2005 — 2007 |
Russo, Scott J |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Nuclear Factor Kappa B, Drug Addiction and Plasticity @ University of Texas SW Med Ctr/Dallas
DESCRIPTION (provided by applicant): Drugs of abuse have been shown to exert long lasting neuroadaptive changes in regions of the mesolimbic dopamine system. These include changes in transcriptional regulation, neuronal morphology, and electrophysiological properties of the neurons. Although many reports have implicated these neuroplastic changes in the behavioral manifestation of sensitization and reward tolerance, fewer studies have examined the connection between intracellular signaling molecules, neuronal morphology and connectivity, and cocaine responsiveness. Nuclear Factor Kappa B (NFKB), a transcription factor induced by inflammation and immune responses, regulates cell survival and neural plasticity and may be an important factor in the long term neuroadaptive changes associated with drug use. Our preliminary data support this hypothesis. The aim of the current proposal is to understand the functional role of NFKB in changes associated with chronic cocaine administration at the behavioral and cellular levels.
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0.913 |
2011 — 2015 |
Russo, Scott J |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms of Structural Plasticity in Stress-Related Disorders @ Icahn School of Medicine At Mount Sinai
DESCRIPTION (provided by applicant): Mood and anxiety disorders such as major depressive disorder (MDD) and post traumatic stress disorder (PTSD) cause overlapping behavioral symptoms marked by hyperarousal, social avoidance, anxiety, increased startle responses and emotional numbing or diminished interest in pleasurable stimuli (anhedonia). A detailed understanding of the neural substrates and molecular mechanisms that mediate these symptoms will provide us with novel and more selective targets for drug development and ultimately increase the efficacy of treatment. Recent studies have provided strong evidence that extracellular signaling molecules, such as neurotrophic factors, glutamate and pro-inflammatory cytokines are elevated in patients with MDD and PTSD. Interestingly, all of these signals converge to activate the transcription factor nuclear factor ?B (NF?B), which has been suggested to play a role in the etiology of mood and anxiety disorders in humans. Using chronic social defeat stress, a mouse model of stress-related mood and anxiety disorders, we have observed an increase in NF?B activity in the nucleus accumbens (NAc), a key brain reward structure. Additionally, we found that chronic social defeat changes the morphology of NAc neurons that underlie the very long-lasting changes in behavior. Using a herpes simplex virus (HSV) expressing a constitutively active I Kappa Kinase (IKKca) to activate NF?B or a dominant negative I Kappa Kinase (IKKdn) to inhibit NF?B, we show that expression of IKKca in the NAc of na[unreadable]ve mice mimics the anxiety phenotype produced by chronic social defeat. In addition, and consistent with findings in defeated mice, IKKca increases dendritic spine number and IKKdn decreases dendritic spine number on NAc medium spiny neurons. Although the biochemical mechanisms of NF?B mediated spine alterations are unknown, intracranial injections of the HSV-IKK mutants into the NAc resulted in gross changes in Rac1-PAK1 signaling, a RhoGTPase pathway known to mediate actin cytoskeletal reorganization and the development of new spines. Inhibition of NF?B with IKKdn decreases activity within the Rac1-PAK1 pathway, whereas, IKKca greatly increases its activity. Interestingly, social defeat also reduces activity of Rac1 and PAK1 in the NAc, and inhibition of Rac1 signaling with a dominant negative mutant, increases susceptibility to stress, further highlighting the importance of these biochemical changes in producing social defeat-induced avoidance. Based on the results thus far, we believe that chronic physical and psychological stress-induced changes in spine density underlie certain aspects of the social defeat behavioral syndrome. We are also further examining whether these stress-induced increases in dendritic spines and behavior are via NF?B regulation of RhoGTPase signaling. PUBLIC HEALTH RELEVANCE: Developing effective compounds to treat psychiatric disorders has been difficult and there are limited treatment options for full remission of disorders such as major depressive disorder and post-traumatic stress disorder. The data from these basic neurobiological studies will lay the groundwork for the development of novel and more selective pharmacological agents targeting nuclear factor kappa B in the brain to treat or prevent anxiety and mood disorders.
