Site-Specific Knockdown of Microglia in the Locus Coeruleus Regulates Hypervigilant Responses to Social Stress in Female Rats

Pate, B. S.; Bouknight, S. J.; Harrington, E. N.; Mott, S. E.; Augenblick, L. M.; Smiley, C. E.; Morgan, C. G.; Calatayud, B. M.; Martines-Muniz, G. A.; Thayer, J. F.; Wood, S. K.

doi:10.1101/2022.10.03.509934

bioRxiv · 10.1101/2022.10.03.509934

Site-Specific Knockdown of Microglia in the Locus Coeruleus Regulates Hypervigilant Responses to Social Stress in Female Rats

Pate, B. S.·Bouknight, S. J.·Harrington, E. N.·Mott, S. E.·Augenblick, L. M.·Smiley, C. E.·Morgan, C. G.·Calatayud, B. M.·Martines-Muniz, G. A.·Thayer, J. F.·Wood, S. K.

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Abstract

BackgroundWomen are at increased risk for psychosocial stress-related anxiety disorders, yet mechanisms regulating this risk are unknown. Psychosocial stressors activate microglia, and the resulting neuroimmune responses that females exhibit heightened sensitivity to may serve as an etiological factor in their elevated risk. However, studies examining the role of microglia during stress in females are lacking. MethodsMicroglia were manipulated in the stress-sensitive locus coeruleus (LC) of female rats in the context of social stress in two ways. First, intra-LC lipopolysaccharide (LPS; 0 or 3g/side, n=5-6/group), a potent TLR4 agonist and microglial activator, was administered. One hour later, rats were exposed to control or an aggressive social defeat encounter between two males (WS, 15-min). In a separate study, females were treated with intra-LC or intra-central amygdala mannosylated liposomes containing clodronate (m-CLD; 0 or 25g/side, n=13-14/group), a compound toxic to microglia. WS-evoked burying, cardiovascular responses, and sucrose preference were measured. Brain and plasma cytokines were quantified, and cardiovascular telemetry assessed autonomic balance. ResultsIntra-LC LPS augmented the WS-induced burying response and increased plasma corticosterone and interleukin-1{beta} (IL-1{beta}). Further, the efficacy and selectivity of microinjected m-CLD was determined. In the context of WS, intra-LC m-CLD attenuated the hypervigilant burying response during WS as well as the accumulation of intra-LC IL-1{beta}. Intra-central amygdala m-CLD had no effect on witness stress-evoked behavior. ConclusionsThese studies highlight an innovative method for depleting microglia in a brain region specific manner and indicate that microglia in the LC differentially regulate hypervigilant WS-evoked behavioral and autonomic responses. HIGHLIGHTSO_LIIntra-LC LPS augments behavioral and physiological responses to social stress C_LIO_LIMannosylated liposomal clodronate site-specifically reduces microglial expression C_LIO_LIMicroglia within the locus coeruleus regulate stress-evoked behavior in female rats C_LI

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Pate, B. S., Bouknight, S. J., Harrington, E. N., Mott, S. E., Augenblick, L. M., Smiley, C. E., Morgan, C. G., Calatayud, B. M., Martines-Muniz, G. A., Thayer, J. F., Wood, S. K.. 2022-10-05. Site-Specific Knockdown of Microglia in the Locus Coeruleus Regulates Hypervigilant Responses to Social Stress in Female Rats. https://doi.org/10.1101/2022.10.03.509934

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