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.
Depression and anxiety are associated with changes in the pro-inflammatory cytokine interleukin-6 (IL-6). However, it is still unclear whether systemic activation of immune cells, and subsequent release of IL-6, is necessary and sufficient for the expression of depression-like behavioral responses or whether it is simply an unrelated biomarker associated with the phenotype. In this proposal we show a functional role for leukocyte derived IL-6 in controlling depression like behaviors in rodents.
| 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 |
| Pfau, Madeline L; Ménard, Caroline; Russo, Scott J (2018) Inflammatory Mediators in Mood Disorders: Therapeutic Opportunities. Annu Rev Pharmacol Toxicol 58:411-428 |
| Labonté, Benoit; Engmann, Olivia; Purushothaman, Immanuel et al. (2017) Sex-specific transcriptional signatures in human depression. Nat Med 23:1102-1111 |
| Flanigan, Meghan; Aleyasin, Hossein; Takahashi, Aki et al. (2017) An emerging role for the lateral habenula in aggressive behavior. Pharmacol Biochem Behav 162:79-86 |
| Brancato, Anna; Bregman, Dana; Ahn, H Francisica et al. (2017) Sub-chronic variable stress induces sex-specific effects on glutamatergic synapses in the nucleus accumbens. Neuroscience 350:180-189 |
| Giannarelli, Chiara; Rodriguez, David T; Zafar, M Urooj et al. (2017) Susceptibility to chronic social stress increases plaque progression, vulnerability and platelet activation. Thromb Haemost 117:816-818 |
Showing the most recent 10 out of 27 publications
