Simons Center for the Social Brain

SCSB Lunch Series: Ian Wickersham, Ph.D.
2017-08-25 12:00 - 13:00 (America/New_York) | Simons Center Conference Room, Bldg. 46, Room 6011, 43 Vassar Street, Cambridge, MA, 02139, United States
Date: Friday, August 25, 2017
Time: 12:00pm – 1:00pm
Speaker: Ian Wickersham, Ph.D.
Affiliation: Principal Research Scientist, McGovern Institute for Brain Research, MIT
Talk Title: Cell-type-specific transgene expression in wild-type animals using endogenous proteins as skeletons for assembling split transcription factors
Abstract: Cell-type-specific manipulations, such as optogenetic or chemogenetic stimulation and inhibition, are critical for dissecting circuit function and dysfunction, but their use so far has almost entirely been restricted to genetically tractable species, in which genomic engineering – such as the insertion of the Cre gene into the parvalbumin locus – is used to restrict transgene expression to a functionally meaningful cell type of interest. Here we introduce a technology for causing expression of transgenes specifically within targeted cell types in wild-type animals. Engineered binding proteins specific to a targeted endogenous protein are separately fused to the two fragments of a split transcription factor. In the presence of the targeted protein, the fusion proteins bind to single molecules of the targeted protein, reconstituting a functional transcription factor complex which causes transgene expression from an exogenously introduced template.
Here we show that this approach can be used to achieve high expression of transgenes selectively in cells expressing calretinin, a calcium binding protein characteristic of important interneuronal subtypes in cerebral cortex, hippocampus, and other brain structures. Using the directed evolution technique of yeast surface display, we engineered binding proteins specific to calretinin, then constructed genetic fusions of the two binding proteins to various DNA binding domains and transcriptional activation domains. We show that the system is robust and modular, working with a variety of DNA binding domains and activation domains in various configurations. We show that the system can be delivered via adeno-associated viral vectors injected stereotaxically in order to cause targeted expression of EGFP or channelrhodopsin specifically in calretinin-expressing neurons in neocortex and hippocampus of wild-type mice and rats. Using whole-cell recordings in acute brain slices, we show that targeted fluorophore expression can be used to selectively record from the neuronal type of interest and that channelrhodopsin is expressed highly enough to allow optical control of the neurons’ activity.
This represents the first successful cell-type-specific transgene expression within any cortical interneuron subtype in wild-type animals of any species.

SCSB Lunch Series: Ev Fedorenko, Ph.D.
2017-07-07 12:00 - 13:00 | Simons Center Conference Room, Bldg. 46, Room 6011, 43 Vassar Street, Cambridge, MA, 02139, United States
Date: Friday, July 7, 2017
Time: 12:00pm – 1:00pm

Speaker: Ev Fedorenko, Ph.D., Assistant Professor, Department of Psychiatry, HMS; Associate Researcher, MGH; Research Affiliate, Department of Brain and Cognitive Sciences, MIT
Talk title: A search for candidate brain-based biomarkers of autism
Abstract: I will talk about two lines of work aimed at discovering brain-based biomarkers of autism.
1. One of the few replicated functional brain differences between individuals with autism spectrum disorders (ASD) and neurotypical (NT) controls appears to be reduced lateralization of language (e.g., Lindell & Hudry, 2013). However, most prior reports have examined differences between ASD and NT individuals at the group level, making interpretation difficult. Using a validated fMRI measure of language lateralization, which is robust at the individual-subject level (Mahowald & Fedorenko, 2016), we compared the degree of lateralization between 28 ASD participants and pairwise-matched NT participants. ASD participants showed less lateralized language responses (due to more robust right hemisphere activations). We then asked whether reduced language lateralization is an endophenotype of disrupted neural development that is associated with autism-related features in NT participants. Indeed, we found that autistic trait load was associated with more bilateral language activations in a set of 139 NT participants. Furthermore, NT male participants (n=42) showed more bilateral language activations than matched (including for autistic trait load) NT female participants, in line with a higher incidence of autism in males. In tandem, these results suggest that reduced lateralization of the language system is a robust neural marker of autism, present in both NT males and NT individuals with high autistic trait load, in line with the complexity of the genetic basis of autism with numerous genes implicated, and each gene explaining only a small proportion of variance.
2. When we understand language, we flexibly use our knowledge of the speaker’s mental states (e.g., Brennan et al., 2010). Do we also keep track of what other listeners do or do not understand? In an ERP study, Rueschmeyer et al. (2015) observed that when a listener knows that a co-listener cannot understand the utterance (e.g., “The girl had a beak and yellow feathers”) because they are lacking the relevant context (e.g., “The girl dressed up as a canary for Halloween”), they show a marker of comprehension difficulty: an N400 effect (Kutas & Hillyard, 1980) to a word (“beak” in the example above) that makes sense to the listener, but not to the co-listener. We term this effect the Social or Empathetic N400. Across two ERP experiments with NT participants, we (i) replicate the Social N400 effect, (ii) show that it obtains spontaneously in the presence of a (confused) co-listener (cf. explicit instructions to think about the co-listener’s mental state in Rueschmeyer’s study), and (iii) show that the magnitude of this effect is related to social abilities. In an ongoing study with ASD participants, we are testing whether the social N400 effect may be reduced or absent.

