A major focus of my research is to study the neural and immunological mechanisms of neuropsychiatric disorders such as depression and anxiety. We use a combination of transgenic mice, immune cell transplantation, optogenetics/electrophysiology, viral mediated gene transfer, behavioral models and molecular methods to understand how the brain and body adapts to stress to control pathological behaviors in depression and anxiety.
Role of distinct glutamatergic inputs to nucleus accumbens in stress disorders
Stress leads to synaptic adaptations within multiple structures throughout the CNS that control mood and emotion leading to the expression of depression- or anxiety-like behaviors . The nucleus accumbens (NAc), is a stress-responsive brain region that undergoes extensive remodeling of excitatory synapses following stress . Recent work demonstrates increased excitatory synaptic input on medium spiny neurons (MSNs) in the NAc following chronic social defeat stress (CSDS), which controls social avoidance and anhedonia [2, 3]. However, the NAc receives multiple glutamatergic inputs from a number of presynaptic regions, including both the prefrontal cortex (PFC) and posterior intralaminar thalamus (ILT), which contains the paraventricular and centromedian nucleus of the thalamus. Recent studies have suggested that distinct glutamatergic inputs to NAc may promote opposing effects on reward-related behavior [4, 5], depending upon how these inputs innervate and activate NAc microcircuitry. While CSDS may impact both pre- and postsynaptic excitatory tone on MSNs, it is unclear what roles PFC versus ILT inputs play in mediating the effects of chronic stress on behavioral and synaptic adaptations.
To understand the role of PFC versus ILT synaptic transmission in CSDS-induced depression- and anxiety-like behavior we will utilize a combination of 2-photon microscopy, electrophysiology, optogenetics and behavior. Our preliminary data identifies increased levels of vesicular glutamate transporter 2 (VGLUT2), but not VGLUT1, within the NAc of susceptible mice, which are presynaptic markers enriched in ILT versus PFC, respectively. Next, using circuit specific optogenetic stimulation with channelrhodopsin (ChR2) of ILT or PFC terminals in NAc coupled to postsynaptic whole cell recording on MSNs, we find evidence for altered synaptic transmission within the ILT-NAc pathway in susceptible mice. We then performed circuit specific in vivo neuronal activation with ChR2 and neuronal inhibition with presynaptic voltage-dependent Ca2+ toxins (tToxins) or halorhodopsin (NpHr) to alter glutamatergic transmission. We find that activation of VGLUT2-containing ILT-NAc-projecting neurons is sufficient for social stress-induced behavioral abnormalities, whereas modulation of VGLUT1 containing NAc-projecting PFC neurons chronically with tToxins had the opposite effect. Interestingly rapid inactivation of only PFC-NAc terminals with NpHr had no effect on social avoidance behavior. Our results suggest a dichotomous role for distinct glutamatergic inputs to NAc in ctronolling the pro-depressant like effects of social stress
Peripheral IL-6 from leukocytes controls susceptibility to social defeat stress
Stress disorders, such as depression and anxiety have been associated with changes in the pro-inflammatory cytokine interleukin-6 (IL-6). IL-6 is produced and secreted by a number of cell types in both the central nervous system (CNS) and peripheral organs. To date, much attention has been focused on CNS mechanisms of the inflammatory response through activation of resident microglia and astrocytes, however, little is known regarding the functional contributions of IL-6 produced and released from circulating leukocytes. To understand the contribution of the peripheral immune system, we utilized a repeated social defeat stress model (RSDS) of depression and anxiety. Importantly, this model allows us to study individual differences in stress responses since approximately 2/3 of all stressed animals termed susceptible exhibit a spectrum of depression-like behavior, such as social avoidance and anhedonia, whereas the remainder are resilient and resist the development of such behaviors. Strikingly, we found that animals reconstituted with bone marrow (BM) hematopoietic progenitors isolated from susceptible animals exhibited depression-like behavior compared to those reconstituted with cells isolated from an unstressed control. Since stromal cells and brain microglia resist lethal irradiation, these results strongly suggest that the BM derived circulating immune system contributes to depression and anxiety in the social defeat model.
