Behavior, Bioinformatics, Biophysics, Computational Biology, Computer Simulation, Depression, Drug Design and Discovery, Integrins, Mathematical and Computational Biology, Membrane Proteins/Channels, Multiple Sclerosis, Protein Complexes, Protein Structure/Function, Signal Transduction, Synapses, Synaptic Plasticity, Synaptogenesis, Theoretical Biology, Theoretical Biophysics
Biophysics and Systems Pharmacology [BSP], Neuroscience [NEU]
PhD, Graduate School and University Center of CUNY
, University of Texas Southwestern Medical Center
Icahn School of Medicine at Mount Sinai Faculty Council Award
Irma T. Hirschl/Monique Weill-Caulier Trust Research Award
Mount Sinai School of Medicine “Best Postdoctoral Mentor” Award
Johnson & Johnson/IMHRO Rising Star Translational Research Award
Dr. Harold and Golden Lamport Research Award
Synaptic mechanisms of addiction and depression
My lab has made fundamental contributions to understanding how brain reward systems adapt to chronic stress and cocaine. Utilizing advanced histological techniques, whole cell electrophysiology and 2 photon glutamate uncaging at single spines, we have found that chronic stress or cocaine increases excitatory synaptic transmission within the nucleus accumbens (NAc) in a cell- and synapse-type specific manner to control depression- and addiction-like behaviors. More recently, we have investigated the role of specific presynaptic glutamatergic inputs to the NAc in meditating depression-like behavior using circuit specific optogenetics and electrophysiology. We have found that social defeat stress, a mouse model of depression, increases synaptic transmission specifically at thalamo-striatal synapses on NAc medium spiny neurons and that this is both necessary and sufficient to promote a depression-like behavioral phenotype.
Neural circuitry of aggression
A few years ago, we observed that highly aggressive mice found aggressive social interaction to be rewarding and we hypothesized that this may directly drive aggressive behavior. Using circuit tracing techniques and slice electrophysiology we identified key differences in the activation of brain reward circuitry between highly aggressive mice and their non-aggressive counterparts. Tools such as circuit specific optogenetics along with in vivo imaging of neural activity in awake behaving mice have allowed us to functionally probe neural circuits that control the rewarding aspects of aggressive behavior. Our initial results show strong activation of a GABAergic projection from the basal forebrain to the lateral habenula (lHb) that controls both aggression and its rewarding properties. Ongoing studies in my lab aim to further dissect the inputs to lHb impacting aggressive behavior and to identify the discreet neural codes associated with such aggressive behavior along with the molecular mechanisms driving these effects.
Neuroimmune mechanisms of depression
We have found that the pro-inflammatory cytokine interleukin-6 (IL-6) is highly up regulated in serum from stress susceptible mice as well as patients with treatment resistant major depression. The source of IL-6 is from bone marrow derived leukocytes, which is released in response to stress and can penetrate the brain and act directly on neural circuits controlling mood and emotion. In order to study peripheral IL-6, we’ve generated bone marrow chimeric mice that lacks the IL-6 gene only in bone marrow derived leukocytes and found the mice were behaviorally resilient to social stress. We also administered systemic monoclonal antibodies to sequester IL-6 and promote resilience. Janssen Pharmaceuticals partially funded our work testing such antibody sequestration strategies, and based on the results, they have recently launched a phase II clinical trial testing the efficacy of Sirukumab, a humanized monoclonal antibody against IL-6, in treatment resistant unipolar depression. Our current investigations aim to define the precise mechanisms by which peripheral immune cells and pro-inflammatory signals impact synaptic mechanisms in brain reward regions
Golden SA, Heshmati M, Flanigan M, Christoffel DJ, Guise K, Pfau ML, Aleyasin H, Menard C, Zhang H, Hodes GE, Bregman D, Khibnik L, Tai J, Rebusi N, Krawitz B, Chaudhury D, Walsh JJ, Han MH, Shapiro ML, Russo SJ. Basal forebrain projections to the lateral habenula modulate aggression reward. Nature 2016 Jun; 534(7609).
Christoffel DJ, Golden SA, Walsh JJ, Guise KG, Heshmati M, Friedman AK, Dey A, Smith M, Rebusi N, Pfau M, Ables JL, Aleyasin H, Khibnik LA, Hodes GE, Ben-Dor GA, Deisseroth K, Shapiro ML, Malenka RC, Ibanez-Tallon I, Han MH, Russo SJ. Excitatory transmission at thalamo-striatal synapses mediates susceptibility to social stress. Nature Neuroscience 2015 Jul; 18(7).
Hodes GE, Kana V, Menard C, Merad M, Russo SJ. Neuroimmune mechanisms of depression. Nature Neuroscience 2015 Oct; 18(10).
Hodes GE, Pfau ML, Purushothaman I, Ahn HF, Golden SA, Christoffel DJ, Magida J, Brancato A, Takahashi A, Flanigan ME, Ménard C, Aleyasin H, Koo JW, Lorsch ZS, Feng J, Heshmati M, Wang M, Turecki G, Neve R, Zhang B, Shen L, Nestler EJ, Russo SJ. Sex Differences in Nucleus Accumbens Transcriptome Profiles Associated with Susceptibility versus Resilience to Subchronic Variable Stress. Journal of Neuroscience 2015 Dec; 35(50).
