Mechanisms of structural plasticity in stress-related disorders
Principal Investigator: Scott J Russo
Abstract: 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.
Funding Period: 2010-11-15 - 2015-10-31
more information: NIH RePORT
- A standardized protocol for repeated social defeat stress in miceSam A Golden
Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, USA
Nat Protoc 6:1183-91. 2011..The automated detection of social avoidance allows a marked increase in throughput, reproducibility and quantitative analysis. This protocol is highly adaptable, but in its most common form it requires 3-4 weeks for completion...
- Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depressionSam A Golden
Fishberg Department of Neuroscience and Friedman Brain Institute, Graduate School of Biomedical Sciences at the Icahn School of Medicine at Mount Sinai, New York, New York, USA
Nat Med 19:337-44. 2013..Taken together, our data identify epigenetic regulation of RAC1 in the NAc as a disease mechanism in depression and reveal a functional role for Rac1 in rodents in regulating stress-related behaviors...
- Prenatal stress induces schizophrenia-like alterations of serotonin 2A and metabotropic glutamate 2 receptors in the adult offspring: role of maternal immune systemTerrell Holloway
Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029, USA
J Neurosci 33:1088-98. 2013..These data strengthen pathophysiological hypotheses that propose an early neurodevelopmental origin for schizophrenia and other psychiatric disorders...
- Neurobiology of resilienceScott J Russo
Department of Neuroscience, Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York, USA
Nat Neurosci 15:1475-84. 2012..The therapeutic implications of these findings are important and can pave the way for an innovative approach to drug development for a range of stress-related syndromes...
- HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activityMitsumasa Kurita
Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA
Nat Neurosci 15:1245-54. 2012..These observations support the view of HDAC2 as a promising new target for schizophrenia treatment...
- Effects of inhibitor of κB kinase activity in the nucleus accumbens on emotional behaviorDaniel J Christoffel
Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA
Neuropsychopharmacology 37:2615-23. 2012..These data show that IκK in NAc is a critical regulator of both depressive- and anxiety-like states and may do so by promoting the formation of immature excitatory synapses...
- Structural and synaptic plasticity in stress-related disordersDaniel J Christoffel
Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY 10029 6574, USA
Rev Neurosci 22:535-49. 2011..Finally, we end by discussing recent brain imaging studies in human depression within the context of these basic findings to provide insight into the underlying mechanisms leading to neural dysfunction in depression...
- The brain reward circuitry in mood disordersScott J Russo
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA edu
Nat Rev Neurosci 14:609-25. 2013..We also discuss some of the molecular and cellular underpinnings of this framework, ranging from adaptations in glutamatergic synapses and neurotrophic factors to transcriptional and epigenetic mechanisms...