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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH104559-04
Application #
9275540
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Desmond, Nancy L
Project Start
2014-07-24
Project End
2019-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
4
Fiscal Year
2017
Total Cost
$596,882
Indirect Cost
$244,581
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
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