2011 WSA Regional 2011 WSA Regional Conference Conference Creating the Dream: The Lifelong Journey with Williams Syndrome Salk Institute September 17 th , 2011 Research Update 10:30-10:50am 1
Williams Syndrome: A Model for Linking Genes, Neural Systems, and Social Phenotype Program Project NICHD HD03113-14 Ursula Bellugi, Director Unlocking the Enigmatic Nature of Williams Syndrome Characterization of Neuroimaging of Neuroimaging of Social Phenotype Social Circuitry Social Circuitry Ursula Bellugi Eric Halgren Eric Halgren Salk Institute UC San Diego UC San Diego Gene Networks for Cellular Social Cognition Architectonics Julie R. Korenberg Katerina Semendeferi Utah University UC San Diego Modeling WS Using Human Neurons Fred Gage Alysson Muotri Salk Institute
Hypersociability: New Perspectives from WS Fascination with faces!! Is anyone a stranger? Once more with feeling
ERP Biomarker: Increased Attention to ERP Biomarker: Increased Attention to Faces in WS Faces in WS ERP reflects increased response to happy faces, decreased to fearful faces in WS. Also in fMRI parallel study! 4 Haas et al, 2009; Mills et al, 2006
New forays: What underlies WS social phenotype New forays: What underlies WS social phenotype Event Related Potentials (ERPs) • Face paradigm, reward paradigm and trust paradigm Psychophysiology • Skin conductance response and heart rate simultaneously recorded to examine autonomic responsivity to social and non-social stimuli, happy vs. scared faces Visual Social Stimuli Visual Non-social Stimuli 5
Williams Syndrome: A Model for Linking Genes, Neural Systems, and Social Phenotype Program Project NICHD HD03113-14 Ursula Bellugi, Director Unlocking the Enigmatic Nature of Williams Syndrome Characterization of Neuroimaging of Neuroimaging of Social Phenotype Social Circuitry Social Circuitry Ursula Bellugi Eric Halgren Eric Halgren Salk Institute UC San Diego UC San Diego Gene Networks for Cellular Social Cognition Architectonics Julie R. Korenberg Katerina Semendeferi Utah University UC San Diego Modeling WS Using Human Neurons Fred Gage Alysson Muotri Salk Institute
What’ ’s going on in Williams Syndrome s going on in Williams Syndrome What’s going on in Williams Syndrome What brains when they see smiling faces? brains when they see smiling faces? brains when they see smiling faces? Genes What are the What do the cells like? genes do? Brain Structure Histology and Function Partial Deletions Stem Cells Social Phenotype Eric Halgren Eric Halgren Eric Halgren Tim Brown Anders Dale Tim Brown Anders Dale Anders Dale Tim Brown Matt Erhardt Matt Erhardt Matt Erhardt University of California San Diego University of California San Diego University of California San Diego Williams Syndrome: A Model for Linking Genes, Williams Syndrome: A Model for Linking Genes, Neural Systems, and Social Phenotype Neural Systems, and Social Phenotype
Brain Structure Brain Structure Brain parts (MRI) (MRI) What parts of the brain make What parts of the brain make the Williams brain special? the Williams brain special? area Right parietal Right occipital Brain pathways Right medial orbital Left entorhinal Brain surface
Brain Movies Brain Movies (from MEG and MRI) (from MEG and MRI) Are Williams brains Are Williams brains specially tuned to specially tuned to happy faces? happy faces? sad neutral happy
Williams Syndrome: A Model for Linking Genes, Neural Systems, and Social Phenotype Program Project NICHD HD03113-14 Ursula Bellugi, Director Unlocking the Enigmatic Nature of Williams Syndrome Characterization of Neuroimaging of Neuroimaging of Social Phenotype Social Circuitry Social Circuitry Ursula Bellugi Eric Halgren Eric Halgren Salk Institute UC San Diego UC San Diego Gene Networks for Cellular Social Cognition Architectonics Julie R. Korenberg Katerina Semendeferi Utah University UC San Diego Modeling WS Using Human Neurons Fred Gage Alysson Muotri Salk Institute
Williams Syndrome Williams Syndrome Williams Syndrome and the Social Brain and the Social Brain and the Social Brain Studies at the cellular level Studies at the cellular level Studies at the cellular level Katerina Semendeferi, P.h.D Katerina Semendeferi, P.h.D Katerina Semendeferi, P.h.D University of California San Diego University of California San Diego University of California San Diego Brain Organization Thinking and Emotions Analyze human brain tissue: Frontal Lobe and Amygdala
Laboratory of Human Comparative Neuroanatomy Brain Organization Thinking and Emotions Analyze human brain tissue: Frontal Lobe and Amygdala Nicole Katerina Kari Hanson Barger Semendeferi Lisa Stefanacci Branca Hrvoj
• One of the most important steps from gene to behavior is how nerve cells are connected to each other and develop into networks. This project will examine the cellular composition of the social brain and characterize the complexity of the neurons. There is more information for you on this project at the research table! 13
Williams Syndrome: A Model for Linking Genes, Neural Systems, and Social Phenotype Program Project NICHD HD03113-14 Ursula Bellugi, Director Unlocking the Enigmatic Nature of Williams Syndrome Characterization of Neuroimaging of Neuroimaging of Social Phenotype Social Circuitry Social Circuitry Ursula Bellugi Eric Halgren Eric Halgren Salk Institute UC San Diego UC San Diego Gene Networks for Cellular Social Cognition Architectonics Julie R. Korenberg Katerina Semendeferi Utah University UC San Diego Modeling WS Using Human Neurons Fred Gage Alysson Muotri Salk Institute
Modeling Williams Syndrome using human neurons Recent advances Dr. Fred Gage Dr. Alysson Muotri Dr. Carol Marchetto
How to study WS Brain cells?
