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Stanley Institute for Cognitive Genomics

The Stanley Institute for Cognitive Genomics is dedicated to brain mainpartgenetics
and neuroscience research that will enhance our understanding of schizophrenia, bipolar disorder, major depression and other cognitive disorders. The goal is to improve the diagnosis and treatment of these disorders.

Work at the Stanley Institute for Cognitive Genomics at CSHL is funded by gifts from Theodore and Vada Stanley and grants from the
National Institute of Mental Health.

DSC 1508aSchizophrenia, bipolar disorder and major recurrent depression are cognitive disorders that create an enormous burden on patients, their families and our health care system.   Because vulnerability to these disorders tends to run in families, genetics is a factor; however the specific genetic components involved and how they impact symptoms or treatments of these disorders has yet to be fully worked out.  With recent advances in genomic technologies, CSHL is now poised to unravel the genetic complexity of cognitive disorders. Simultaneously, advanced technologies in neuroscience are allowing CSHL researchers to understand how the brain assembles neural circuits to control behaviors and cognitive processes like attention and decision-making. At the CSHL Stanley Institute for Cognitive Genomics, these two approaches – genetics and neuroscience – are integrated to form a dual-strategy aimed at improving the diagnosis and treatment of schizophrenia, bipolar disorder, depression and other cognitive disorders.

Researchers at CSHL began working on the genetics of cognitive disorders in 2005 following a generous gift from Ted and Vada Stanley. Under the leadership of James Watson, this effort grew substantially in 2007 with a gift from the Stanley’s to establish the Stanley Institute for Cognitive Genomics. At that time, new DNA sequencing technologies, called “Next Generation Sequencing” were being developed. CSHL Professor and sequencing pioneer W. Richard McCombie was one of the first to apply this technology to study the genetics of cognitive disorders putting the Stanley Institute on the map.

With the goal of improving diagnosis and the potential for personalized therapy, the Stanley Center began applying state-of-the-art genomics technologies to identify genetic variants contributing to schizophrenia, bipolar disorder and major depression. Together with collaborators in the U.S., Scotland, Ireland, Pakistan and Australia, CSHL focused first on sequencing the complete genomes or protein coding regions of the genomes of families that had many members suffering from mental illness. One of the key findings demonstrated an overlap among genes contributing to schizophrenia and autism. CSHL also showed a link between the genes involved in the modification of chromatin structure and schizophrenia.

In 2014, with continuing support from Ted and Vada Stanley, the Stanley Institute incorporated the efforts of CSHL neuroscientists focused on understanding how brain circuits assemble and function. Like the genetics group, neuroscientists are developing and applying new technologies, including sophisticated brain mapping technologies and novel behavioral paradigms for studying decision making, attention and other processes. Stanley Institute neuroscientists are now studying the function of genes that have been implicated in cognitive disorders.

Penzo, M. A., Robert, V., Tucciarone, J., De Bundel, D., Wang, M., Van Aelst, L., Darvas, M., Parada, L. F., Palmiter, R. D., He, M., Huang, Z. J., Li, B. (2015) The paraventricular thalamus controls a central amygdala fear circuit. Nature, 519 (7544). pp. 455-459. ISSN 0028-0836

Krishnan, K., Wang, B. S., Lu, J., Wang, L., Maffei, A., Cang, J., Huang, Z. J. (2015) MeCP2 regulates the timing of critical period plasticity that shapes functional connectivity in primary visual cortex. Proc Natl Acad Sci U S A, 112 (34).

Kim, Yongsoo, Venkataraju, Kannan Umadevi, Pradhan, Kith, Mende, Carolin, Taranda, Julian, Turaga, Srinivas C, Arganda-Carreras, Ignacio, Ng, Lydia, Hawrylycz, Michael J, Rockland, Kathleen S, Seung, H.  Sebastian, Osten, Pavel (2015) Mapping Social Behavior-Induced Brain Activation at Cellular Resolution in the Mouse. Cell Reports, 10 (2). pp. 292-305. ISSN 2211-1247

Wang M, Perova Z, Arenkiel BR, Li B. Synaptic modifications in the medial prefrontal cortex in susceptibility and resilience to stress. J Neurosci. 2014 May 28;34(22):7485-92.