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1 |
2013 — 2014 |
Russo, Scott J |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Sex Differences in Stress-Induced Genome-Wide Transcriptional Profiles @ Icahn School of Medicine At Mount Sinai
DESCRIPTION (provided by applicant): Depression and anxiety disorders are large health burdens to our society with reported yearly prevalence rates of 9-18% in the general population. Although women are twice as likely to suffer from depression or anxiety, and exhibit more severe symptoms, the great majority of studies at the basic science level have used only male rodents to determine the underlying biological mechanisms. As a consequence, there is far less known about the mechanisms of depression in females. Here we use the chronic variable stress (CVS) paradigm, a model that induces robust depression- and anxiety-like behavior in mice. Our findings show that females are more sensitive to CVS than males on 5 established depression and anxiety behavioral and neurochemical domains. For example, females exhibit greater immobility on the forced swim test (FST), anhedonic responses on sucrose preference tests (SPT), decreased time grooming on the splash test, increased latency to feed on novelty suppressed feeding (NSF), and increased serum corticosterone levels. Although the direct mechanisms driving these sex differences are unclear, we used RNA sequencing and found that there are approximately 800 genes regulated by CVS in males and females and less than 3% of them overlap. Interestingly, CVS regulates more genes in males than females, suggesting that the lack of behavioral response in males may not be a passive one. Rather, males may engage alternate transcriptional pathways providing a mechanism for acting coping. In this application, we will measure the detailed sex differences in stress-induced changes across the transcriptome using high resolution paired end RNA sequencing and advanced bioinformatics analysis to identify splicing events, alternative promoter usage and microRNA processing. All data sets will be further analyzed into functional biological clusters to determine sex differences in the major pathways regulated by stress. We believe that this work will provide an enormously important resource of information for future stress studies and initiate a program to test the functional relevance of these transcriptome differences. The latter will aide in the development of new personalized anti- anxiety and anti-depression therapeutic strategies.
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1 |
2014 — 2018 |
Merad, Miriam (co-PI) [⬀] Russo, Scott J |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Peripheral Il-6 From Leukocytes Controls Susceptibility to Social Defeat Stress @ Icahn School of Medicine At Mount Sinai
DESCRIPTION (provided by applicant): Stress disorders such as depression and anxiety are associated with increases in the pro-inflammatory cytokine interleukin-6 (IL-6), however, the source and functional relevance of this elevation remains unknown. Using a repeated social defeat stress model in mice, we find individual differences in the peripheral immune response to stress-measured by increased IL-6 release from leukocytes-that predicts stress susceptibility. Susceptible mice develop social avoidance and anhedonia, which are established measures of depression-like behavior in rodents. To understand whether leukocyte derived IL-6 is necessary and sufficient for the development of social avoidance and anhedonia, we generated bone marrow (BM) chimeras transplanted with stem cells from stress susceptible or IL-6 knockout (IL-6-/-) mice. Stress susceptible BM chimeras exhibit baseline anhedonia and increased stress-induced social avoidance, whereas IL-6-/- BM chimeras were resistant to the effects of stress on these behaviors. In addition, we have preliminary evidence that IL-6 may be acting within key brain reward regions, such as the nucleus accumbens and prefrontal cortex, to mediate these behavioral effects. Together our work shows that pre-existing differences in stress responsive IL-6 release from leukocytes functionally contributes to depression-like behavioral phenotypes. In this application we will define the detailed mechanisms by which susceptible mice produce and release more IL-6. We will further define the functional relevance of such changes to development of depression-like behavior and test novel therapeutic strategies, such as bone marrow re-engineering to reduce stress susceptibility. We believe that this work holds promise for developing predictive diagnostic tests based on hyperactive IL-6 responses, as well as verification of important targets for novel antidepressant development.
