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Microglial Targeting as a Therapeutic Strategy for Social Stress Susceptibility

Social stress is a common risk factor for anxiety and cardiovascular disease (CVD). Women are more likely than men to suffer from comorbid anxiety and CVD. While the underlying neural mechanisms linking these pathological conditions remain unclear, the locus coeruleus (LC) is a stress‐sensitive region known to facilitate both behavioral and cardiovascular responses to social stress. Importantly, neuroinflammation has been shown to play a causative role in generating anxiety‐like behavior, yet whether pharmacological manipulation of microglia represent a strategy to regulate stress susceptibility in a female population remains to be determined. Here, we utilize mannosylated liposomal clodronate, a small hydrophilic molecule toxic to microglia. Both the liposomes and the drug clodronate (CLD) are selective for macrophages/microglia, making this intra‐LC administration a targeted depletion of microglial cells. Two separate studies were conducted to test the hypothesis that microglial targeting is effective in regulating susceptibility to social stress. In study #1, following recovery from surgical implantation of cardiovascular transmitters (HD‐S11, DSI) and bilateral LC cannulae, rats were treated with liposomal CLD injections (5 or 25 μg/side) or empty‐liposomal vehicle (0 μg/side). Female rats were then subjected to witnessing an aggressive social defeat encounter between a male intruder and a novel male resident for 15 min on 5 consecutive days. This study identified that witness stress exposure increased anxiety‐like burying compared with controls and that partial microglial depletion in the LC attenuated this burying response. Interestingly, intra‐LC CLD had no cardiovascular effect upon the first exposure to stress, yet promoted the pressor response following repeated stress exposure (day 5). To further examine whether microglia are controlling the behavioral and cardiovascular responses to stress, female rats were treated with intra‐LC LPS (0, 1, 3 ug/rat) with or without a TLR‐4 selective microglial inhibitor (LPS‐RS and (+)‐ naloxone) prior to witness stress exposure. While these treatments had no effect under non‐stress conditions, witnesses treated with LPS alone exhibited greater burying duration compared with those treated with vehicle, and this was blocked by the microglial inhibitor. Taken together, these studies reveal a novel role for microglia in regulating behavioral and cardiovascular responses to social stress and demonstrate that selective targeting of microglia may be a therapeutic strategy to alter stress susceptibility.