SCSB Lunch Series: Joshua Tenenbaum, Ph.D.
2017-05-19 12:00 - 13:00 | Simons Center Conference Room, Bldg. 46, Room 6011, 43 Vassar Street, Cambridge, MA, 02139, United States
Date: Friday, May 19, 2017
Time: 12:00pm – 1:00pm
Speaker: Joshua Tenenbaum, Ph.D.
Affiliation: Professor of Computational Cognitive Science, Department of Brain and Cognitive Sciences, MIT
Talk Title: Computational Models of Social Cognition
Abstract: to be provided later…

SCSB Colloquium Series: Mustafa Sahin, M.D., Ph.D.
2017-05-10 16:00 - 17:00 | Singleton Auditorium, Bldg. 46, Room 3002, 43 Vassar Street, Cambridge, MA, 02139, United States
Wednesday, May 10, 2017
Time: 4:00 pm-5:00 pm, followed by reception
Speaker: Mustafa Sahin, M.D., Ph.D.
Affiliation: Rosamund Stone Zander Chair; Director, Translational Neuroscience Center at Boston Children’s Hospital; Professor of Neurology Harvard Medical School
Host: Mriganka Sur, Ph.D., FRS
Talk Title: Autism in Tuberous Sclerosis: From Circuits to Treatments
Abstract: Autism spectrum disorder is a common occurrence in individuals affected with a genetic disease, tuberous sclerosis complex (TSC). Using cell-based, animal model and clinical studies, the Sahin lab and their collaborators have started to shed light on the molecular, cellular and neural circuit abnormalities underlying the neurobehavioral problems in TSC. His research group at Boston Children’s Hospital has also led a national consortium to identify biomarkers that correlate with autism symptoms in TSC. Updates will be provided from the results of the ongoing biomarker and treatment trials with children with TSC.
[Video of the talk]

SCSB Lunch Series: Pawan Sinha, Ph.D.
2017-04-28 12:00 - 13:00 | Simons Center Conference Room, Bldg. 46, Room 6011, 43 Vassar Street, Cambridge, MA, 02139, United States
Date: Friday, April 28, 2017
Time: 12:00pm – 1:00pm

Speakers:
Pawan Sinha, Ph.D., Professor of Vision and Computational Neuroscience, MIT
Dagmar Sternad, Ph.D., Professor, Departments of Biology, Electrical & Computer Engineering, and Physics, Northeastern University
Nouchine Hadjikhani, M.D., Ph.D., Associate Professor in Radiology, Harvard Medical School, Associate Neuroscientist and Director of Neurolimbic Research, Mass General Hospital, Visiting Professor, GNC, Gothenburg University, Sweden
Talk title: The Predictive Impairment in Autism hypothesis: An empirical assessment
Abstract: About two years ago, we proposed that multiple aspects of the autism phenotype may be manifestations of an underlying difficulty in prediction (Sinha et al. 2014, PNAS). This proposal, along with a few related conceptualizations from other labs (Pellicano and Burr, 2012; Van de Cruys et al., 2014), has spurred several targeted empirical investigations of predictive processes in autism. In this talk, we review the data accumulated thus far. The picture that has emerged is a mixed one, providing equivocal support for the PIA hypothesis. We shall consider both positive and negative findings and also describe efforts currently underway in our labs to further test the proposal.

SCSB Colloquium Series: Nikolaos Mellios, M.D., Ph.D.
2017-04-26 16:00 - 17:00 | Singleton Auditorium, Bldg. 46, Room 3002, 43 Vassar Street, Cambridge, MA, 02139, United States
Wednesday, April 26, 2017
Time: 4:00 pm-5:00 pm, followed by reception
Speaker: Nikolaos Mellios, M.D., Ph.D.
Affiliation: Assistant Professor, Department of Neurosciences, University of New Mexico
Host: Mriganka Sur, Ph.D., FRS
Talk title: Out with the old and in with the new – the role of circular RNAs in psychiatric disorders.
Abstract: Schizophrenia (SCZ) and Bipolar disorder (BD) are heterogeneous psychiatric disorders with severe socioeconomic impacts and unknown pathogenesis, despite the plethora of genomics and genetic studies focused on protein-coding genes. However, the emerging consensus is that protein-coding genes are only the tip of the iceberg of the mammalian transcriptome, given the plethora of actively transcribed non-coding RNAs (ncRNAs). Circular RNAs (circRNAs) are a novel category of ncRNAs that are derived from the back-splicing and covalent joining of exons, yet lack the capacity to become translated into protein. Recent studies have suggested that circRNAs are enriched in the brain, are preferentially generated from brain plasticity-associated genes, and are abundant in dendrites and synapses. However, very little is known about the function of circRNAs in the human brain and their potential involvement in neuropsychiatric disease. Here we carried out systematic profiling of circRNA expression in a large cohort of human postmortem brains from subjects with SCZ and BD disorder and uncovered a subset of differentially expressed circRNAs produced from genes with known links to synaptic plasticity and neuronal excitability. We validated the expression of psychiatric disease-altered circRNAs in human postmortem brain with qRT-PCR and uncovered a subset of circRNAs that were also dysregulated in induced pluripotent stem cell (iPSC)-derived human neuronal progenitor and immature neuronal cultures from subjects with BD and SCZ. In silico analysis of RNA-Binding proteins (RBPs) that could bind to psychiatric disease-associated circRNAs revealed potential interactions with RBPs that affect alternative splicing and dendritic and synaptic trafficking. Ongoing experiments using circRNA shRNA knockdown in iPSC neuronal cultures are attempting to elucidate the function of SCZ- and BD-associated circRNAs in human neuronal development and maturation and their interplay with RBPs and disease-related molecular pathways. Collectively, our experiments will shed light into the unexplored role of circRNAs in brain function and disease.
[Video of the talk]

SCSB Colloquium Series: Peyman Golshani, M.D., Ph.D.
2017-04-12 16:00 - 17:00 | Singleton Auditorium, Bldg. 46, Room 3002, 43 Vassar Street, Cambridge, MA, 02139, United States
Wednesday, April 12, 2017
Time: 4:00 pm-5:00 pm, followed by reception
Speaker: Peyman Golshani, M.D., Ph.D.
Affiliation: Associate Professor, Departments of Neurology and Psychiatry, David Geffen School of Medicine, UCLA
Host: Mark Harnett
Talk title: Changes in inhibitory/excitatory connectivity and neural network dynamics in a model of autism
Abstract: A large number of genetic changes have been associated with autism and intellectual disability but how these change alter cortical circuits and neural network dynamics are not understood. We show that there are dramatic alterations in the excitatory and inhibitory connectivity in the mPFC of the CNTNAP2 model of autism and show how these changes correlate with altered oscillatory dynamics in-vivo. We have also developed a new generation of open-source miniature microscopes with wireless capability which will facilitate the study of neural network dynamics during social interactions in mouse models of autism.
[Video of the talk]

