Simons Center for the Social Brain

SCSB Lunch Series: Siyuan Rao, Ph.D.
2018-03-23 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, March 23, 2018
Time: 12:00pm – 1:00pm
Speaker: Siyuan Rao, Ph.D.
Affiliation: Polina Anikeeva Laboratory, Research Laboratory of Electronics and Simons Center for Social Brain, MIT
Talk Title: Magnetochemogenetic Technique for Remote Manipulation of Genetically Identifiable Neurons
Abstract: For the rodent models of Autism Spectrum Disorders, whose behavior is sensitive to the implanted foreign objects, investigation of the neural circuits underlying their abnormal behavioral phenotypes via invasive optogenetic and electrical neuromodulation devices poses a challenge. Here we developed a minimally invasive neuromodulation tool for magnetothermal deep brain interrogation of genetically identifiable neural populations in freely moving rodents. This approach enabled 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 achieved the implant-free convenience of magnetothermal neuromodulation concomitantly with the genetic precision of chemogenetics, and thus enabled spatial and temporal modulation for behavioral investigation. We anticipate that the magnetochemogenetic tools will facilitate investigation of neural circuits during behavioral experiments and enable neuromodulation studies in rodent models incompatible with permanently implanted hardware.

SCSB Colloquium Series - Randall Carpenter, M.D.
2018-03-21 10:00 - 11:00 | Singleton Auditorium, Bldg. 46, Room 3002, 43 Vassar Street, Cambridge, MA, 02139, United States
Randall Carpenter, MD, Co-Founder, President and CEO Seaside Therapeutics..photo by www.mckeephotography.com..For use and publication by Seaside Therapeutic and editorial publications…For more information about the photograph, mckeephotography.com, matt@mckeephotography.com.617-910-9314
Wednesday, March 21, 2018
Time: 4:00 pm-5:00 pm, followed by reception . NEW TIME: 10:00 am-11:00 am
Speaker: Randall L. Carpenter, M.D.
Affiliation: Chief Scientific Officer, Rett Syndrome Research Trust; Research Affiliate, Picower Institute for Learning and Memory
Host: Mark Bear, Ph.D.
Talk title: Development of Targeted Therapeutics for Autism Spectrum Disorders.
Abstract: Twelve years ago, I co-founded Seaside Therapeutics ​with an MIT professor based upon a strong sense of optimism that substantial progress would soon be realized in treatment of neurodevelopmental disorders. A new era of molecular genetics and neurobiology suggested that genetic diagnoses need not equate to permanent mental disability, but can actually provide insights toward disease-altering treatments. A number of highly penetrant genetic mutations had been discovered and reproduced in animal models. ​novel therapeutics targeting the underlying pathophysiology were ​being ​validated in these animal models and preliminary human trials ​were demonstrat​ing​ promising efficacy. However, ​subsequent larger definitive trials failed to demonstrate convincing therapeutic benefit. This lecture will address how these failures are informing therapeutic discovery and development with a particular focus on ​the ​R​ett S​yndrome ​R​esearch ​T​rust​’s ​R​oadmap ​to a Cure for Rett Syndrome. ​
[Video of the talk]

SCSB Colloquium Series - Joshua Kaplan, Ph.D.
2018-02-21 16:00 - 17:00 | Singleton Auditorium, Bldg. 46, Room 3002, 43 Vassar Street, Cambridge, MA, 02139, United States
Wednesday, February 21, 2018
Time: 4:00 pm-5:00 pm, followed by reception
Speaker: Joshua Kaplan, Ph.D.
Affiliation: Professor of Neurobiology, MGH/Harvard Medical School
Host: Steven Flavell, Ph.D.
Talk title: From compost to the clinic: using C. elegans to study psychiatric disorders.
Abstract: Recent human genetic studies suggest that mutations in ~500 genes are linked to autism spectrum disorder. Although many of these genes encode proteins that are localized at synapses, relatively little is known about how these mutations alter brain function or development. An important goal for the field is to identify specific cellular defects caused by mutations linked to Autism and to determine how (and if) these defects contribute to the cognitive and developmental deficits found in Autism. My lab uses a simple model organism (Caenorhabditis elegans) as a genetic platform to investigate the impact of Autism-linked genes on brain development and function. C. elegans is a small worm (1 mm long as an adult) that lives in rotting organic matter (like compost heaps).
Our studies suggest that mutations linked to Autism in humans alter retrograde synaptic signals, the strength of inhibitory synapses, and activity-induced gene expression in worms. We propose that these cellular defects play an important role in the pathophysiology of Autism.