Karakas E, Furukawa H. Crystal structure of a heterotetrameric NMDA receptor ion channel. Science. 2014 May 30;344(6187):992-7

McCarthy SE, Gillis J, Kramer M, Lihm J, Yoon S, Berstein Y, Mistry M, Pavlidis P, Solomon R, Ghiban E, Antoniou E, Kelleher E, O'Brien C, Donohoe G, Gill M, Morris DW, McCombie WR, Corvin A. De novo mutations in schizophrenia implicate chromatin remodeling and support a genetic overlap with autism and intellectual disability. Molecular Psychiatry. 2014 Jun; 19(6):652-8.

Thomson, P.A., J.S. Parla, A.F. McRae, M. Kramer, K. Ramakrishnan, J. Yao, D.C. Soares, S. McCarthy, S.W. Morris, L. Cardone, S. Cass, E. Ghiban, W. Hennah, K.L. Evans, D. Rebolini, J.K. Millar, S.E. Harris, J.M. Starr, D.J. Macintyre, S. Generation, A.M. McIntosh, J.D. Watson, I.J. Deary, P.M. Visscher, D.H. Blackwood, W.R. McCombie, and D.J. Porteous, 708 Common and 2010 rare DISC1 locus variants identified in 1542 subjects: analysis for association with psychiatric disorder and cognitive traits. Molecular Psychiatry, 2014. 19 (6) p.668-675 Jun.


Mistry, M., J. Gillis, and P. Pavlidis, Genome-wide expression profiling of schizophrenia using a large combined cohort. Molecular Psychiatry, 2013. 18(2): p. 215-25PMCID

Ragan T, Kadiri LR, Venkataraju KU, Bahlmann K, Sutin J, Taranda J, Arganda-Carreras I, Kim Y, Seung HS, Osten P. Serial two-photon tomography for automated ex vivo mouse brain imaging. Nat Methods. 2012 Jan 15;9(3):255-8.

Parla, J.S., I. Iossifov, I. Grabill, M.S. Spector, M. Kramer, and W.R. McCombie, A comparative analysis of exome capture. Genome Biology, 2011. 12(9): p. R97.

Malhotra, D., S. McCarthy, J.J. Michaelson, V. Vacic, K.E. Burdick, S. Yoon, S. Cichon, A. Corvin, S. Gary, E.S. Gershon, M. Gill, M. Karayiorgou, J.R. Kelsoe, O. Krastoshevsky, V. Krause, E. Leibenluft, D.L. Levy, V. Makarov, A. Bhandari, A.K. Malhotra, F.J. McMahon, M.M. Nöthen, J.B. Potash, M. Rietschel, T.G. Schulze, and J. Sebat, High frequencies of de novo cnvs in bipolar disorder and schizophrenia. Neuron, 2011. 72(6): p. 951-963.

Ragan T, Kadiri LR, Venkataraju KU, Bahlmann K, Sutin J, Taranda J, Arganda-Carreras I, Kim Y, Seung HS, Osten P. Serial two-photon tomography for automated ex vivo mouse brain imaging. Nat Methods. 2012 Jan 15;9(3):255-8.

