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.

Public Health Relevance

Major depressive disorder is associated with heightened peripheral inflammation that is casually linked to depression symptoms. Despite years of intensive research and ongoing clinical trials to test antidepressant efficacy of immune modulatory drugs that target systemic inflammation, it is still unclear how the peripheral immune system interfaces with mood-related brain circuitry to control depression-like behavioral responses. In this proposal we show that chronic stress induces neurovascular damage that weakens the blood brain barrier to allow immune infiltration and expression of depression-like behaviors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH104559-07
Application #
9840932
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Tonelli, Leonardo H
Project Start
2014-07-24
Project End
2023-10-31
Budget Start
2019-11-01
Budget End
2020-10-31
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost
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
Pfau, Madeline L; Ménard, Caroline; Russo, Scott J (2018) Inflammatory Mediators in Mood Disorders: Therapeutic Opportunities. Annu Rev Pharmacol Toxicol 58:411-428
Aleyasin, Hossein; Flanigan, Meghan E; Golden, Sam A et al. (2018) Cell-Type-Specific Role of ?FosB in Nucleus Accumbens In Modulating Intermale Aggression. J Neurosci 38:5913-5924
Calipari, Erin S; Godino, Arthur; Peck, Emily G et al. (2018) Granulocyte-colony stimulating factor controls neural and behavioral plasticity in response to cocaine. Nat Commun 9:9
Takahashi, Aki; Flanigan, Meghan E; McEwen, Bruce S et al. (2018) Aggression, Social Stress, and the Immune System in Humans and Animal Models. Front Behav Neurosci 12:56
Liu, Jia; Dietz, Karen; Hodes, Georgia E et al. (2018) Widespread transcriptional alternations in oligodendrocytes in the adult mouse brain following chronic stress. Dev Neurobiol 78:152-162
Wang, Jun; Hodes, Georgia E; Zhang, Hongxing et al. (2018) Epigenetic modulation of inflammation and synaptic plasticity promotes resilience against stress in mice. Nat Commun 9:477
Kiraly, D D; Horn, S R; Van Dam, N T et al. (2017) Altered peripheral immune profiles in treatment-resistant depression: response to ketamine and prediction of treatment outcome. Transl Psychiatry 7:e1065
Takahashi, Aki; Chung, Jia-Ru; Zhang, Song et al. (2017) Establishment of a repeated social defeat stress model in female mice. Sci Rep 7:12838
Menard, Caroline; Pfau, Madeline L; Hodes, Georgia E et al. (2017) Social stress induces neurovascular pathology promoting depression. Nat Neurosci 20:1752-1760
Hodes, Georgia E; Walker, Deena M; Labonté, Benoit et al. (2017) Understanding the epigenetic basis of sex differences in depression. J Neurosci Res 95:692-702

Showing the most recent 10 out of 27 publications