SCSB Lunch Series: Dara Manoach, Ph.D.
2018-02-16 12:00 - 13:00 | Simons Center Conference Room, Bldg. 46, Room 6011, 43 Vassar Street, Cambridge, MA, 02139, United States
Date: Friday, February 16, 2018
Time: 12:00pm – 1:00pm
Speaker: Dara S. Manoach, Ph.D.
Affiliation: Professor of Psychology, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School
Talk Title: Abnormal sleep spindles in neurodevelopmental disorders: Treatable endophenotypes that link risk genes to impaired cognition?
Abstract: Although neurodevelopmental disorders are defined by waking phenomena, abnormal sleep is a pervasive feature that may contribute to their manifestations. In schizophrenia, there is convincing evidence that sleep spindle deficits impair memory consolidation. Sleep spindles, a defining EEG oscillation of Stage 2 sleep, are initiated in the thalamic reticular nucleus and are a product of thalamocortical interactions. I will review evidence that spindle deficits in schizophrenia are: (i) genetically-mediated, (ii) associated with abnormal thalamocortical interactions, (iii) impair sleep-dependent memory consolidation, (iv) contribute to symptoms and (v) are a novel treatment biomarker. I will end by describing our collaborative study of sleep spindles in autism.
Dara Manoach is a Professor of Psychology in the Department of Psychiatry at Massachusetts General Hospital and Harvard Medical School. She is a neuropsychologist whose research program uses multimodal neuroimaging to illuminate the neural bases of cognitive deficits in neuropsychiatric and neurodevelopmental disorders, particularly schizophrenia and autism. The ultimate goal of this work is to identify mechanisms of cognitive impairment that can guide the development of treatment. Her primary area of research focuses on the contribution of abnormal sleep to memory consolidation deficits. Dr. Manoach received her doctorate from Harvard University in Experimental Psychology, completed a clinical psychology internship at McLean Hospital and a postdoctoral fellowship in clinical neuropsychology at Beth Israel Hospital of Harvard Medical School. At MGH she directs the Laboratory for Multimodal Neuroimaging of Cognition in Psychopathology (Manoach Lab) at the Athinoula A. Martinos Center for Biomedical Imaging.

SCSB Lunch Series: Ted Gibson, Ph.D.
2018-02-09 12:00 - 13:00 | MA
Date: Friday, February 9, 2018
Time: 12:00pm – 1:00pm
Speaker: Ted Gibson, Ph.D.
Affiliation: Professor of Cognitive Science, Department of Brain & Cognitive Sciences, MIT
Talk Title: The structure of pragmatic reasoning and the scope of the communicative impairment in ASD.
Abstract: Language comprehension entails more than simply decoding the literal meaning of an utterance: our interpretation is powerfully shaped by the perceived intent of the speaker, the linguistic and social context of the utterance, and our general world knowledge. This ability to exploit speaker intent and background knowledge to go beyond the literal meaning is referred to as “pragmatics”, and is at the core of communicative success. The term “pragmatics”, as used in the literature, encompasses a wide range of diverse phenomena, from irony and sarcasm, to understanding scalar implicatures, to using prosodic cues, to making world-knowledge-based inferences. In an ongoing project, we are using an individual-differences approach to investigate the structure of mental processes relevant to pragmatic reasoning. To do this, we developed an extensive battery consisting of 20 tasks that tap 11 distinct phenomena. Across a large sample of neurotypical adults (n=~400) tested on Mechanical Turk, factoring out IQ, we discovered a remarkably clear clustering of tasks into sensible categories. The biggest category included phenomena that appear to involve higher-order expectations about social norms, like irony, white lies, and humor. Other categories included world-knowledge-based inferences, prosodic processing, and understanding scalar implicatures. We then asked which of these components of pragmatic reasoning are impaired in individuals with ASD. In a sample of 18 participants (data collection ongoing), we found impairments in a) the component that deals with higher-order expectations about social norms, and b) world-knowledge-based inferences, but not in prosodic processing or understanding scalar implicatures. Thus, we are making some progress in both carving up the mental architecture of pragmatic processing, and trying to delineate the scope of the communicative impairment in ASD.