Archived Publications

2016

Detailed images of NMDA receptor show how zinc and a potential drug affect its function | December 1, 2016
CSHL research reveals for the first time the structure of a portion of an important brain cell receptor, called the NMDA (N-methyl D-aspartate) receptor. 
Innovative tools will shed clarifying light on inhibitory neurons | September 21, 2016
Researchers at Cold Spring Harbor Laboratory (CSHL) have created an innovative set of tools that combine a small handful of genetic markers and virus particles to target GABA cell types with a high degree of specificity.
Was it better or worse than you expected? Your basal ganglia know – so you can act accordingly | September 21, 2016
Neuroscientists from Cold Spring Harbor Laboratory report they have uncovered a neural circuit that processes evaluations and have succeeded in identifying its sources.
Our brain uses statistics to calculate confidence, make decisions | May 4, 2016 
The brain produces feelings of confidence that inform decisions the same way statistics pulls patterns out of noisy data
First structural views of the NMDA receptor in action will aid drug development | May 2, 2016
CSHL Associate Professor Hiro Furukawa led a research team to obtained images of the NMDA (N-methyl, D-aspartate) receptor in active, non-active, and inhibited states. 
CSHL scientists Bo Li and Je Lee win HFSP Research Grant awards | April 12, 2016
Two scientists, both leaders of research labs at CSHL, are among 25 teams that have won Human Frontier Science Program(HFSP) Research Program Grants for 2016. 

2015

Discovery of a new X-linked intellectual disability syndrome is aided by web communication tools | December 3, 2015
A CSHL geneticist has used powerful internet and social media tools to find doctors and researchers in nine U.S. states and eight other nations to help him confirm, document, and describe a new genetic syndrome in young boys that he first came across five years ago.   
Surprised? Cholinergic neurons send brain-wide broadcasts enabling us to learn from the unexpected | August 27, 2015
CSHL neuroscientists have discovered a set of dedicated neurons in the forebrain that broadcast a message throughout the cerebral cortex, rapidly informing multiple distributed subregions of any surprising rewards or punishments.
Members of the Masthead Cove Yacht Club raised $7,124 from their annual Masthead Race, donating proceeds to support cancer research conducted by CSHL Professor Nicholas Tonks. 
Scientists discover important communication mechanism between two brain areas implicated in schizophrenia | April 7, 2015
Disruptions in an inhibitory brain circuit between the thalamus and prefrontal cortex may underlie cognitive disorders such as schizophrenia
A new brain circuit that controls fear is identified | January 19, 2015
CSHL researchers identified a new pathway that controls fear memories and behavior in the mouse brain, offering mechanistic insight into how anxiety disorders may arise. 
Imaging method linking brainwide cell activation & behavior shows what it means for mice to have sex in mind | January 5, 2015
A completely automated method allows researchers to detect the activity of neurons during specific behaviors, at the resolution of individual brain cells throughout the entire mouse brain.

2014

Neuronal circuits filter out distractions in the brain | December 15, 2014
Study identifies neural circuit in the mouse brain that controls attention and sensory processing, providing insight into how the brain filters out distractions. 
Four CSHL scientists will contribute to President’s BRAIN Initiative under new NIH grants | September 30, 2014
The CSHL grants are among more than 100 issued by the National Institutes of Health (NIH), totaling $46 million for the 2014-15 fiscal year. They are NIH’s initial funding for the BRAIN Initiative.   
A shift in the code: new method reveals hidden genetic landscape | August 18, 2014
A new way to analyze genome sequences that pinpoints so-called insertion and deletion mutations (known as “indels”) in genomes of people with diseases such as autism, obsessive-compulsive disorder and Tourette syndrome.
Unprecedented detail of intact neuronal receptor offers blueprint for drug developers | May 29, 2014
Biologists at CSHL report today that they have succeeded in obtaining an unprecedented view of a type of brain-cell receptor that is implicated in a range of neurological illnesses.
Dealing with stress – to cope or to quit? | May 27, 2014
Neuroscientists at CSHL have identified the group of neurons in the brain that determines how a mouse responds to stress — whether with resilience or defeat, providing major insight into the neuronal basis of depression.
Research sees overlap in altered genes found in schizophrenia, autism and intellectual disability | April 28, 2014
Multinational team of scientists presents new evidence supporting the theory that in at least some cases of schizophrenia, autism and intellectual disability (ID), malfunctions in some of the same genes are contributing to pathology.     
Scientists discover a new pathway for fear deep within the brain | February 12, 2014
CSHL scientists announce the discovery of a new neural circuit in the brain that directly links the site of fear memory with an area of the brainstem that controls behavior. 