SCSB Lunch Series: Ashley Watson, Ph.D.
2017-04-07 12:00 - 13:00 | Simons Center Conference Room, Bldg. 46, Room 6011, 43 Vassar Street, Cambridge, MA, 02139, United States
Date: Friday, April 7, 2017
Time: 12:00pm – 1:00pm
Speaker: Ashley Watson, Ph.D.
Affiliation: Postdoctoral Fellow, Dr. Li-Huei Tsai’s laboratory, Picower Institute for Learning and Memory
Talk Title: Chromatin organization and function in the molecular etiology of autism
Abstract: Spatial organization of the genome in three dimensions (3D) is an important aspect of tissue-specific developmental transcriptional regulation that involves chromatin remodeling factors, architectural proteins, and interactions between distal regulatory elements. The zinc finger protein CTCF has emerged as a critical factor in mediating long-range chromatin interactions to regulate transcription. Recent exome sequencing of autism spectrum disorder (ASD) patients identified multiple haploinsufficient mutations in the zinc finger DNA-binding domain of CTCF, suggesting that alterations in CTCF binding may contribute to abnormal neurodevelopment and disease pathogenesis. To investigate the relationship between CTCF-mediated chromatin topology and transcriptional regulation, we generated isogenic human induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) harboring autism spectrum disorder (ASD)-linked CTCF mutation. I will present transcriptomic and epigenomic data to support the role of CTCF in orchestrating transcriptional programs essential for neurodevelopment. These findings shed light on the consequence of specific ASD-linked mutations and have important implications for transcriptional regulation via 3D chromatin organization in neurodevelopment.

SCSB Colloquium Series: Joseph Piven, M.D.
2017-03-22 16:00 - 17:00 | Singleton Auditorium, Bldg. 46, Room 3002, 43 Vassar Street, Cambridge, MA, 02139, United States
Wednesday, March 22, 2017
Time: 4:00 pm-5:00 pm, followed by reception
Speaker: Joseph Piven, M.D.
Affiliation: Thomas E. Castelloe Distinguished Professor of Psychiatry, University of North Carolina
Host: Helen Tager-Flusberg, Boaz Barak
Talk title: Imaging Infant Brain Development in Autism
Abstract: Autism is the quintessential developmental disorder yet almost all studies are cross-sectional and include subjects a wide range of ages. The Infant Brain Imaging Study (IBIS) is a prospective study of infants at high familial risk for autism. Subjects are examined at multiple time points between 3 and 36 months of age with behavioral and brain imaging assessments. Data from the IBIS Network have revealed that during the first two years of life there are disorder specific brain changes over time such that the ‘neural signature’ of autism is ‘change over time’. Brain differences are present by 6 months of age in multiple brain areas. Early brain and behavior changes in autism likely have downstream cascading effects, producing later manifestations of autism and later brain changes. These findings have led to development of early prediction models that predict autism at 24 months of age from imaging data in the first year of life. These findings have significant potential public health implications.
[Video of the talk]

SCSB Colloquium Series: Sally Temple Ph.D.
2017-03-08 16:00 - 17:00 | Singleton Auditorium, Bldg. 46, Room 3002, 43 Vassar Street, Cambridge, MA, 02139, United States
Wednesday, March 8, 2017
Time: 4:00 pm-5:00 pm, followed by reception
Speaker: Sally Temple Ph.D.
Affiliation: Scientific Director, Neural Stem Cell Institute
Host: Li-Huei Tsai, Ph.D.
Talk title: Temporal programs in Neural Stem cell Development and Aging
Abstract: Neural stem cells (NSCs) are foundational cells in mammalian central nervous system development, and they continue to contribute new neurons and glial cells throughout life in areas of the adult brain important for learning and memory. During development, NSCs produce diverse progeny on a precise time-schedule. For example, during cerebral cortical development, they produce layer-specific neurons in order, from deep to superficial, prior to generating glia. Notably, these temporal changes are programmed within individual progenitor cells , as they can be recapitulated by single cells isolated from the brain and dividing in clonal culture, shown by following cell lineages by time-lapse analysis. In the adult brain, temporal changes also dominate NSC behavior, as they deplete during aging, contributing to memory impairment. Our work is aimed at understanding how NSC gene pathways and networks change over time in mice and human, to provide insight into fundamental neural developmental and aging mechanisms, and how they may lead to congenital defects and age-related neurodegenerative disease.

SCSB Lunch Series: Ian Wickersham, Ph.D.
2017-03-03 12:00 - 13:00 | Simons Center Conference Room, Bldg. 46, Room 6011, 43 Vassar Street, Cambridge, MA, 02139, United States
Date: Friday, March 3, 2017
Time: 12:00pm – 1:00pm
Speaker: Ian Wickersham, Ph.D.
Affiliation: Principal Research Scientist, McGovern Institute for Brain Research, MIT
Talk Title: New circuit-specific and cell-type-specific techniques for targeting neurons
Abstract: Every region of the brain is a complex network of many different cell types, all playing unique functional roles and connected to each other following rules that are highly precise but very incompletely understood. Deciphering the organization and operation of such circuitry requires being able to selectively express the powerful genetic tools of modern neuroscience – fluorophores, opsins, activity indicators, and so on – in meaningful groups of neurons based on their synaptic connectivity or patterns of gene expression. This is the focus of my lab. In this talk I’ll describe two ongoing projects. The first is our work towards developing a completely nontoxic system for transducing neurons that are monosynaptically connected to a targeted neuronal population. Among other applications, this should allow the systematic study of how the activity patterns of neurons’ inputs are converted into their outputs, defined both by their instantaneous spiking activity as well as by the changes in their synaptic connectivity. The second project is our development of a system for cell-type-specific transgene expression in wild-type animals. This should result in a set of powerful new tools for manipulating defined neuronal types in nonhuman primate models, allowing a broad set of new experimental designs that are likely to yield major insights into the mechanisms of cognition and behavior as well as the biological bases of neurological disorders.