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1 |
2015 — 2019 |
Russo, Scott J |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Pasinetti: Project 1; Preservation of Psychological Resilience Under Chronic Stress (Russo) @ Icahn School of Medicine At Mount Sinai
Summary/Abstract Chronic stress has been shown to negatively impact mental health and can precipitate depression and anxiety. Currently available medications to treat these disorders are only effective in approximately half of patients. It is thought that these medications don't adequately target the range of underlying etiologies that define stress disorders. Recent evidence suggests that dysregulation of peripheral inflammatory signaling in humans is linked to mood and anxiety disorders. Using an animal model of repeated social defeat stress (RSDS) in which c57BL/6J mice are repeatedly attacked by a large CD1 aggressor mouse, we find similar dysregulation of inflammatory signaling, which we have now shown is causally linked to depression and anxiety-like behavioral responses. Targeting of peripheral inflammatory signaling is sufficient to reverse the maladaptive behavioral responses to stress through alterations of plasticity directly within the brain. Interestingly, we recently found that botanical supplements promote resilience to social stress, possibly by reducing systemic inflammation and preventing maladaptive plasticity in the CNS. Thus, in this application, we will define the role of phenolic compounds in promoting psychological resilience and test the functional mechanisms responsible. Our goal is to identify alternative therapeutic approaches to ultimately promote resilience to stress disorders in humans.
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1 |
2016 — 2020 |
Russo, Scott J |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Thalamic Versus Cortical Inputs to Nucleus Accumbens in Stress-Related Disorders @ Icahn School of Medicine At Mount Sinai
? DESCRIPTION (provided by applicant): Chronic social defeat stress (CSDS) is a trauma based paradigm used to model depression- and anxiety-like behavior in rodents. We found previously that CSDS increases glutamatergic synapses on nucleus accumbens (NAc) medium spiny neurons, however the detailed circuitry meditating these effects is unclear. Previous work shows that the NAc receives dense glutamatergic innervation from the intralaminar thalamus (ILT) and prefrontal cortex (PFC). Thus, we analyzed levels of vesicular glutamate transporter 2 (VGLUT2) and VGLUT1, which are predominately found in ILT-NAc or PFC-NAc synapses, respectively. We found increased levels of VGLUT2 in susceptible mice that negatively correlated with social interaction ratio, suggesting that changes in ILT-NAc circuitry may regulate depression- or anxiety-like behavioral phenotypes following CSDS. To establish the functional relevance of these circuits in CSDS-induced depression- or anxiety-like behavior, we utilized circuit specific optogenetic approaches to modulate activity of the ILT-NAc or PFC-NAc. Our results show that rapid activation of the ILT-NAc circuit is both necessary and sufficient for the expression of stress-induced behavior, while rapid stimulation of PFC-NAc circuit had no effect. Interestingly, we also find that the ILT-NAc circuit selectively regulates activity of cholinergic interneurons, which seem to be necessary for the pro-depressant effects of ILT stimulation. In sum, our results identify circuit specific effects of different glutamate inputs wihin the NAc that control depression- or anxiety-like behavioral phenotypes. This provides us with unique insight into how stress impacts NAc circuitry and may inform a greater understanding of the mechanisms by which NAc deep brain stimulation is antidepressant in humans.
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1 |
2017 — 2021 |
Russo, Scott J |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Lateral Habenula Orexin Receptor Signaling in Aggressive Social Behavior @ Icahn School of Medicine At Mount Sinai
Abstract: Abnormal social behavior, such as maladaptive aggression or social anxiety to a lack of interest in social relationships, is associated with a number of neuropsychiatric disorders including schizophrenia, mood disorders and autism. Such disruptions in social behavior are thought to result, in part, from inappropriate activation of brain reward systems in response to social stimuli. A series of nuclei within the ventral midbrain that control mood and emotion are known to encode certain aspects of aggressive and nonaggressive social interaction; however, little is known about the neural circuit mechanisms that directly modulate the motivational or rewarding component of social behavior. To address this question, we established a mouse behavioral model for investigating individual differences in social behavior. In this model, approximately 70% of outbred mice engage in aggressive behavior with a resident intruder and find such interaction rewarding, whereas the remaining 30% are not aggressive at all and find intruder interactions aversive. The lateral habenula (LHb) is a major hub within the brain's reward circuit and can encode information about positive and negative social stimuli. Interestingly, the LHb is differentially activated by intruder-based social interaction in aggressive and nonaggressive mice and we hypothesize that it plays a critical role in mediating social behavior. Indeed, our preliminary results show that the neuropeptide, orexin (also known as hypocretin) signals directly within the LHb to control initiation of aggressive social behavior and the valence of social interaction during the resident intruder paradigm in aggressive mice. In this application, we will dissect the complex microcircuitry of the LHb using cell type specific molecular tools to control orexin receptor signaling along with in vivo monitoring of neural activity in awake behaving animals to understand LHb function in social behavior. A basic understanding of these circuits is absolutely critical for developing new treatment strategies for social deficits in a range of psychiatric illnesses.