Importantly, we find that susceptible mice exhibit nearly 100 fold higher sera IL-6 than resilient mice after their first defeat and this remains elevated 48 hours after the last defeat. When we isolated leukocytes prior to any stress exposure and stimulated them ex-vivo with lipopolysaccharide (LPS), animals that later developed a susceptible phenotype following RSDS initially showed an exaggerated release of IL-6 that negatively correlated with social interaction (SI) ratio. To test the functional relevance of this heightened peripheral IL-6 response to stress, we blocked susceptibility to RSDS by systemically injecting an antibody that neutralized IL-6 in the periphery. We then performed transplants of BM hematopoietic progenitors from IL-6 knockout mice into control mice that had their peripheral immune system depleted by irradiation. BM transplantation from IL-6 knockout mice promoted resiliency to RSDS, while BM transplantation from susceptible mice induced social avoidance following a sub-threshold defeat. Together our studies indicate that individual differences in the inflammatory response to stress underlie the development of social avoidance in the social defeat model. The goals of this project are to further define the mechanisms of individual differences in the peripheral inflammatory response to stress and its relevance to depression- and anxiety-like behavior.
Neural circuits controlling motivational aspects of aggressive behavior
Social behavior is a highly complex term defined generally as interactions among social organisms directed at one another and includes both nonaggressive and aggressive social behavior. In general, aggressive social behavior is antagonistic in nature while nonaggressive social behavior can be either agonistic or neutral. A number of psychiatric disorders including autism, schizophrenia and mood disorders are characterized by disturbances in social behavior, thought to result in part, from altered function of reward circuits. Various subnuclei within the ventral midbrain that control mood and emotion have been shown to encode certain aspects of aggressive and nonaggressive social interaction. For example, the hypothalamus is known to encode the initiation of aggression, while the ventral striatum and its targets control social reward and motivation. However, we lack detailed information regarding behavioral and neural circuit mechanisms that control aggressive and nonaggressive social behavior. We hypothesize that deficits within various domains of social behavior result, in part, from inappropriate activation of brain reward systems in response to social stimuli. This in turn alters the motivational valence of such social interactions to guide behavioral responses toward social targets.
To identify neural circuits that control social behavior, we first established a mouse behavioral model for investigating individual differences in social interaction with an intruder. In this model, aggressors (AGG) develop a conditioned place preference (CPP), while nonaggressors (NON) develop a conditioned place aversion (CPA), to the intruder-paired context. Further, we identify an inhibitory GABAergic projection from the nucleus accumbens (NAc) to the lateral habenula (lHb) that controls intruder CPP. Circuit specific optogenetic silencing of inhibitory GABAergic NAc-lHb terminals of AGG with halorhodopsin (NpHR) increases lHb neuronal firing and abolishes CPP to the intruder-paired side. Conversely, activation of GABAergic NAc-lHb terminals of NON with channelrhodopsin (ChR2) decreases lHb neuronal firing and promotes CPP to the intruder-paired side. Lastly, direct optogenetic stimulation or inhibition of lHb cell bodies in AGG and NON recapitulates the NAc circuit specific behavioral phenotyes. These results demonstrate that NAc-lHb circuit plays a critical role in regulating the rewarding or aversive components of intruder interactions, and provide novel mechanistic insight into the neural circuits modulating social behavior and motivation. In this project, we use a combination of optogenetics/electrophysiology and detailed behavioral analysis to determine whether differences in NAc-lHb circuitry control hedonic drive during nonaggressive versus aggressive social investigation and interaction.
New Research Shows Bullying Impacts The Reward Center Of The Brain — July 5, 2016
— Wisconsin Public Radio
Gender Differences in the Stressed-Out Brain — April 14, 2016
— Primemind, by Signe Brewster
Research Into More Effective Depression Therapies
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 29;534(7609):688-92. doi: 10.1038/nature18601.
Nugent BM, Wright CL, Shetty AC, Hodes GE, Lenz KM, Mahurkar A, Russo SJ, Devine SE, McCarthy MM. Brain feminization requires active repression of masculinization via DNA methylation. Nat Neurosci. 2015 May;18(5):690-7.
Koo JW, Mazei-Robison MS, LaPlant Q, Egervari G, Braunscheidel KM, Adank DN, Ferguson D, Feng J, Sun H, Scobie KN, Damez-Werno DM, Ribeiro E, Peña CJ, Walker D, Bagot RC, Cahill ME, Anderson SA, Labonté B, Hodes GE, Browne H, Chadwick B, Robison AJ, Vialou VF, Dias C, Lorsch Z, Mouzon E, Lobo MK, Dietz DM, Russo SJ, Neve RL, Hurd YL, Nestler EJ. Epigenetic basis of opiate suppression of Bdnf gene expression in the ventral tegmental area. Nat Neurosci. 2015 Mar;18(3):415-22.
