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?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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH090264-02
Application #
8196832
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Desmond, Nancy L
Project Start
2010-11-15
Project End
2015-10-31
Budget Start
2011-11-01
Budget End
2012-10-31
Support Year
2
Fiscal Year
2012
Total Cost
$421,348
Indirect Cost
$171,348
Name
Icahn School of Medicine at Mount Sinai
Department
Neurosciences
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Golden, Sam A; Heshmati, Mitra; Flanigan, Meghan et al. (2016) Basal forebrain projections to the lateral habenula modulate aggression reward. Nature 534:688-92
Daskalakis, Nikolaos P; Cohen, Hagit; Nievergelt, Caroline M et al. (2016) New translational perspectives for blood-based biomarkers of PTSD: From glucocorticoid to immune mediators of stress susceptibility. Exp Neurol 284:133-140
Pfau, Madeline L; Russo, Scott J (2016) Neuroinflammation Regulates Cognitive Impairment in Socially Defeated Mice. Trends Neurosci 39:353-5
Golden, S A; Aleyasin, H; Heins, R et al. (2016) Persistent conditioned place preference to aggression experience in adult male sexually-experienced CD-1 mice. Genes Brain Behav :
Heshmati, Mitra; Golden, Sam A; Pfau, Madeline L et al. (2016) Mefloquine in the nucleus accumbens promotes social avoidance and anxiety-like behavior in mice. Neuropharmacology 101:351-7
Hodes, Georgia E; Ménard, Caroline; Russo, Scott J (2016) Integrating Interleukin-6 into depression diagnosis and treatment. Neurobiol Stress 4:15-22
Khibnik, Lena A; Beaumont, Michael; Doyle, Marie et al. (2016) Stress and Cocaine Trigger Divergent and Cell Type-Specific Regulation of Synaptic Transmission at Single Spines in Nucleus Accumbens. Biol Psychiatry 79:898-905
Ménard, C; Hodes, G E; Russo, S J (2016) Pathogenesis of depression: Insights from human and rodent studies. Neuroscience 321:138-62
Hodes, Georgia E; Pfau, Madeline L; Purushothaman, Immanuel et al. (2015) Sex Differences in Nucleus Accumbens Transcriptome Profiles Associated with Susceptibility versus Resilience to Subchronic Variable Stress. J Neurosci 35:16362-76
Heshmati, Mitra; Russo, Scott J (2015) Anhedonia and the brain reward circuitry in depression. Curr Behav Neurosci Rep 2:146-153

Showing the most recent 10 out of 29 publications