SCSB Lunch Series: Oliver Wilder-Smith, Northeastern University
2017-02-17 12:00 - 13:00 | Simons Center Conference Room, Bldg. 46, Room 6011, 43 Vassar Street, Cambridge, MA, 02139, United States
Date: Friday, February 17, 2017
Time: 12:00pm – 1:00pm
Speaker: Oliver Wilder-Smith, Northeastern University, Ph.D. Candidate
Affiliation: Northeastern University; Simons Center Postdoctoral Fellow (Fall 2017)
Talk Title: Quantitative Analysis of Socio-Affective Dynamics in Autism Using Interpersonal Physiology
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. As such, it is important to consider the child, their caretaker, and their dyadic interaction as three separate but complimentary lines of inquiry when exploring social cognition and social reciprocity in the developing brain. A growing body of work in interpersonal physiology – the study of psychophysiological signals across two or more people – may offer a powerful new means for non-invasive ambulatory assessment of socio-affective processes in children with ASD. I will present techniques and preliminary data from our on-going Simon’s funded enTRAIN study, in which we are applying interpersonal physiological analysis to study social reciprocity and socio-affective dynamics between young children with and without an autism diagnosis and their parent.

SCSB Colloquium Series: Christopher J. McDougle, M.D.
2017-02-08 16:00 - 17:00 | Simons Center Conference Room, Bldg. 46, Room 6011, 43 Vassar Street, Cambridge, MA, 02139, United States
Wednesday, February 8, 2017
Time: 4:00 pm-5:00 pm, followed by reception
Speaker: Christopher J. McDougle, M.D.
Affiliation: Director, Lurie Center for Autism; Professor of Psychiatry and Pediatrics, MGH and MassGeneral Hospital for Children; Nancy Lurie Marks Professor in the Field of Autism, Harvard Medical School.
Host: Mriganka Sur, Ph.D., FRS
Talk title: Toward an Inflammation-Related Subtype of Autism Spectrum Disorder
Abstract: The etiology of autism spectrum disorder (ASD) is largely unknown. A prominent challenge to the field’s efforts to identify the causes of ASD has been the inability to identify meaningful subtypes due to the significant clinical and likely biological heterogeneity that exists. Since the publication of Leo Kanner’s seminal description of children with ASD in 1943, there has been accumulating evidence that inflammation may play a role in the pathophysiology of a subtype of individuals with ASD. Data in support of this purported subtype has come from descriptive studies, family and other studies demonstrating an increased prevalence of autoimmune disorders in first- and second-degree relatives of probands with ASD, neuroimaging and post-mortem investigation, animal models and preliminary findings from trials of anti-inflammatory drugs. This presentation will review some of this literature and present findings from some of our pilot research, including results from preclinical animal model work and neuroimaging of adult subjects with ASD.
[Video of the talk]

SCSB Lunch Series: Yeong Shin Yim, Ph.D.
2017-02-03 12:00 - 13:00 | Simons Center Conference Room, Bldg. 46, Room 6011, 43 Vassar Street, Cambridge, MA, 02139, United States
Date: Friday, February 3, 2017
Time: 12:00pm – 1:00pm
Speaker: Yeong Shin Yim, Ph.D.
Affiliation: Simons Center Postdoctoral Fellow, Gloria Choi Laboratory, McGovern Institute for Brain Research, MIT
Talk Title: Reversing autism-like behaviors in mouse offspring exposed to maternal inflammation
Abstract: Viral infection during pregnancy has been correlated with increased frequency of autism spectrum disorder (ASD) in offspring. This phenomenon has been modeled in mice prenatally subjected to maternal immune activation (MIA). We previously showed that the T helper 17 (Th17) cell/interleukin-17a (IL-17a) pathway is crucial for the induction of both cortical and behavioral abnormalities observed in MIA-affected offspring. However, it remains unclear if and how cortical abnormalities serve as causative factors for the aberrant behavioral phenotypes. Here, we show that cortical abnormalities are preferentially localized to a region encompassing the dysgranular zone of the primary somatosensory cortex (S1DZ) in the adult MIA offspring and that the presence and size of cortical patches tightly correlate with manifestation and severity of ASD-like behavioral phenotypes. More specifically, we demonstrate that the selective loss of parvalbumin (PV)-expressing interneurons and a concomitant increase in neural activity is causal to the emergence of MIA behavioral phenotypes. Indeed, activation of pyramidal neurons in the S1DZ was sufficient to induce ASD-like behaviors in wild-type (WT) animals, while reduction in neural activity in this cortical region rescued the behavioral abnormalities in the MIA offspring. Furthermore, we identified the temporal association area (TeA) as a S1DZ downstream target involved in the selective modulation of sociability phenotypes, but not the expression of repetitive behaviors. Our work identifies a cortical region primarily, if not exclusively, centered on the S1DZ as the major node of a neural network whose increased neural activity mediates ASD-like behavioral abnormalities observed in offspring exposed to maternal inflammation.

SCSB Colloquium Series: Casey Lew-Williams, Ph.D.
2017-01-25 16:00 - 17:00 | Singleton Auditorium, Bldg. 46, Room 3002, 43 Vassar Street, Cambridge, MA, 02139, United States
Date: Wednesday, January 25, 2017
Time: 4:00 pm-5:00 pm, followed by reception
Speaker: Casey Lew-Williams, Ph.D.
Affiliation: Assistant Professor, Department of Psychology, Princeton University.
Host: Rebecca Saxe, Ph.D.
Talk title: Breaking into language: How infants find structure in patterned input
Abstract: In the first year of life, two signatures of human cognition begin to interact: our capacity for detecting and remembering patterns, and our interest in communicating with others. Using language as a window into the developing mind, I will present lots of behavioral experiments showing that typically developing infants thrive in breaking into structure when they have ample ‘high-quality’ data to operate over. Their learning abilities are well-matched to input that is communicatively relevant, naturally variable, and packaged with accessible statistics. I will conclude by discussing how some children miss these opportunities for learning, whether over the course of seconds or years. Investigations into the detection, processing, and learning of structure may be important for understanding the mystery of how infants learn language so quickly, and also how children who lack access to enriching experience are often hindered in the same pursuit.

