow

Laboratories: Rudolf Jaenisch, Ph.D., Li-Huei Tsai, Ph.D.

Abstract
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. 

2015

Large-volume nanoscale imaging of synaptic proteins to understand the molecular mechanisms of autism

Jae-Byum Chang, Simons Fellow

Laboratories: Ed Boyden, Ph.D., Guoping Feng, Ph.D.

Abstract
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.

 

Investigating the role of IL17Ra during brain development in autistic model mice

Yeong Shin Yim, Simons Fellow

Laboratories: Gloria Choi, Ph.D., Jun Huh, Ph.D.

Abstract
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.

 

Analysis of CTCF-mediated chromatin organization and function in the molecular etiology of autism

Ashley Watson, Simons Fellow

Laboratories: Li-Huei Tsai, Ph.D.Elly Nedivi, Ph.D.

Abstract
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. 

2014

Investigating the dynamic interactions between brain regions involved in social cognitive processes

Stefano Anzellotti, PhD, Simons Fellow

Laboratories: Rebeca Saxe, Ph.D., Emery N. Brown, M.D., Ph.D.

Abstract
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.

 

Use of CRISPRs for the removal of a spontaneous mutation causing abnormal Autism-like behaviors.

Fernando Bustos, Simons Fellow 

Laboratories: Martha Constantine-Paton, Ph.D., Feng Zhang, Ph.D

Abstract

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.

 

Behavioral and neurological characterization of mice with loss-of-function CHD8 mutation

Ian Slaymaker, Simons Fellow

Laboratories: Feng Zhang, Ph.D., Guoping Feng, Ph.D.

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

 

Single cell resolution optogenetics: development and application to autism functional connectomics

Or Shemesh, Simons Fellow 

Laboratories: Ed Boyden, Ph.D., Martha Constantine-Paton, Ph.D.

Abstract
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.

2013

High-throughput characterization of neural circuit dysfunction in larval zebrafish models of autism

Limor Freifeld, Simons Fellow

Laboratories: Edward Boyden, Ph.D., Hazel Sive, Ph.D.

Abstract
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.

(Grant renewed for second year.)

 

Electrophysiological Correlates of Repetitive Behavior in a Mouse Model of Autism

Ulrich Froriep, Simons Fellow

Laboratories: Polina Anikeeva, Ph.D., Guoping Feng, Ph.D.

Abstract

In the current project we strive to correlate repetitive behavior under autistic conditions to the underlying mechanisms in the brain. To deconstruct the circuits involved we develop a novel neural probe architecture followed by its application in a model of autism.

(Grant renewed for second year.)

 

Time course and functional specialization of face processing in Autism: a simultaneous EEG-fMRI investigation

Elizabeth Norton, SCSB Schwinn Family Postdoctoral Fellow

Laboratories: John Gabrieli, Ph.D., Margaret Kjelgaard, Ph.D.

Abstract

My project aims to use simultaneous EEG-fMRI to understand the brain basis of human face processing among individuals with autism spectrum disorders. Combining EEG and fMRI allows us to accurately determine the timing and location of brain activity. Identifying the precise differences in face processing in ASDs could help us better understand the causes of ASDs and lead to more accurate early diagnosis.

(Grant renewed for second year.) 

 

Social affiliation and imitation in the typically developing brain

Lindsey Powell, Simons Fellow 

Laboratories: Rebecca Saxe, Ph.D., Elizabeth Spelke, Ph.D.

Abstract
Currently little is known about the organization of the social brain in infancy and early childhood, but understanding the neural substrates that support the typical development of social behavior will provide a necessary guide when investigating the neural bases of deficits in basic social behaviors. I plan to study the typical development of the neural systems that process socially relevant information (e.g. affiliation) and actions (e.g. social mimicry) using functional neuroimaging techniques (fNIRS and fMRI) with infants and children.

(Grant renewed for second year.)

 

Understanding CNVs and autism: genetic interactions of the 16p11.2 region

Bradley Carter, Simons Center Fellow

Laboratories: Hazel Sive, Ph.D., Steven Haggarty, M.D.

Abstract
Recent work in autism genetics has found significant associations between autism spectrum disorders (ASD) and copy number variants (CNVs). CNVs are genomic regions that can containing multiple genes and vary in their expression between individuals (ie. instead of standard 2 copies of specific DNA region, deletion (1 copy) or duplication (eg. 3 copies) can occur). Among these CNV associations, the 16p11.2 CNV has one of the highest correlations with ASD. I am investigating the role of genetic interactions of 16p11.2 genes in brain physiology and behavior using the zebrafish.

(Grant renewed for second year.)

 

Comprehensive structural and molecular phenotyping of mouse models for Rett syndrome

Sung-Yon Kim, Simons Fellow

Laboratories: Kwanghun Chung, Ph.D.

Abstract
In the Chung lab, Sung-Yon is developing novel methods for rapid extraction of system-wide structural, molecular and genomic information from intact brain and applying them to understand function and dysfunction of the neural network at a global perspective.

(Grant renewed for second year.)

 

Optogenetic dissection of the neural circuitry underlying social interaction

Gillian Matthews, Simons Fellow

Laboratories: Kay Tye, Ph.D., Mark Bear, Ph.D.

