Role of distinct glutamatergic inputs to nucleus accumbens in stress disorders
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.
Scott J Russo, PhD
Director, Center for Affective Neuroscience
Lab: ICAHN ICAHN 10-02
Office: ICAHN 10-20c
Cell-type-specific role for nucleus accumbens neuroligin-2 in depression and stress susceptibility.. Heshmati M1,2, Aleyasin H1,2, Menard C1,2, Christoffel DJ3, Flanigan ME1,2, Pfau ML1,2, Hodes GE1,2, Lepack AE1,2, Bicks LK1,2, Takahashi A1,2,4, Chandra R5, Turecki G6, Lobo MK5, Maze I1,2, Golden SA7, Russo SJ8,2.
Social stress induces neurovascular pathology promoting depression.. Menard C1,2, Pfau ML1, Hodes GE1, Kana V3, Wang VX4, Bouchard S1, Takahashi A1,5, Flanigan ME1, Aleyasin H1, LeClair KB1, Janssen WG1, Labonté B1, Parise EM1, Lorsch ZS1, Golden SA1, Heshmati M1, Tamminga C6, Turecki G7, Campbell M8, Fayad ZA4, Tang CY4, Merad M3, Russo SJ9.
Meet the Team
Charles J. Burnett
visiting Postdoctoral Fellow
Visiting PHD student
Aki Takahashi, Ph.D.
Visiting Assistant Professor
MD, PhD Student
Visiting Assistant Professor
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”
2017 Neuroscience Mentorship Distinction Award
2013-2016 F30 Ruth L. Kirschstein Predoctoral Individual National Research Service Award (NRSA), National Institute of Mental Health (Mitra Heshmati PI)
2014-2016 F31 Ruth L. Kirschstein Predoctoral Individual National Research Service Award (NRSA), National Institute of Mental Health (Madeline Pfau PI)
2017 Recruitment of science and technology personnel, Ministry of Science and Technology Grand in Taiwan, China Medical University (Hsiao-yun Lin PI)
2017-2019 Brain and Behavior Research Foundation Young Investigator Grant (Caroline Menard PI)
2017-2019 F31 Ruth L. Kirschstein Predoctoral Individual National Research Service Award (NRSA), National Institute of Mental Health (Meghan Flanigan PI)
2017-2019 Early Postdoc Mobility Fellowship, Swiss National Science Foundation; Walter and Gertrud Siegenthaler Postdoctoral Fellowship (Flurin Cathomas PI)
2016 American College of Neuropsychopharmacology (ACNP) travel award for ACNP meeting, Hollywood (USA) (Caroline Menard)
2017 Society for Neuroscience (SfN) travel award for Japan Neuroscience Society meeting, Chiba (Japan) (Meghan Flanigan)
Neuroscience of bullying: Why do some find it rewarding?
Stress-related inflammation may increase risk for depression
A Bully’s Brain Perceives Subordinating Others as a “Reward”
His stress is not like her stress
Study reveals that people with stress-related inflammation may suffer from depression
One Mind Institute
Inflammation and Depression: Translating Basic Discoveries into New Therapeutics – Dr. Scott Russo
How stress ups depression risk
New Research Shows Bullying Impacts The Reward Center Of The Brain