SCSB Lunch Series: Ian Slaymaker, Ph.D.
2016-12-09 12:00 - 13:00 | Simons Center Conference Room, Bldg. 46, Room 6011, 43 Vassar Street, Cambridge, MA, 02139, United States
Date: Friday, December 9, 2016
Time: 12:00pm – 1:00pm
Speaker: Ian Slaymaker, Ph.D.
Affiliation: Simons Center Postdoctoral Fellow, Feng Zhang Laboratory, McGovern Institute; Broad Institute, MIT
Talk Title: Knockdown of Chd8 causes nucleus accumbens linked autism-like phenotypes in mice.
Abstract: Autism spectrum disorder (ASD) is a heterogeneous disease, but genetically defined models can provide an entry point to studying the molecular underpinnings of this disorder. We have generated germline mutant mice with loss-of-function mutations in Chd8, a de novo mutation strongly associated with ASD, and demonstrated that these mice display hallmark ASD behaviors, macrocephaly, and craniofacial abnormalities similar to patient phenotypes. Chd8 mutant mice display a broad, brain-region specific dysregulation of major regulatory and cellular processes, most notably histone and chromatin modification, mRNA and protein processing, Wnt signaling, and cell cycle regulation.
Furthermore, we find altered synaptic physiology in medium spiny neurons of the nucleus accumbens and perturbation of Chd8 in adult mice recapitulates improved acquired motor learning behavior found in mutant Chd8 animals, strongly suggesting a role for CHD8 in adult striatal circuits. These results indicate a mechanism linking chromatin modification to striatal dysfunction and the molecular pathology of ASD.

SCSB Lunch Series: Rebecca Saxe, Ph.D.
2016-12-02 12:00 - 13:00 | Simons Center Conference Room, Bldg. 46, Room 6011, 43 Vassar Street, Cambridge, MA, 02139, United States
Date: Friday, December 2, 2016
Time: 12:00 pm-1:00 pm
Speaker: Rebecca Saxe, Ph.D.
Affiliation: Professor of Cognitive Science, Martinos Imaging Center, McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences

Talk Title: Social information processing in the brains of people with ASD: two wrong hypotheses, and the road ahead.
Abstract: In this talk I will describe my first two hypotheses about the neural basis of social deficits in ASD. Hypothesis 1: individuals with ASD rely on compensatory mechanisms to answer social questions that other people solve “naturally”. Hypothesis 2: deficits in social processing are most acute when abstract social information must be extracted from a dynamic variable and naturalistic stimulus. I will show the experiments we did and the data we collected that disconfirm these hypotheses. Then I will speculate about where we go from here.

CANCELED: SCSB Colloquium Series: Patrick R. Hof, M.D.
2016-11-30 12:00 - 13:00 | McGovern Auditorium, room 46-3189, 43 Vassar Street, Cambridge, MA, 02139, United States
Patrick R. Hof, M.D.
Please note that this Seminar is canceled and will be rescheduled for a later date.
Date: Wednesday, November 30, 2016
Location: McGovern Seminar room, 46-3189
Time: 12:00 pm-1:00 pm
Speaker: Patrick R. Hof, M.D.
Affiliation: Irving and Dorothy Regenstreif Professor of Neuroscience, Fishberg Department of Neuroscience, Seaver Center for Autism Research, and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York
Host: Mriganka Sur, Ph.D., FRS
Talk title: Neuropathology of autism and the spectrum of selective neuronal alterations in neuropsychiatric diseases
Abstract: The lecture will review the concept of selective neuronal vulnerability as applied to the study of autism spectrum disorder, in postmortem brain or in animal models. Guided by evidence from functional brain imaging studies in patients with autism, we reasoned that local differences in activation of specific systems would result from alteration of key population of pyramidal neurons with highly restricted distribution. We were able to identify such changes in the fusiform face area, Broca’s area, and insular and anterior cingulate cortex in brains from patients with autism using a rigorous stereology approach, revealing that a regionally constrained and cell type-specific pathology occurs in the neocortex in these patients. We also studied cellular and synaptic pathology in a mouse model of Phelan-McDermid syndrome unraveling complex developmental abnormalities that can inform mechanisms of disease progression more generally for idiopathic autism. We further expand these analyses to a large-scale endeavor of comparative and evolutionary studies of the neuronal architecture across mammals. These studies permitted the discovery of particular cell types specific to only some mammals, which, in human, turned out to be a marker of vulnerability in certain conditions such as frontotemporal dementia and autism. This work linked brain evolutionary traits with brain diseases unique to human.

SCSB Lunch Series: Paul Blainey, Ph.D.
2016-11-04 12:00 - 13:00 | Simons Center Conference Room, Bldg. 46, Room 6011, 43 Vassar Street, Cambridge, MA, 02139, United States
Date: Friday, November 4, 2016
Time: 12:00 pm-1:00 pm
Speaker: Paul Blainey, Ph.D.
Affiliation: Assistant Professor of Biological Engineering, MIT; Core Member, Broad Institute of Harvard and MIT

Talk Title: High content pooled genomic screening
Abstract: The majority of ASD is not associated with a single genetic variant. Genome-wide association of multiple rare variants is plagued by low signal to noise in genetically heterogeneous backgrounds that characterize natural populations of individuals. In principle, functional genomics allows testing of putative rare variant combinations against a uniform genetic background in vitro. However, neurons are not suited for flow-sorting and do not divide in culture, preventing the use of efficient pooled screening approaches that have the scale needed to test variant combinations. Here we develop a new genomic perturbation and screening concept that combines major advantages of pooled perturbation with neuron-compatible imaging assays for the physical structure, molecular contents, and functional activities of cells. Specifically, we screen pooled genomic perturbations (with barcoded CRISPR-Cas9 single-guide RNAs) using microscopy to read out phenotypes AND to identify perturbed genes at the single-cell level. Perturbed genes are identified by sgRNA-associated expressed barcodes in situ by RNA fluorescence in situ hybridization (RNA-FISH) or in situ sequencing (IS). We image millions of cells per day on a standard research microscope, which we expect would enable small laboratories to routinely conduct genome-wide screens. Recent progress in the development of this method and its applicability to cultured primary neurons will be reported.

