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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

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 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 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 Li - Associate 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 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 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 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 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.