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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Desmond, Nancy L
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Icahn School of Medicine at Mount Sinai
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New York
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Hodes, Georgia E; Pfau, Madeline L; Leboeuf, Marylene et al. (2014) Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc Natl Acad Sci U S A 111:16136-41
Heshmati, Mitra; Russo, Scott J (2013) Learning to deal with life's ups and downs. Nat Neurosci 16:658-9
Russo, Scott J; Charney, Dennis S (2013) Next generation antidepressants. Proc Natl Acad Sci U S A 110:4441-2
Russo, Scott J; Nestler, Eric J (2013) The brain reward circuitry in mood disorders. Nat Rev Neurosci 14:609-25
Golden, Sam A; Christoffel, Daniel J; Heshmati, Mitra et al. (2013) Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression. Nat Med 19:337-44
Holloway, Terrell; Moreno, Jose L; Umali, Adrienne et al. (2013) 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 33:1088-98
Russo, Scott J (2012) GR-owing up stressed: implications for anxiety and addiction. Biol Psychiatry 71:182-3
Christoffel, Daniel J; Golden, Sam A; Russo, Scott J (2011) Structural and synaptic plasticity in stress-related disorders. Rev Neurosci 22:535-49
Golden, Sam A; Covington 3rd, Herbert E; Berton, Olivier et al. (2011) A standardized protocol for repeated social defeat stress in mice. Nat Protoc 6:1183-91