SCSB Colloquium Series: Francesca Happé, Ph.D.
2016-11-02 16:00 - 17:30 | Singleton Auditorium, Bldg. 46, Room 3002, 43 Vassar Street, Cambridge, MA, 02139, United States
Wednesday, November 2, 2016
Time: 4:00 pm-5:00 pm, followed by reception
Speaker: Francesca Happé, Ph.D.
Affiliation: Professor of Cognitive Neuroscience and Director of the MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
Host: Evelina Fedorenko, Ph.D.
Talk title: ‘Theory of mind’ and Autism: 30 years on
Abstract: In this talk Dr. Happé will take a personal perspective on how the notion of impaired ‘theory of mind’ has influenced the study of autism spectrum disorder (ASD). It’s a little over 30 years since the seminal paper by Baron-Cohen, Leslie and Frith; how has that cognitive theory affected our understanding of ASD? Are cognitive accounts even necessary to understand a neurodevelopmental condition where genes and synapses might be considered the most relevant levels of analysis? Drawing on old and new work, she will discuss the uses and limitations of the theory of mind account, and its place in our wider understanding of the full symptom profile of ASD, and in a wider mapping of the distinct elements of social cognition.

SCSB Colloquium Series: Kimberly Huber, Ph.D.
2016-10-26 16:00 - 17:30 | Singleton Auditorium, Bldg. 46, Room 3002, 43 Vassar Street, Cambridge, MA, 02139, United States
Wednesday, October 26, 2016
Time: 4:00 pm-5:00 pm, followed by reception
Speaker: Kimberly Huber, Ph.D.
Affiliation: Professor of Neuroscience, UT Southwestern Medical Center
Host: Weifeng Xu, Ph.D.
Talk title: Mechanisms of Sensory Circuit Hyperexcitability in Fragile X Syndrome: Implications for Therapeutics and Biomarker Development
Abstract: Sensory hypersensitivity is a common occurrence in autism spectrum disorders and contributes significantly to behavioral problems. Dr. Huber’s work has focused on a monogenic cause of ASD, Fragile X Syndrome, where she has established hyperexcitability of cortical microcircuits in the Fragile X Syndrome mouse model (Fmr1 KO). Dr. Huber will discuss her discoveries regarding the synaptic and circuit mechanisms of circuit hyperexcitability as well as her ongoing efforts to develop neurophysiological biomarkers for sensory circuit dysfunction in Fragile X in mice and humans.

SCSB Lunch Series: Eleni K. Maneta, M.D. and Themistoklis P. Sapsis, Ph.D.
2016-10-21 12:00 - 13:00 | Simons Center Conference Room, Bldg. 46, Room 6011, 43 Vassar Street, Cambridge, MA, 02139, United States
Date: Friday, October 21, 2016
Time: 12:00 pm-1:00 pm
Speaker: Eleni K. Maneta, M.D. and Themistoklis P. Sapsis, Ph.D.
Affiliation: Department of Psychiatry, Boston Children’s Hospital; Harvard Medical School
Department of Mechanical Engineering; Massachusetts Institute of Technology

Talk Title: Learning, categorization and generalization in Autism Spectrum Disorder
Abstract: One of the most intriguing aspects of ASD is the fact that individuals with the condition have very different learning styles regardless of level of intelligence. These differences in learning play an important role in how individuals with ASD perceive the world and are thought to be central in the challenges they face. For example, if an individual with ASD were unable to learn from previous experiences, then each situation would be viewed as unique, and overwhelming. Multiple studies to date have attempted to uncover the mechanisms underlying differential learning in ASD; however, there continues to be a lack of consensus and a need for further exploration. In the first part of this talk we will present some basic facts about learning and ASD. We will give a brief overview of various theories that have been proposed to explain differential learning in ASD, focusing mainly on learning through prototypes, categorization and generalization. Building on this framework we will subsequently discuss a qualitative connection between dimensionality-reduction, categorization and generalization skills. The second part of the talk will concentrate on the mathematical modeling of the relationship between capability for categorization and the effectiveness of generalization. Using a Bayesian formalism we will show that simultaneously processing a large number of features associated with a stimulus, i.e. working with high-dimensional stimuli, results in poor categorization capabilities, even if the prototype has been learned correctly. At a technical level, this result is a direct consequence of the “curse” of dimensionality, which rises when one is working in high-dimensional spaces. Exceptions will be discussed and experiments from the literature will be interpreted through the developed analysis. The results pave the way for the design of new experimental protocols and measures that will i) lead to a better understanding of the challenges individuals with ASD face when it comes to categorization and in particular whether these are caused by impaired prototype formation or by the utilization of high-dimensional stimuli or a combination of the two, and ii) rigorously quantify learning styles and assess/predict the capability to perceive qualitatively different stimuli.

SCSB Colloquium Series: Sara Jane Webb, Ph.D.
2016-10-12 16:00 - 17:00 | Singleton Auditorium, Bldg. 46, Room 3002, 43 Vassar Street, Cambridge, MA, 02139, United States
Wednesday, October 12, 2016
Time: 4:00 pm-5:00 pm, followed by reception
Speaker: Sara Jane Webb, Ph.D.
Affiliation: Associate Professor, Psychiatry and Behavioral Science, University of Washington & Seattle Children’s Research Institute
Host: Susan Faja, Ph.D.
Talk title: Face processing as a biomarker in early autism
Abstract: Autism Spectrum Disorder (ASD) is characterized by impairment in social communication and restricted and repetitive interests. While not included in the diagnostic characterization, aspects of face processing and learning have shown disruptions at all stages of development in ASD, although the exact nature and extent of the impairment varies. Active experience is critical to learning and children who are developing ASD may have subtly different visual environments early in development. Face learning is a life-long necessity, as the social world of individual only broadens with age. This presentation will focus on the role of very early developmental atypicalities in basic face processing, including their contribution to the impaired trajectory of social communicative skills in individuals with ASD.