SCSB Colloquium Series - Lauren Atlas, Ph.D.
2018-01-24 16:00 - 17:00 | Singleton Auditorium, Bldg. 46, Room 3002, 43 Vassar Street, Cambridge, MA, 02139, United States
Wednesday, January 24, 2018
Time: 4:00 pm-5:00 pm, followed by reception
Speaker: Lauren Atlas, Ph.D.
Affiliation: Clinical Investigator / Section Chief, National Institutes of Health (National Center for Complementary and Integrative Health, National Institutes on Drug Abuse)
Host: Ev Fedorenko, Ph.D.
Talk title: How instructions, expectations, and conditioning modulate pain and aversive learning
Abstract: In this talk I will present recent work examining how instructions, expectations, and associative learning jointly influence pain and aversive learning. In a series of experiments, we combined experimental manipulations with computational models to isolate the influences of these factors on subjective pain, aversive learning, and physiological responses. We found that these factors were supported by both interactions and dissociations in neural pathways. More recent work indicates that individual differences in state anxiety moderate these effects. I will discuss the clinical implications of these findings, as well as broader conclusions about how cognitive factors shape perception, including subjective outcomes such as pain.
[Video of the talk]

SCSB Lunch Series: Michael Strano, Ph.D.
2017-12-08 12:00 - 13:00 | Simons Center Conference Room, Bldg. 46, Room 6011, 43 Vassar Street, Cambridge, MA, 02139, United States
Date: Friday, December 8, 2017
Time: 12:00pm – 1:00pm
Speaker: Michael Strano, Ph.D.
Affiliation: Carbon P. Dubbs Professor, Department of Chemical Engineering, MIT
Talk Title: Applications of Nanosensors to Understanding Biochemical Signaling Within the Human Body
Abstract: The human body is a vast network of biochemical signaling pathways dictating physiological and pathological processes. To probe this network, our research group has introduced Corona Phase Molecular Recognition, or CoPhMoRe, for discovering synthetic, heteropolymer corona phases that form molecular recognition sites at the nanoparticle interface. By screening libraries of synthetic heteropolymers chemically adsorbed onto single-walled carbon nanotubes (SWNT), we have engineered new optical biosensors that exhibit highly selective recognition for specific molecules, including riboflavin, L-thyroxine, dopamine, nitric oxide, sugar alcohols, estradiol, as well as proteins such as fibrinogen. The results have significant potential in that nanoparticles such as SWNT can be interfaced to biological systems at the sub-cellular level, allowing monitoring of sub-cellular, cellular, tissue, and whole-organism processes. With deep tissue penetration, we demonstrated our nanosensors in vitro with no photobleaching, and in vivo with no fluorescence degradation (400+ days).
Engineering the nanoparticle corona in this way offers significant potential to translate sensor technology to previously inaccessible environments. We have measured dopamine efflux from PC12 cells, which may allow monitoring of neuroendocrine production and signaling. Additionally, we have synthesized selective cortisol and progesterone sensors and are currently performing in vivo measurements of progesterone in mice. Cortisol has been implicated in numerous pathological conditions, including depression, post-traumatic stress disorder, bipolar disorder, and autism, whereas progesterone is the primary female sex hormone dictating fertility. Monitoring these, as well as other steroid hormones, could provide significant insight about the etiology of various endocrine-related pathologies. In the diabetes space, we have synthesized an insulin sensor and are currently designing glucose responsive insulins (GRI). Interfacing insulin sensors and a GRI with currently available continuous glucose monitors may revolutionize diabetes treatment, as insulin dosages will be more tightly controlled in a closed loop fashion. Last, I will discuss our current work in cancer. One major challenge in cancer is the ability to have an accurate and comprehensive picture of the intratumoral delivery and localization of chemotherapeutic drugs. The tumor heterogeneity has a significant impact on drug delivery, drug uptake, and therapeutic effectiveness. Our nanosensor platform can provide real-time spatiotemporal information about tumor metabolites and chemotherapeutic drug delivery. This feedback will give physicians and patients information about the tumor molecular response significantly earlier in a matter of hours or days compared to the weeks or months needed to see measurable size changes on CT or MRI.

