Stress is the main environmental cause for depression, known to cause brain immune
alterations. As major brain immune cells, microglia undergo transcriptional and,
consequently, morphological changes that result in tissue damage, including new cell
generation impairment. Even so, few brain regions have been thoroughly studied,
excluding key regulators as the hypothalamus, in which this process remains partially
unknown. Moreover, there is a poor understanding in physiology related to behavioral
outcome. Therefore, it would be interesting to study the relationship between microglia
and cell proliferation in stressed mice while controlling for behavior.
Here, we used the social defeat stress (SDS) paradigm as a depression-inducing protocol
in 8-week-old male C57BL/6J mice for 10 consecutive days. Intruder mice behavior was
analyzed to assess depression using behavioral tests and K-means clustering. By
immunohistochemical and imaging procedures, microglial morphology, and
distribution, as well as cell survival, were analyzed in the hypothalamic paraventricular,
ventromedial and arcuate nucleus. Finally, statistical mediation analysis was conducted
to evaluate the relationship among variables.
Results show mice response to SDS was different, being half the mice resilient and half
sensitive to depressive-like symptoms. Microglial morphological activation was
enhanced in the ventromedial and arcuate nucleus, especially in stress sensitive animals.
Similar results were observed in cell survival, which was particularly affected in
sensitive mice. Strikingly, these cell survival changes were statistically mediated by
As a conclusion, hypothalamic regions were found to respond differently to stress,
accordingly to behavioral outcome, in terms of microglial activation and subsequent
decrease in cell survival.