A new model for human condition? Brain Cells Patient Are they Different? Control
The Tooth Fairy Kit Collection The Tooth Fairy Kit Collection
Proliferation of WS Brain Cells Proliferation of WS Brain Cells 9665 (Control) 5225 (typical WS) Day 0 Day 4
Proliferation of WS Brain Cells Proliferation of WS Brain Cells
WS Heart Cells Can we find chemicals to help WS heart cells feels better?
Williams Syndrome: A Model for Linking Genes, Neural Systems, and Social Phenotype Program Project NICHD HD03113-14 Ursula Bellugi, Director Unlocking the Enigmatic Nature of Williams Syndrome Characterization of Neuroimaging of Neuroimaging of Social Phenotype Social Circuitry Social Circuitry Ursula Bellugi Eric Halgren Eric Halgren Salk Institute UC San Diego UC San Diego Gene Networks for Cellular Social Cognition Architectonics Julie R. Korenberg Katerina Semendeferi Utah University UC San Diego Modeling WS Using Human Neurons Fred Gage Alysson Muotri Salk Institute
Williams Syndrome: A Model for Linking Genes, Neural Systems, and Social Phenotype Gene Networks for Social Cognition in Williams Syndrome Julie R. Korenberg, MD, PhD Li Dai, PhD University of Utah
The Goal of Genetics in Williams syndrome To understand how specific genes disturb specific brain development and result in the positive and problematic social behavior and emotion in WS. • Which WS genes are important for social behavior? • Which WS genes are important for Neural Imaging such as MEG? • How do the deleted genes change the interactions of the other 30,000 genes in WS? • Are these genes active in the social brain regions? • Can we find a way to alter the genetic disturbance and the behaviors in WS?
What is different in Williams syndrome? From the person, their brain, their behavior, their emotion, Chr7 FKBP6 FZD9 to their genes BAZ1B BCL7B TBL2 WBSCR14 STX1A CLDN4 Typical WS CLDN3 Rare WS ELN LIMK1 WSCR1 RFC2 CYLN2 GTF2IRD1 GTF2I Genes deleted in WS Human: ~1.7meter Chromosome: 2-10 micrometer
What do we do? Study genetics at many levels. Person √ Social behavior Cells √ Brain function Proteins √ DNA/RNA √ Genes
A story of a little girl with WS and small deletion identifies a gene, GTF2I, contributing to sociability in WS GTF2IRD1 GTF2I STX1A FKBP6 CYLN2 LIMK1 FZD9 ELN Typical Deletion 5889 Deletion Reduced sociability in 5889: • Reduced global sociability • Reduced global approach • Reduced approach strangers Dai Korenberg et al., 2008;
Recent advances: The different social and emotional behavior in WS come from differences in their genes. Brain synapse genes are different in WS Genetic pathway analysis Cells from blood Future: brain and neurons Circuits in brain Electrical and chemical contacts between neurons in brain
Recent advances Hypothesis: WS region, social genes alter social neural pathways and then social behaviors Our current studies will reveal whether social brain hormones that affect trust and response to happy and fearful faces in controls, are changed in WS.
Genetics to understand behavior Emotion & Behavior WS Brain Neuroimaging Sociability Expression GENETICS Neuroendocrine Person to cells to DNA/RNA Multilevel studies Social brain hormones Neural Pathways Cellular Pathways Development ERPs Future: use gene knowledge to help WS and to understand other social disorders such as anxiety and autism.
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