2013

Team demonstrates power of precision medicine in successful treatment of patient with disabling OCD | October 3, 2013
Psychiatrist, geneticist, neurosurgeon & genome sequencers generate data on one patient, with powerful implications for care and counseling. 
Hiro
Hiro Furukawa - Professor

We seek to understand the effect of various genetic mutations in N-methyl-D-aspartate receptors (NMDARs)at the protein level by “visualizing” changes in molecular architecture caused by the mutations. Our structural biology studies serve as molecular blueprints for designing new drugs for neurological disorders involving NMDAR dysfunction.
Jesse
Jesse Gillis - Assistant Professor

Gene networks allow us to find commonalities among disease genes in neuropsychiatric disorders, but the methods are mostly complex and ad hoc. Our group is developing an online network analysis laboratory that allows systematic analysis at a very sophisticated level. This will facilitate replication of prior results and refocusing research questions based on new data.
Z. Josh
Z. Josh Huang - Professor

One focus of our lab is the chandelier cell (ChC), a distinct type of inhibitory interneuron in the neocortex that may regulate neural circuit operations underlying information processing. Deficiency of ChCs is implicated in schizophrenia pathology. We seek to discover how altered ChC function contributes to behavioral deficits in schizophrenia.
Adam
Adam Kepecs - Professor

My lab studies cognition and decision-making. We have developed sensitive behavioral tests in rodents that we can link to similar behaviors in humans, for example assessing their decision confidence. This allows us to uncover the neural basis of complex behaviors that will inform development of therapies for diseases such as schizophrenia, major depression and Alzheimer's disease. In complementary work, we are using computational approaches to assess people across various cognitive dimensions in order to develop data-driven, quantitative classification methods for psychiatric disorders.
Bo
Bo Li - Professor

My lab seeks to understand the link between neural circuits and behavior. By probing and manipulating specific circuits in the rodent brain, we study synaptic and circuit mechanisms underlying cognitive functions such as attention, learning and memory, and dysfunctions associated with pathophysiology in schizophrenia, depression and anxiety.
Gholson
Gholson Lyon - Assistant Professor

Our lab is interested in the pathophysiology of severe neuropsychiatric disorders. We use whole genome sequencing, induced pluripotent stem cells and deep brain stimulation to perform detailed functional studies of gene mutations that we have identified in families with increased prevalence of intellectual disability, autism, Tourette syndrome and schizophrenia.
W. Richard
W. Richard McCombie - Professor

Schizophrenia, bipolar disorder and major depression have significant genetic components in their causation. We carry out both family studies in case control studies to better identify likely genetic variants contributing to these disorders. We also seek to determine the likely neurological function of the genes we identify.
Alea
Alea Mills - Professor

My group is focused on defining how chromatin dynamics controls differentiation of neural stem cells, dendritic architecture, and behavior. We use a multi-faceted functional approach to elucidate genetic/epigenetic processes controlling brain pathologies, and generate novel models for neurological syndromes that could pave the way for designing more effective clinical interventions.
Pavel
Pavel Osten - Associate Professor

Disruptions in GABAergic circuits are leading risk factors for mental disorders, including schizophrenia. We are generating the first quantitative anatomical atlas featuring precise cell counts and 3D distribution of GABAergic cell types in the mouse brain. This will inform studies of disruptions of GABAergic circuits in schizophrenia mouse models.
Jessica
Jessica Tollkuhn - Assistant Professor

My lab seeks to understand how transient events during development exert lasting effects on the brain and behavior. We study how steroid hormones establish and regulate sexually dimorphic neural circuits. Our goal is to provide a mechanistic link between the epigenetic events that occur during development and the consequent sex differences in social behavior.