Christoffel DJ, Walsh JJ, Golden SA, Heshmati M, Friedman AK, Dey A, Smith M, Rebusi N, Pfau M, Ables JL, Hodes GE, Deisseroth K, Ibanez-Tallon I, Han MH, Russo SJ. Excitatory transmission at thalamo-striatal synapses mediates susceptibility to social stress. Nat Neurosci, 2015.
Khibnik LA, Beaumont M, Doyle M, Heshmati M, Slesinger PA, Nestler EJ, Russo SJ. Stress and Cocaine Trigger Divergent and Cell Type-Specific Regulation of Synaptic Transmission at Single Spines in Nucleus Accumbens. Biol Psychiatry, 2015 Jun 6. pii: S0006-3223(15)00471-0.
Sun H, Damez-Werno DM, Scobie KN, Shao NY, Dias C, Rabkin J, Koo JW, Korb E, Bagot RC, Ahn FH, Cahill ME, Labonté B, Mouzon E, Heller EA, Cates H, Golden SA, Gleason K, Russo SJ, Andrews S, Neve R, Kennedy PJ, Maze I, Dietz DM, Allis CD, Turecki G, Varga-Weisz P, Tamminga C, Shen L, Nestler EJ. ACF chromatin-remodeling complex mediates stress-induced depressive-like behavior. Nat Med. 2015 Oct;21(10):1146-53.
Birey F, Kloc M, Chavali M, Hussein I, Wilson M, Christoffel DJ, Chen T, Frohman MA, Robinson JK, Russo SJ, Maffei A, Aguirre A. Genetic and Stress-Induced Loss of NG2 Glia Triggers Emergence of Depressive- like Behaviors through Reduced Secretion of FGF2. Neuron. 2015 Dec 2;88(5):941-56.
Hodes GE, Pfau ML, Purushothaman I, Ahn HF, Golden SA, Christoffel DJ, Menard CA, Magida J, 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 sub-chronic variable stress. J Neurosci. 2015 Dec 16;35(50):16362-76.
Hodes GE, Pfau ML, Leboeuf M, Golden SA, Christoffe DJ, Bregman D, Rebusi N, Heshmati M, Aleyasin H, Warren BL, Lebonté B, Horn S, Lapidus KA, Stelzhammer V, Wong EHF, 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, Proc Natl Acad Sci U S A. 2014 Nov 11;111(45):16136-41.
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 24;493(7433):532-6.
Holloway T, Moreno JL, Umali A, Rayannavar V, Hodes GE, Russo SJ, González-Maeso J. Prenatal Stress Induces Schizophrenia-Like Alterations of Serotonin 2A and Metabotropic Glutamate 2 Receptors in the Adult Offspring: Role of Maternal Immune System. J Neurosci. 2013 Jan 16;33(3):1088-98.
Golden SA, Christoffel DJ, Heshmati M, Magida J, Hodes GE, Davis K, Cahill M, Dias C, Ribero E, Ables JL, Maeso-Gonzalez J, Neve RL, Ghose S, Tamminga CA, and Russo SJ. Epigenetic regulation of synaptic remodeling in depression. Nature Medicine. 2013 Mar 19;110(12):4441-2.
Walsh JJ, Friedman AK, Sun H, Heller EA, Ku SM, Juarez B, Burnham VL, Mazei-Robison MS, Ferguson D, Golden SA, Koo JW, Chaudhury D, Christoffel DJ, Pomeranz L, Friedman JM, Russo SJ, Nestler EJ, Han MH. Stress and CRF gate neural activation of BDNF in the mesolimbic reward pathway. Nat Neurosci. Jan;17(1):27-9.
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. Nat Neurosci. 2012 Jun;15(6):891-6.
Kurita M, Holloway T, García-Bea A, Kozlenkov A, Friedman AK, Moreno JL, Heshmati M, Golden SA, Kennedy PJ, Takahashi N, Dietz DM, Mocci G, Gabilondo AM, Hanks J, Umali A, Callado LF, Gallitano AL, Neve RL, Shen L, Buxbaum JD, Han MH, Nestler EJ, Meana JJ, Russo SJ, González-Maeso J. HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity. Nat Neurosci. 2012 Sep;15(9):1245-54.