SCSB Lunch Series: Mehmet Kanik, Ph.D.
2017-12-01 12:00 - 13:00 | Simons Center Conference Room, Bldg. 46, Room 6011, 43 Vassar Street, Cambridge, MA, 02139, United States
Date: Friday, December 1, 2017
Time: 12:00pm – 1:00pm
Speaker: Mehmet Kanik, Ph.D.
Affiliation: Simons Postdoctoral Fellow, Polina Anikeeva Lab, Research Laboratory of Electronics, Department of Materials Science and Engineering, MIT
Talk Title: Brain Challenges and Materials Solutions.
Abstract: Electrophysiological recording requires precise tools that produce minimal tissue damage while allowing stable and reliable, low signal to noise ratio recording from specific regions of the brain. Probes made of stiff materials that have a significant mechanical mismatch with the brain cause drastic changes in neural dynamics in both chronic and acute implantations. Probes fabricated using metals, glasses, and semiconductors often fail to deliver high-quality recording in long-term experiments. Next generation neural probes should be designed to integrate multiple capabilities such as simultaneous light delivery and electrophysiological recording, infusion of pharmacological compounds and viral vectors, while maintaining a small footprint (< 500 um) to accommodate repeated behavioral evaluation over the course of several months.
Recently developed fiber-based flexible devices use biocompatible materials which exhibit mechanical properties similar to the brain. In addition, polymer probes developed in the Bioelectronics lab address the challenges in neural probe engineering by enabling simultaneous electrical recording, optical excitation, and microfluidic functions while reducing the foreign body response as compared to commercially available tools. Here, we introduce fiber neural probes to map the cortical circuits involved in interleukin-17a (IL-17a) dependent maternal immune activation (MIA) driven autism spectrum disorder (ASD) mouse model.

SCSB Colloquium Series - Benjamin Philpot, Ph.D.
2017-11-29 16:00 - 17:00 | Singleton Auditorium, Bldg. 46, Room 3002, 43 Vassar Street, Cambridge, MA, 02139, United States
Wednesday, November 29, 2017
Time: 4:00 pm-5:00 pm, followed by reception
Speaker: Benjamin Philpot, Ph.D.
Affiliation: Kenan Distinguished Professor; Associate Director, University of North Carolina, Neuroscience Center
Host: Mark Bear, Ph.D.
Talk title: Angelman syndrome treatment opportunities and clinical biomarkers
Abstract: Synaptic and circuit level defects in Angelman syndrome. Angelman syndrome is a severe neurodevelopmental disorder characterized by lack of speech, intellectual disability, and seizures. The disorder is caused by a loss of the maternal UBE3A allele; because the paternal allele is epigenetically silenced in neurons, loss of the maternal allele practically eliminates UBE3A protein from the brain. My lab strives to understand the basic pathophysiology underlying Angelman syndrome, and our research has provided synaptic and circuit insights into the basis for hyperexcitability in the Angelman syndrome brain. Simultaneous to our basic research studies, we have performed drug discovery that identified small molecules that can unsilence the paternal UBE3A allele and, hence, provide a treatment approach. Our research and that of others suggests that clinical trials are looming on the horizon. Given the increased interest in performing clinical trials, we have recently turned our attention towards identifying potential biomarkers in Angelman syndrome, including EEG recordings and MRI-DTI measurements of white matter integrity. In this talk, I will provide an overview of our understanding of Angelman syndrome pathophysiology and possible outcome measures that might be used in upcoming clinical trials.