SCSB Lunch Series: Xin Tang, Ph.D.
2016-10-07 12:00 - 13:00 | Simons Center Conference Room, Bldg. 46, Room 6011, 43 Vassar Street, Cambridge, MA, 02139, United States
Date: Friday, October 7, 2016
Time: 12:00 pm-1:00 pm
Speaker: Xin Tang, Ph.D.
Affiliation: Simons Postdoctoral Fellow, Rudolf Jaenisch Lab, Whitehead Institute and Picower Institute for Learning & Memory, MIT

Talk Title: Identification of Small Molecule Compounds to Treat Rett Syndrome with a Human Neuron-based Drug Screening Platform
Abstract: A disruption in the balance between excitatory and inhibitory neuronal signaling (E/I balance) is observed in various neurological diseases including Rett Syndrome (RTT), a severe neurodevelopmental disorder with autism phenotypes. Our previous work reported a reduction in the level of KCC2, a neuron-specific gene crucial for the maintenance of E/I balance, in cultured human RTT patient-derived neurons and in brains of RTT mouse model. In the current project, we aim to identify drugs that increase KCC2 expression in human RTT neurons. We have applied CRISPR/Cas9 gene editing technologies to human embryonic stem cells to develop a chemical compound screening platform, and have identified and validated the first batch of KCC2 expression enhancer compounds from a screen of multiple compound libraries. We propose that results from our research will help the development of novel therapies that target KCC2 to treat RTT and other brain disorders with impairments in E/I balance.

SCSB Colloquium Series: Janine LaSalle, Ph.D.
2016-09-28 16:00 - 17:30 | Singleton Auditorium, Bldg. 46, Room 3002, 43 Vassar Street, Cambridge, MA, 02139, United States
Wednesday, September 28, 2016
Time: 4:00 pm-5:00 pm, followed by reception
Speaker: Janine LaSalle, Ph.D.
Affiliation: Associate Director of Genomics, Genome Center; Professor, Medical Microbiology and Immunology, MIND Institute, University of California, Davis
Host: Steven Flavell, Ph.D.
Talk title: The landscape of DNA methylation amidst a perfect storm of autism etiologies
Abstract: Increasing evidence points to a complex interplay between genes and environment in autism spectrum disorder. Epigenetic mechanisms such as DNA methylation act at this interface, reflecting plasticity in metabolic and neurodevelopmentally regulated gene pathways. Rare genetic forms of ASD, such as Rett syndrome and de novo mutations in chromatin genes highlight the importance of DNA methylation and chromatin regulation.
Epigenetic layers of DNA methylation and histone modifications are dynamic during brain development and implicated in the etiology of autism. Utilizing whole genome bisulfite sequencing, we show that both chromosome 15q11.2-q13.3 maternal duplication brain and a neuronal cell culture model exhibit significant global DNA hypomethylation, particularly over synaptic genes, impacting their transcriptional stability. The cumulative effect of multiple chromosomal duplications and exposure to the pervasive persistent organic pollutant PCB 95 altered methylation of >1,000 genes. Mechanistically, hypomethylated genes were enriched for gene-body H2A.Z, and increased maternal UBE3A in Dup15q reduced levels of RING1B and monoubiquitinated acetylated H2A.Z, a bivalent mark of poised transcription. These results demonstrate the compounding effects of genetic and environmental insults on the neuronal methylome that converge in the dysregulation of chromatin and synaptic gene pathways. Since many epigenetically dysregulated genes identified in this multi-hit study are known drug targets, we expect these results to be informative in improving therapies for autism. The dynamic developmental landscape of DNA methylation is vulnerable to a plethora of genetic and environmental insults, therefore understanding the pathways central to this “perfect storm” will be critical to improved diagnosis and treatment of ASD.

SCSB Lunch Series: Alan P. Jasanoff, Ph.D.
2016-09-23 12:00 - 13:00 | Simons Center Conference Room, Bldg. 46, Room 6011, 43 Vassar Street, Cambridge, MA, 02139, United States
Date: Friday, September 23, 2016
Time: 12:00 pm-1:00 pm
Location: Simons Center Conference Room 6011, Building 46 @MIT
Speaker: Alan Jasanoff, Professor of Biological Engineering, Brain & Cognitive Sciences, Nuclear Science & Engineering, MIT

Talk Title: Dissecting functional brain connectivity in a rodent model of ASD

Abstract: Autism spectrum disorders (ASDs) appear to be marked by altered correlations in brain-wide activity patterns observable by functional magnetic resonance imaging (fMRI). Analysis of these “functional connectivity” (FC) differences could contribute to understanding the pathology of autism, and might also yield biomarkers useful for clinical diagnosis and treatment monitoring. Here we describe an approach to performing FC studies in unanesthetized rats, where mechanistic analysis of sources and coupling mechanisms is possible. We apply this method to the measurement of functional connectivity perturbations in an FMR1 knock-out line, which is a syndromic model of ASDs. Our studies so far suggest a consistent pattern of hypoconnectivity in subcortical networks of FMR1 animals, with respect to wild type. This hypoconnectivity may be related to changes in the mean hemodynamic activity levels observed in different brain structures. To test for neural factors that might cause the observed changes, we are deploying targeted inactivation techniques.