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1 |
2019 — 2021 |
Russo, Scott J |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms of Stress-Induced Neurovascular Damage Promoting Immune Infiltration and Depression-Like Behaviors @ Icahn School of Medicine At Mount Sinai
Multiple clinical studies suggest that heightened peripheral inflammation contributes to major depressive disorder (MDD) pathogenesis. Co-morbidity of inflammatory disease with MDD is highly prevalent, and MDD patients have a higher risk of developing those diseases. It has been hypothesized that circulating inflammatory molecules are released following chronic stress, penetrate the blood brain barrier (BBB), and affect neural circuits, mediating stress vulnerability and depression. However, despite years of intensive research into the role of cytokines in depression, we have very little direct evidence of how cytokines enter the brain and in which circuits they act. Recently, we have begun to investigate the effect of chronic social defeat stress (CSDS), a mouse model of stress that induces depression-like behavior, on BBB permeability. Endothelial cells and astrocytes play critical roles in maintaining vascular impermeability. Endothelial cells, via expression of tight junction proteins, establish the paracellular barrier between the perivascular space and brain parenchyma. Breakdown of the endothelial barrier can lead to infiltration of peripheral immune signals? such as IL-6?that we have shown previously to increase stress susceptibility. Our new data shows that 10 days of CSDS downregulates expression of the tight junction protein Cldn5 in the NAc of stress-susceptible mice leading to loss of integrity of the endothelial barrier, immune infiltration and expression of depression-like behaviors. Expanding upon these preliminary observations, we will probe the detailed molecular and cellular mechanisms by which peripheral immune signals interface with mood-related brain circuitry to control depression-like behaviors following social stress. By understanding how chronic stress affects the BBB we may be able to augment current antidepressant treatment or design new therapeutic strategies promoting vascular health by preventing BBB degeneration.
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1 |
2021 |
Russo, Scott J |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neural Circuit Mechanisms of Stress-Impaired Social Reward @ Icahn School of Medicine At Mount Sinai
Abstract: Traumatic social experience in humans can impair brain reward function leading to severe social avoidance. Rodent stress models such as chronic social defeat stress (CSDS), can also cause severe social-avoidance mediated, in part, through altered reward circuit function. One of the prominent questions arising from such rodent studies is whether such social avoidance behaviors occurs due to a loss of social reward or preference. Using a standard CSDS model, we measured social interaction with threatening (aggressive CD-1 mice) and non-threatening (same sex 3-week old juvenile C57BL6/J mice) social target mice. We find that CSDS leads to social avoidance to both threatening and non-threatening social targets in a subset of male and female mice termed susceptible. Control and resilient mice do not exhibit social avoidance to either target mouse. To measure social reward, we utilized a social conditioned place preference (CPP) assay, where experimental mice were conditioned with a same sex 3-week old juvenile C57BL6/J. We find that that CSDS impairs formation of social CPP in susceptible, but not resilient, male and female mice. We next used whole brain iDisco clearing and c-Fos mapping following juvenile social interaction in CSDS-exposed mice and found several brain regions with increased c-Fos expression specifically in susceptible mice. The lateral septum (LS)?a stress responsive brain region?was highly activated in susceptible mice, but not resilient or control mice. We performed in situ hybridization to identify specific cell types in the LS and found a neurotensin (LSNT) positive GABAergic population activated during juvenile social interaction only in susceptible mice. We next utilized in vivo fiber photometry and GCAMP6-mediated Ca2+ imaging along with and chemogenetics to confirm that LSNT neurons are activated in real-time during juvenile social interaction and they regulate social avoidance and social CPP. To determine downstream LSNT connections, we used predicted correlation matrices from iDisco c-Fos expression maps to identify functionally connected regions and then confirmed these connections with viral tracing tools and optogenetics. We found a functional connection between LSNT neurons and the nucleus accumbens shell/nucleus of the diagonal band that regulates social interaction. Our research provides a circuit- level framework to understanding deficits in social behavior, that are common among many stress-related illnesses, such as depression.
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