SCSB Colloquium Series - Helen Tager-Flusberg, Ph.D.
2017-11-08 16:00 - 17:00 | Singleton Auditorium, Bldg. 46, Room 3002, 43 Vassar Street, Cambridge, MA, 02139, United States
David Fox Photographer; professional photographer Boston; professional photography Boston, portrait photographer boston, personal portrait photographer boston
Wednesday, November 8, 2017
Time: 4:00 pm-5:00 pm, followed by reception
Speaker: Helen Tager-Flusberg, Ph.D.
Affiliation: Professor, Psychological and Brain Sciences, Boston University
Host: Dara Manoach, Ph.D.
Talk title: Exploring Language Phenotypes in Autism Spectrum Disorder
Abstract: There is enormous variability in the language outcomes of children with ASD – from minimally verbal to intact linguistic knowledge. Over the past two decades, significant progress has been made in parsing this variability, investigating the relationship between language in ASD and in other disorders, and understanding the developmental progression and neural foundations for language from infancy through adulthood. In this presentation, I will discuss what we currently know about language in ASD taking a developmental and neurobiological perspective, and then outline future directions for research.
[Video of the talk]

SCSB Lunch Series: Ritchie Chen, Ph.D.
2017-11-03 12:00 - 13:00 | Simons Center Conference Room, Bldg. 46, Room 6011, 43 Vassar Street, Cambridge, MA, 02139, United States
Date: Friday, November 3, 2017
Time: 12:00pm – 1:00pm
Speaker: Ritchie Chen, Ph.D.
Affiliation: Postdoctoral Fellow, Chung Laboratory, Institute for Medical Engineering and Science, MIT
Talk Title: Simultaneous profiling of nucleotides, proteins, and fluorescence activity in transparent tissue enabled by flexible and multifunctional fixatives.
Abstract: Holistic understanding of complex biological systems, from single biomolecules to cell interactions across whole organs, will require integrated methodologies that can simultaneously probe both nucleotides and proteins in intact tissue. While several fixation strategies have been explored to preserve individual molecular features (e.g fluorescent activity of protein reporters, mRNA transcripts, or protein antigenicity), a universal tissue clearing method to profile all biomolecule types remains to be developed. Here, we demonstrate how multifunctional cross-linkers with tightly regulated reaction kinetics can form cohesive tissue gels by binding together biomolecules of interest. We find that these flexible and multifunctional linkers protected proteins and nucleotides from deteriorating in harsh chemical conditions by forming both intra- and intermolecular bonds. This strategy, called SHIELD, enables simultaneous molecular profiling of nucleotides, proteins, and fluorescent reporters in intact tissue, such that correlative studies, from single transcripts to whole organ features, can be performed.