Christoffel DJ, Golden SA, Heshmati M, Graham A, Birnbaum S, Neve RL, Hodes G and Russo SJ. Effects of Inhibitor of kB Kinase Activity in the Nucleus Accumbens on Emotional Behavior. Neuropyschopharmacology. 2012 Nov;37(12):2615-23.
Koo JW, Mazei-Robison MS, Chaudhury D, Juarez B, LaPlant Q, Ferguson D, Feng J, Sun H, Scobie KN, Damez-Werno D, Crumiller M, Ohnishi YN, Ohnishi YH, Mouzon E, Dietz DM, Lobo MK, Neve RL, Russo SJ, Han MH, and Nestler EJ, Novel Role of BDNF as a Negative Modulator of Morphine Action. Science 2012 Oct 5;338(6103):124-8.
Christoffel DJ, Golden SA, Dumitriu D, Robison AJ, Janssen WG, Ahn HF, Krishnan V, Reyes C, Han MH, Ables JL, Eisch AJ, Dietz DM, Ferguson D, Neve RL, Greengard P, Kim Y, Morrison JH, and Russo SJ. IkappaB kinase regulates social defeat stress induced synaptic and behavioral plasticity. J Neurosci. 2011 Jan 5;31(1):314-21. “Must Read” in F1000.
Dietz DM, Laplant Q, Watts EL, Hodes GE, Russo SJ, Feng J, Oosting RS, Vialou V, Nestler EJ. Paternal transmission of stress-induced pathologies. Biol Psychiatry. 2011. Golden SA, Covington HE, Berton O, and Russo SJ. Repeated social defeat stress in mice: a high throughput protocol. Nat Protocol. 2011 Aug 6(8): 1183-1191.
Mazei-Robison MS, Koo JW, Friedman AK, Lansink CS, Robison AJ, Vinish M, Krishnan V, Kim S, Siuta MA, Galli A, Niswender KD, Appasani R, Horvath MC, Neve RL, Worley PF, Snyder SH, Hurd YL, Cheer JF, Han MH, Russo SJ, Nestler EJ. Role for mTOR Signaling and Neuronal Activity in Morphine-Induced Adaptations in Ventral Tegmental Area Dopamine Neurons. Neuron. 2011 Dec 22;72(6):977-90.
Meet the Team
Research track Assistant Professor
Aki Takahashi, Ph.D.
Visiting Assistant Professor
Visiting PHD student
Funding & Awards
Peripheral IL-6 from leukocytes controls susceptibility to social defeat stress.
The goal of this award is to understand the molecular mechanisms within leukocytes that control susceptibility versus resilience to social stress.
1P50AT008661-01 (Russo PI for project 1)
Project 1: Preservation of psychological resilience
The goal of this grant is to test the mechanisms by which grape derived polyphenol extracts promote psychological resilience.
1R01 MH090264 (Russo PI)
NIMH Role of thalamic versus cortical inputs to nucleus accumbens in stress related disorders
The goal of this award is to define the electrophysiological and behavioral effects of thalamic versus cortical glutamate inputs to the NAc in the chronic social defeat stress model.
Irma T. Hirschl/Monique Weill-Caulier Trust Research Award (Russo PI)
Leukocyte derived IL-6 predicts individual differences in susceptibility to social defeat stress
The goal of this award is to understand whether IL-6 from leukocytes controls the pro-depressant effects of chronic social defeat stress.
2003 CUNY Robert L. Thompson Award for Excellence
2005 Postdoctoral Ruth L. Kirschstein National Research Service Award (NIH)
2006 Keystone Symposia Scholarship Award
2006 Grand Prize; University of Texas Southwestern Medical Center Postdoctoral Symposium
2006 NARSAD Young Investigator Award
2007 Invited travel award for NIDA mini-convention at SFN
2008 NARSAD Young Investigator Award
2009 National Academy of Science Kavli Frontiers Fellow
2012 Johnson & Johnson/IMHRO Rising Star Translational Research Award
2012 Dr. Harold and Golden Lamport Research Award
2012 Mount Sinai School of Medicine “Best Postdoctoral Mentor” Award
2013 Irma T. Hirschl/Monique Weill-Caulier Trust Research Award
2014 Icahn School of Medicine at Mount Sinai Faculty Council Award
2015 Thomson Reuters “Highly Cited Researcher”
2015 Thomson Reuters “Most Influential Scientific Minds”