Abstract
My project focuses on elucidating the role of a subset of dopamine neurons in social behavior. I am employing optogenetics, freely-moving behavior, and in vivo and ex vivo electrophysiology to dissect this population at the neural circuit level, and investigate synaptic changes underlying social interaction.

(Grant renewed for second year.)

 

Super-Resolution Imaging of Synaptic Proteins and their Roles in Synaptic Plasticity

Philipp S. Stawski, Simons Fellow

Laboratories: Alice Y. Ting, Ph.D., Xiaowei Zhuang, Ph.D.

Abstract
In order to gain a better understanding of the molecular processes involved in memory and learning in both healthy and dysfunctional synapses, we will map the nanoscale localization of key synaptic proteins such as AMPA and NMDA receptors and monitor their dynamics during plasticity events building on advances in fluorophore ligation and superresolution imaging techniques. We will then address how mutations of specific synaptic proteins such as neuroligins, which have been linked to autism spectrum disorder, influence the nanoscale “landscape” of excitatory synapses.

2012

Discovering the neural circuit responsible for social behavior in mice

Boaz Barak, Ph.D., Simons Fellow

Laboratories: Guoping Feng, Ph.D., Weifeng Xu, Ph.D.

Abstract
Social interaction deficit is a hallmark symptom of Autism spectrum disorders, although only little is known about the neural circuitry mechanisms responsible for that deficit. Combining genetic, optogenetics, electrophysiological and behavioral approaches, I plan to define the brain regions and neural circuits responsible for social interactions using conditional knockout mice that present social abnormalities.

(Grant renewed for second year.)

 

Characterization of Shank function in drosophila

Kathryn Harris, Simons Fellow 

Laboratories: Troy Littleton, M.D, Ph.D., Guoping Feng, Ph.D.

Abstract
Shank is a well-characterized synaptic scaffolding molecule that is proposed to organize postsynaptic architecture. Along with several other genes that are involved in synaptic assembly and organization, SHANK has been linked to autism in genetic studies. I propose to mutagenize Shank in Drosophila and use this model to answer key questions about the mechanisms by which Shank regulates synaptic function and development.

(Grant renewed for second year.)

 

Molecular tuning of Wnt signaling by the Autism-associated gene CHD8

Yea Jin Kaeser-Woo, Simons Fellow

Laboratories: Li-Huei Tsai, Ph.D., Hazel Sive, Ph.D.

Abstract
My research will determine how dysregulation of Wnt signaling contributes to autism spectrum disorders (ASDs). Recently, Chromodomain Helicase DNA-binding 8 (CHD8), a down-regulator of Wnt-β-catenin signaling, has been identified as an ASD risk factor. I will focus on investigating the molecular mechanisms by which CHD8 controls Wnt signaling during neural development and disease.

(Grant renewed for second year.)

 

Learning by doing: A longitudinal investigation into the relationship between early exploratory play behaviors and developmental disorders

Paul Muentener, Simons Fellow

Laboratories: Laura Schulz, Ph.D., Emily Feinberg, Sc.D.

Abstract
As a Simons Postdoctoral Fellow, Paul investigates individual differences in infants’ exploratory play behaviors (e.g. rate of habituation, sustained exploration, perseveration, inductive inference, pedagogical imitation, face preference) and whether they can facilitate early detection and diagnosis of developmental disorders such as autism and other cognitive impairments.

(Grant renewed for second year.)

 

Using Genome Engineering to Model Angelman Syndrome: Creation of human cell models of autism

Neville Sanjana, Simons Fellow

Laboratories:  Feng Zhang, Ph.D., Guoping Feng, Ph.D.

Abstract
Genome engineering in human pluripotent stem cells using TAL effectors to and differentiation into neuronal subtypes.

(Grant renewed for second year.)

 

Three-dimensional Microelectrode Recording of Neural Circuit Dynamics in Autistic Model Mice

Jorg Scholvin, Simons Fellow

Laboratories: Ed Boyden, Ph.D., Guoping Feng, Ph.D.

Abstract
Our project will deploy a novel, scalable 3-D microelectrode recording technology capable of recording extracellular neural activity from thousands of individually chosen sites in the mouse brain. Using mice carrying the Shank3B mutant gene, which results in autism-like mice, we will apply our technology to analyze how neural codes and computations differ during social behavior tasks in autism-like mutant and wild-type mice.

(Grant renewed for second year.)

 

Investigating the role of dopamine and stress in social interactions

Romy Wichmnn, Simons Fellow

Laboratories: Kay M. Tye, Ph.D., Li-Huei Tsai, Ph.D.

Abstract
By using an innovative approach integrating cutting-edge optogenetic techniques, pharmacological manipulations and electrophysiological recordings in vivo, we will investigate how dopamine and stress can affect social behaviors. This approach will effectively and successfully allow us to thoroughly analyze fundamental neurobiological principles mediating social interaction and might provide useful information to understand social deficits in humans.

 

Developing TALENs Mediated Genome Engineering Technology in Rodent and Primate Cells for Autism Research

Yang Zhou, Simons Fellow

Laboratories: Guoping Feng, Ph.D., Feng Zhang, Ph.D.

Abstract
We are applying TALE nuclease to manipulate genome of rodent and human pluripotent stem cells for modeling of ASDs, and studying the functional consequence after mutation of ASD related genes at cellular, circuit, and systematical level.

(Grant renewed for second year.)