SCSB Special Seminar - Dr. Tobias Grossmann
2017-11-01 10:00 - 11:00 | Singleton Auditorium, Bldg. 46, Room 3002, 43 Vassar Street, Cambridge, MA, 02139, United States
Wednesday, November 1, 2017
Time: 10:00 am-11:00 am
Speaker: Tobias Grossmann, Ph.D.
Affiliation: Associate Professor​, Department of Psychology, University of Virginia and Max Planck Institute for Human Cognitive and Brain Sciences
Host: Rebecca Saxe, Ph.D., Department of Brain and Cognitive Sciences, MIT
Talk title: The cradle of human sociality
Abstract: Sensitive responding to others’ emotional states is a hallmark feature of human social functioning. How this essential social ability develops during infancy will be the main question addressed in my talk. In particular, I will present recent neuroscience work to argue that emotion processing: (1) undergoes critical development during the first year of life, (2) is multifaceted in response to facial, vocal, and bodily cues, (3) ​can ​operate independently of conscious awareness, and (4) varies as a function of epigenetic modifications in the oxytocin system. I will also present longitudinal work showing that variability in infants’ responses to fear (distress) in others selectively predict​s​ their altruistic helping behavior as toddlers. Taken together, the research program summarized in this talk will paint a rich picture of when and how emotion processing skills emerge in the developing brain and what cooperative functions they serve. This offers a fresh look at the developmental and brain origins of human (pro)sociality.​

SCSB Lunch Series: David C. Page, Ph.D.
2017-10-27 12:00 - 13:00 | Singleton Auditorium, Bldg. 46, Room 3002, 43 Vassar Street, Cambridge, MA, 02139, United States
Date: Friday, October 27, 2017
Time: 12:00pm – 1:00pm
Speaker: David C. Page, Ph.D.
Affiliation: Director, Whitehead Institute; Professor of Biology, MIT; Investigator of the Howard Hughes Medical Institute
Talk Title: “Sex and Disease: Do males and females read their genomes differently?”
Abstract:
“Nothing in biology makes sense except in the light of evolution.”
Theodosius Dobzhansky, 1973
Dobzhansky’s oft-quoted dictum is highly relevant to our understanding of the manifold differences between males and females in health and disease, both within and beyond the reproductive tract. From the origins of sexual reproduction, in single-celled organisms, to the morphing of our own sex chromosomes from ordinary autosomes during the past 200-300 million years, comparative and evolutionary analyses offer deep, biologically grounded insights into the epigenetic, genomic, and phenotypic differences between the sexes. The emerging evolutionary view serves as an alternative, or complement, to the model (chromosomal sex → gonadal sex → phenotypic sex) that has guided teaching and research for the last half century. The opportunity now presents itself to capitalize upon this emerging evolutionary view of sex differences and their origins.
Most recently, my colleagues and I have conducted comparative genomic and evolutionary studies of the sex chromosomes of humans, other mammals, birds, and reptiles. These studies have revealed that the Y chromosome’s gene content became specialized, through natural selection, to maintain the ancestral dosage of homologous X-Y gene pairs that function as broadly expressed regulators of the genome and gene activity; these X-Y gene pairs regulate transcription, translation and protein stability (Bellott et al. [2014] Nature 508: 494; Bellott et al. [2017] Nature Genetics 49: 387). As a result, there exists a fundamental sexual dimorphism, at a biochemical level, and throughout the body, that derives directly from genetic differences between the X and Y chromosomes. This fundamental sexual dimorphism may play an unappreciated role in health and disease in both males and females.
***Please note this event will be held in Singleton Auditorium (46-3002)

SCSB Colloquium Series - Susan Rivera, Ph.D.
2017-10-25 16:00 - 17:00 | Singleton Auditorium, Bldg. 46, Room 3002, 43 Vassar Street, Cambridge, MA, 02139, United States
Wednesday, October 25, 2017
Time: 4:00 pm-5:00 pm, followed by reception
Speaker: Susan M. Rivera, Ph.D.
Affiliation: Professor, University of California, Davis. Department of Psychology and the MIND Institute
Host: Zsuzsa Kaldy, Ph.D., Lindsey Powell, Ph.D.
Talk title: Visual attention as a window into understanding brain development in autism and fragile X syndrome
Abstract: Visual processing can provide a window onto the broader capabilities of the developing brain. Our laboratory has for years been involved in assessing different aspects of visual attention in children with and without developmental disorders, including low-level motion and coherence processing, higher-level violation of expectation, and attentional biases towards certain types of emotion information. Our findings have illustrated how eye movements can be used to uncover development of brain functioning in both typically and atypically developing children and in some cases provide suggested avenues for treatment.
[Video of the talk]