Special Seminar: Book Night with Ed Yong
2016-09-20 16:30 - 18:00 | Singleton Auditorium, Bldg. 46, Room 3002, 43 Vassar Street, Cambridge, MA, 02139, United States
Date: Tuesday, September 20, 2016
Time: 4:30 pm – 6:00 pm
Location: MIT Building 46-3002 (Singleton Auditorium), 3rd Floor, 43 Vassar Street, Cambridge, MA 02139
This event is co-hosted by the Knight Science Journalism at MIT & Simons Center for the Social Brain.
Description: Every animal is an entire world—a thriving ecosystem that teems with trillions of microbes. These invisible companions sculpt our organs, protect us from diseases, guide our behaviour, and bombard us with their genes.
In this talk, based on his New York Times bestselling book I Contain Multitudes: The Microbes Within Us and a Grander View of Life, science writer Ed Yong will take us on a tour of our microbial partners and the astonishing ways in which they shape our lives. You’ll learn how bacteria have shaped animal evolution, why breastfeeding is about more than just babies, how animals can survive without mouths or guts, why Australian scientists are fighting tropical diseases by releasing infected mosquitoes, and what the microbiome means for human health.
***Books will be available for purchase beginning at 4:00 pm in the Atrium (3rd floor, building 46). The MIT Press Bookstore is offering a 20% discount (retail price: $27.99, with discount: $22.39). Payments accepted: cash, check, and credit cards (MasterCard, Visa, American Express, & Discover).
___________
Title: I Contain Multitudes: The Microbes Within Us and a Grander View of Life
Author: Ed Yong
ISBN: 9780062368591
Publisher: Ecco Press
US SRP: $27.99
Binding: Hardcover
Pub Date: August 09, 2016

SCSB Colloquium Series: Charles A. Nelson, Ph.D.
2016-09-07 16:00 - 17:30 | Singleton Auditorium, Bldg. 46, Room 3002, 43 Vassar Street, Cambridge, MA, 02139, United States
C. 2009 by Fred Field fredfield.com
Wednesday, September 7, 2016
Time: 4:00 pm-5:00 pm, followed by reception
Speaker: Charles A. Nelson, Ph.D.
Affiliation: Professor of Pediatrics and Neuroscience, Harvard Medical School; Professor of Education, Harvard University; Richard David Scott Chair in Pediatric Developmental Medicine Research, Boston Children’s Hospital
Host: Mriganka Sur, Ph.D., FRS
Talk title: Using the visual system to quantitatively evaluate cortical function in Rett syndrome and Tuberous Sclerosis Complex
Abstract: There are a variety of genetic variants that confer high risk for developing autism. We have been conducting a line of research with children with Tuberous Sclerosis Complex (TSC) and Rett Syndrome focused on the development of predictive models for autism, and neurophysiological assays that can be used as readout for cortical function. In this talk I will focus on how EEG frequency spectra and the visual evoked potential can shed light on brain function in children with TSC and Rett.

SCSB Lunch Series: Barak Boaz, Ph.D.
2016-06-10 12:00 - 13:00 | Simons Center Conference Room, Bldg. 46, Room 6011, 43 Vassar Street, Cambridge, MA, 02139, United States
Date: Friday, June 10 , 2016
Time: 12:00 pm-1:00 pm
Speaker: Barak Boaz, Ph.D.
Affiliation: Simons Fellow, Guoping Feng lab, McGovern Institute for Brain Research, MIT

Talk title: Neurobiology of social behavior abnormalities and the role of Gtf2i in the etiology of Williams syndrome
Abstract: Social behavior abnormalities are common feature of several neurodevelopmental and psychiatric disorders, yet the exact neural circuits, genetic contribution and biological mechanisms remain mainly unknowTwo neuropsychiatric disorders that involve opposite social behavior abnormalities are autism spectrum disorders (ASD), which are characterized mainly by hyposociability, and Williams syndrome (WS), which exhibits hypersociability.
In this talk I will first discuss the social behavior abnormalities of ASD and WS, and discuss three key theories, representing the physiological, functional and systemic aspects of the theories in the field of social behavior.
In the second part of my talk I will present our main recent findings in a research project focused on WS, supporting the critical role of Gtf2i, a general transcription factor deleted in WS, in the etiology of the hypersocial behavior. Briefly, we characterized brain regions and cell type that are abnormally active in Gtf2i-hetrozygous mouse model for WS, and consequently knockedout Gtf2i specifically in those regions to define the molecular, neuroanatomical and behavioral outcomes.
Using a novel Gtf2i conditional knockout mouse we induced Gtf2i-knockout only from excitatory neurons located mainly in the cortex and hippocampus and study the behavioral and molecular consequences in a neurodevelopmental perspective. We show that this selective Gtf2i-deletion is sufficient to cause severe neuroanatomical impairments, hypersociability and increased levels of anxiety-like behavior. Interestingly, RNAseq results and biochemical studies demonstrated substantial abnormalities of the transcriptome caused by Gtf2i-deletion from neurons, suggesting a novel role for major synaptic modifications in the etiology of WS.

SCSB Colloquium Series: David Amaral, Ph.D.
2016-05-25 16:00 - 17:00 | Singleton Auditorium, Bldg. 46, Room 3002, 43 Vassar Street, Cambridge, MA, 02139, United States
Dr. David Amaral, professor in the department of Psychiatry and Behavioral Sciences and Center for Neuroscience at UC Davis. He is the Research Director of the MIND Institute at the University of California Davis Health System.
Wednesday, May 25, 2016
Time: 4:00 pm-5:00 pm, followed by reception
Speaker: David G. Amaral, Ph.D.
Affiliation: Professor of Psychiatry and Neuroscience, Beneto Foundation Chair and Research Director, The MIND Institute, UC Davis
Host: Mriganka Sur, Ph.D., FRS
Talk title: The Pursuit of Neurophenotypes in Autism Spectrum Disorder
Abstract: There have been hundreds of neuroimaging studies of individuals with autism spectrum disorder (ASD). But, most of these have had very small samples of subjects, few of these have been longitudinal and almost all have not included subjects with severe ASD and intellectual disability. I will briefly describe the Autism Phenome Project which is a large, multidisciplinary study of young children with autism spectrum disorder. I will summarize some of our neuroimaging data that support the view that autism has many biological subtypes. To date, over 300 children (2-3 ½-years old) with autism spectrum disorder or age-matched typically developing controls have received structural and functional MRI scans. I will focus my comments on data related to total brain size as well as alterations in the development of the amygdala. These data provide ample evidence for different “neurophenotypes” of ASD. I will more briefly discuss recent findings of altered brain structure in children as young as 6 months of age that later attain a diagnosis of autism spectrum disorder.
