Depletion of Brain Perivascular Macrophages Mitigates Depressive‐like Behavioral Consequences of Chronic Mild Stress

Despite intensive research, the etiology of depression remains poorly understood. Stress is implicated in the pathogenesis of most depressive disorders, as reflected by the preponderance of animal models that employ chronic stress to induce depressive‐like behavior. There is increasing evidence for involvement of immune/inflammatory mechanisms in the genesis of depression, in part by mediating the effects of stress, with microglia and also macrophage‐type immune cells in the brain being implicated. Recent work from our laboratory has identified brain perivascular macrophages (PVM), not only as crucial mediators of inflammatory signaling from the periphery to the CNS, but as also involved in mediating the consequences of acute emotional stress on central neuroendocrine and inflammatory responses. The objective of the current pilot experiment was to evaluate the potential involvement of brain PVM in the induction of depressive‐like behaviors caused by chronic stress exposure. Adult male rats either remained untreated ( n =6) or received an intracerebroventricular injection of mannosylated liposomes containing the pro‐apoptotic drug, clodronate ( n =6), to exploit the constitutive phagocytic activity of PVM, leading to depletion of this cell type, but not microglia, throughout the brain within 3–5 d. Both groups were then subjected to 5 weeks of chronic mild stress (CMS), a well‐established protocol for the induction of depression through repeated and unpredictable exposure to a variety of mild insults. Anhedonic behavior, a key component of depression, was assessed by monitoring sucrose intake (provided as a 2% solution twice weekly before and during the CMS phase). Additional behavioral tests (open field/OF, elevated plus maze/EPM, Porsolt forced swim test/PFST) were used to assess further key components of depressive‐like behavior. All animals preferred sucrose strongly over normal drinking water. However, there was a significant drop in sucrose intake after 1 week of CMS in the control group, which was sustained for the duration of the experiment. No such effect was observed in the PVM‐depleted group. In addition, stressed control animals displayed a significant decrease in exploratory behavior in the EPM, remaining almost exclusively in the closed arms of the maze, an effect that was not observed in PVM‐depleted rats. In the PFST, which is often used to assess the potency of anti‐depressant drugs, PVM‐depleted rats tried significantly longer to escape from a water‐filled jar than animals from the control group. No differences in general locomotor activity (OF) were observed among groups at any time point. These findings support the hypothesis that brain PVMs are involved in depressive behaviors seen in a chronic mild stress model. Support or Funding Information NIH grant NS21182, Clayton Medical Research Foundation, German Research Foundation (DFG) grant GR4370/1‐1, CONACyT Mexico