SCSB Lunch Series: Nader Morshed
2017-10-20 12:00 - 13:00 | Simons Center Conference Room, Bldg. 46, Room 6011, 43 Vassar Street, Cambridge, MA, 02139, United States
Date: Friday, October 20, 2017
Time: 12:00pm – 1:00pm
Speaker: Nader Morshed
Affiliation: Graduate Student, White Lab, David H. Koch Institute for Integrative Cancer Research, MIT
Talk Title: Using phosphoproteomics to study signaling dysregulation in neurodevelopmental and neurodegenerative diseases.
Abstract: Cellular signaling networks play an essential role in brain function and are commonly mediated by protein phosphorylation. Using mass spectrometry, we have quantified protein phosphorylation changes in models of Rett’s syndrome and Alzheimer’s disease. This phosphoproteome allows us to link cellular phenotypes, such as synaptic deficits or glial responses, to the dysregulation of the kinases and phosphatases coordinating them. We hope that by understanding which signaling pathways are disrupted in brain development and aging, we may be able to identify new treatments for patients.

SCSB Colloquium Series - Dan Feldman, Ph.D.
2017-10-04 16:00 - 17:00 | Singleton Auditorium, Bldg. 46, Room 3002, 43 Vassar Street, Cambridge, MA, 02139, United States
Wednesday, October 4, 2017
Time: 4:00 pm-5:00 pm, followed by reception
Speaker: Dan Feldman, Ph.D.
Affiliation: Professor of Neurobiology, Dept. of Molecular & Cell Biology, and Helen Wills Neuroscience Institute, UC Berkeley
Host: Dr. Michale Fee
Talk title: Comparison of circuit defects in cerebral cortex across multiple mouse models of autism
Abstract: Distinct genetic forms of autism have been proposed share a common circuit basis in increased excitation-inhibition (E-I) ratio in cerebral cortex, resulting in circuit hyperexcitability and degraded information processing. We are testing this model by comparing synapse and circuit physiology and in vivo sensory coding across 4 genetically distinct mouse models of autism. We use whisker somatosensory cortex (S1) as a model system, because circuit dysfunction may relate to tactile sensory abnormalities, which are highly prevalent in autism. Increasing evidence suggests reduced inhibition in autism. However, it is critical to understand whether this is a direct result of genetic mutations and promotes the cognitive phenotypes of autism, or whether it may be a common homeostatic response that works to normalize cortical activity.

SCSB Colloquium Series - Thomas Bourgeron, Ph.D.
2017-09-27 16:00 - 17:00 | Singleton Auditorium, Bldg. 46, Room 3002, 43 Vassar Street, Cambridge, MA, 02139, United States
Wednesday, September 27, 2017
Time: 4:00 pm-5:00 pm, followed by reception
Speaker: Thomas Bourgeron, Ph.D.
Affiliation: Professor, University Paris Diderot / Institut Pasteur
Host: Benjamin Neale, MGH, HMS, Broad Institute/MIT
Talk title: Tackling the genetic and synaptic heterogeneity in autism from risk to resilience
Abstract: The genetic architecture of autism is complex made of a combination of common and rare variants. Our previous studies pointed at one biological pathway associated with autism related to the synapse. Among the causative genes, synaptic cell adhesion molecules (neuroligins and neurexins) and scaffolding proteins (SHANK) are crucial for synapse formation/maintenance as well as correct balance between inhibitory and excitatory synaptic currents. These findings significantly advanced our knowledge on the possible causes of autism. However, they also (unintentionally) contributed to the emergence of a simplistic conception of autism as a binary trait: mutated vs. non-mutated or affected vs. non-affected. This simplification neglects the large phenotypic heterogeneity of autism, whose genetic architecture – like most complex diseases – cannot be reduced to a single gene. In this presentation, I will discuss our recent results coming from human studies in large populations and genetic isolates as well as mouse studies that shed new light on the inheritance of autism and some of the underlying mechanisms. Finally, I will illustrate how we are currently studying Resilience to understand why some carriers of deleterious mutations seem to be protected (The Resilients) while others are severely affected.
[Video of the talk]