Hodes GE, Pfau ML, Leboeuf M, Golden SA, Christoffel DJ, Bregman D, Rebusi N, Heshmati M, Aleyasin H, Warren BL, Lebonté B, Horn S, Lapidus KA, Stelzhammer V, Wong EH, Bahn S, Krishnan V, Bolaños-Guzman CA, Murrough JW, Merad M, Russo SJ. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proceedings of the National Academy of Sciences of the United States of America 2014 Nov; 111(45).
Russo SJ, Nestler EJ. The brain reward circuitry in mood disorders [review]. Nature Reviews Neuroscience 2013 Oct; 14(10): 736.
Golden SA, Christoffel DJ, Heshmati M, Hodes GE, Magida J, Davis K, Cahill ME, Dias C, Ribeiro E, Ables JL, Kennedy PJ, Robison AJ, Gonzalez-Maeso J, Neve RL, Turecki G, Ghose S, Tamminga CA, Russo SJ. Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression. Nature Medicine 2013 Mar; 19(3).
Chaudhury D, Walsh JJ, Friedman AK, Juarez B, Ku SM, Koo JW, Ferguson D, Tsai HC, Pomeranz L, Christoffel DJ, Nectow AR, Ekstrand M, Domingos A, Mazei-Robison MS, Mouzon E, Lobo MK, Neve RL, Friedman JM, Russo SJ, Deisseroth K, Nestler EJ, Han MH. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature 2013 Jan; 493(7433).
Dietz DM, Sun H, Lobo MK, Cahill ME, Chadwick B, Gao V, Koo JW, Mazei-Robison MS, Dias C, Maze I, Damez-Werno D, Dietz KC, Scobie KN, Ferguson D, Christoffel D, Ohnishi Y, Hodes GE, Zheng Y, Neve RL, Hahn KM, Russo SJ, Nestler EJ. Rac1 is essential in cocaine-induced structural plasticity of nucleus accumbens neurons. Nature Neuroscience 2012 Jun; 15(6).
Golden SA, Covington HE, Berton O, Russo SJ. A standardized protocol for repeated social defeat stress in mice. Nature Protocols 2011 Jul; 6(8).
Christoffel DJ, Golden SA, Dumitriu D, Robison AJ, Janssen WG, Ahn HF, Krishnan V, Reyes CM, Han MH, Ables JL, Eisch AJ, Dietz DM, Ferguson D, Neve RL, Greengard P, Kim Y, Morrison JH, Russo SJ. IκB kinase regulates social defeat stress-induced synaptic and behavioral plasticity. Journal of Neuroscience 2011 Jan; 31(1).
Russo SJ, Dietz DM, Dumtriu D, Morrison JH, Malenka RC, Nestler EJ. The addicted synapse: mechanisms of synaptic and structural plasticity in nucleus accumbens [review]. Trends in Neuroscience 2010 Jun; 33(6): 7652-63.
Koo J, Russo SJ, Ferguson D, Nestler EJ, Duman RS. Nuclear factor-κB is a critical mediator of stress-impaired neurogenesis and depressive behavior. Proceedings of the National Academy of Sciences of the United States of America 2010; 107(6): 2669-2674.
Maze I, Covington HE, Dietz DM, LaPlant Q, Renthal W, Russo SJ, Mechanic M, Mouzon E, Neve RL, Haggarty SJ, Ren Y, Sampath SC, Hurd YL, Greengard P, Tarakhovsky A, Schaefer A, Nestler EJ. Essential Role of the Histone Methyltransferase G9a in Cocaine-induced Plasticity . Science 2010; 327(5962): 213-216.
Krishnan V, Han MH, Graham DL, Berton O, Renthal W, Russo SJ, Laplant Q, Graham A, Lutter M, Lagace DC, Ghose S, Reister R, Tannous P, Green TA, Neve RL, Chakravarty S, Eisch AJ, Self DW, Lee FS, Tamminga C, Cooper DC, Gershenfeld HK, Nestler EJ. Molecular Mechanisms Underlying Susceptibility and Resistance to Social Defeat in Brain Reward Regions. Cell 2007; 131(2): 391-404.
Russo SJ, Bolanos CA, Theobald DE, DeCarolis NA, Renthal W, Kumar A, Winstanley CA, Renthal NE, Wiley MD, Self DW, Russell D, Neve RL, Eisch AJ, Nestler EJ. IRS2-Akt pathway in midbrain dopamine neurons regulates behavioral and cellular responses to opiates. Nature Neuroscience 2007; 10(1): 93-99.
Berton O, McClung CA, Dileone RJ, Krishnan V, Renthal W, Russo SJ, Graham D, Tsankova NM, Bolanos CA, Rios M, E. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 2006; 311(5762): 864-868.
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Dr.Russo did not report having any of the following types of financial relationships with industry during 2015 and/or 2016: consulting, scientific advisory board, industry-sponsored lectures, service on Board of Directors, participation on industry-sponsored committees, equity ownership valued at greater than 5% of a publicly traded company or any value in a privately held company. Please note that this information may differ from information posted on corporate sites due to timing or classification differences.
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