SCSB Lunch Series: Hector Luis Penagos-Vargas, Ph.D.
2017-09-22 12:00 - 13:00 | Simons Center Conference Room, Bldg. 46, Room 6011, 43 Vassar Street, Cambridge, MA, 02139, United States
Date: Friday, September 22, 2017
Time: 12:00pm – 1:00pm
Speaker: Hector Luis Penagos-Vargas, Ph.D.
Affiliation: Research Scientist, Wilson Laboratory, Picower Institute for Learning and Memory, MIT
Talk Title: Increases in reward elicit the expression of a joint offline state in the rodent hippocampus and retrosplenial cortex.
Abstract: The hippocampus is a brain structure implicated in a range of cognitive functions including navigation, planning, imagination and the formation of episodic memories. The reactivation, or replay, of hippocampal spiking patterns during sleep and periods of quiet waking has been associated with memory consolidation or navigation and planning, respectively. All these functions rely on the successful integration of information by the neocortex, which may be mediated by hippocampal replay. Consistent with this notion, different regions of neocortex have been shown to engage in a bidirectional dialog with the hippocampus during periods of sleep reactivation. Contrasting with this well-established sleep interaction, little is known about how the hippocampus and neocortex interact during awake replay. In this talk, I will describe a novel waking state in which the hippocampus and retrosplenial cortex, a structure also implicated in higher cognitive functions, jointly transition into an offline state in which they replicate well-known sleep relationships. Understanding these interactions at a mechanistic level could yield insights into cortical integration, which tends to be affected in neurological disorders.

SCSB Colloquium Series - Rob Knight, Ph.D.
2017-09-13 16:00 - 17:00 | Singleton Auditorium, Bldg. 46, Room 3002, 43 Vassar Street, Cambridge, MA, 02139, United States
Rob Knight at UC San Diego in La Jolla, Calif. on Tuesday June 16, 2015. Photograph by Tracy Boulian and David Ahntholz© Copyright 2015 Tracy Boulian and David Ahntholzhttp://www.tracydavid.com
Wednesday, September 13, 2017
Time: 4:00 pm-5:00 pm, followed by reception
Speaker: Rob Knight, Ph.D.
Affiliation: Professor, Department of Pediatrics and Department of Computer Science, Director for the Center for Microbiome Innovation, University of California, San Diego
Hosts: Eric Alm; Mriganka Sur
Talk title: Our Dynamic Microbiomes and the Brain
Abstract: Our lifespans are ever-increasing, but our healthspans are not, leading to long periods of unpleasant and expensive suffering with chronic conditions. Many of these conditions have recently been linked to the microbiome, via advances in DNA sequencing technology and software to interpret those sequences. We change our microbiomes every day through the foods we eat, the environments we experience, even the people we live and work with. The implications of these changes in the microbiome for our health are just beginning to be understood. And many of the effects are systemic: what happens in the gut doesn’t stay in the gut, and your gut microbiome can affect your liver, your joints, and even your brain. Through the American Gut Project, the largest crowdsourced and crowdfunded citizen-science project yet conducted, we now know about the microbiomes of many types of people, from the healthiest (student-athletes, centenarians) to the sickest (cancer patients, ICU patients, those with depression, those with C. diff). Amazingly, diet has an especially profound effect on our microbiomes, often outweighing the effects of disease or medications. This raises the prospect of a system for real-time analysis of our microbiomes that helps guide our daily decisions in a way that optimizes our microbiomes for extending our health-span.
[Video of the talk]

SCSB Lunch Series: Ian Wickersham, Ph.D.
2017-08-25 12:00 - 13:00 | 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.
