Microglia depletion in early life programs persistent changes in social, mood-related, and locomotor behavior in male and female rats

Abstract

Microglia, the innate immune cells of the central nervous system, regulate brain development by promoting cell genesis, pruning synapses, and removing dying, newly-born or progenitor cells. However, the role of microglia in the early life programming of behavior under normal conditions is not well characterized. We used central infusion of liposomal clodronate to selectively deplete microglia from the neonatal rat brain and subsequently assessed the impact of microglial depletion on programming of juvenile and adult motivated behaviors. Liposomal clodronate treatment on postnatal days one and four led to greater than 70% loss of forebrain microglia by postnatal day 6 that lasted for approximately ten days. Neonatal microglia depletion led to reduced juvenile and adult anxiety behavior on the elevated plus maze and open field test, and increased locomotor activity. On a test of juvenile social play, microglial depletion led to decreased chase behaviors relative to control animals. There was no change in active social behavior in adults on a reciprocal social interaction test, but there was decreased passive interaction time and an increased number of social avoidance behaviors in clodronate treated rats relative to controls. There was an overall decrease in behavioral despair on the forced swim test in adult rats treated neonatally with clodronate. Females, but not males, treated neonatally with clodronate showed a blunted corticosterone response after acute stress in adulthood. These results show that microglia are important for the early life programming of juvenile and adult motivated behavior.

Temporary Depletion of Microglia during the Early Postnatal Period Induces Lasting Sex-Dependent and Sex-Independent Effects on Behavior in Rats

“…Conspecific recognition is one aspect of a social interaction, and further studies are needed to examine whether the observed social impairments extend to more complex social behaviors. Along these lines, a recent report in rats found that neonatal microglia depletion induced minor deficits in juvenile play behavior and increased social avoidance in adulthood (Nelson and Lenz, 2016), consistent with our findings here.…”

“…To this point, in pilot studies and the data presented here, nearly 20% of microglia-depleted animals jumped off of the elevated plus maze during the test and continued to explore the testing room. One such animal ended the test in this manner in fewer than 5 s. Our findings are strikingly similar to those of Nelson and Lenz (2016), who found increased locomotion and decreased anxiety-like behavior in the open field and elevated plus maze, even observing comparable numbers of animals that jumped off the elevated plus maze open arms.…”

“…One such study, published during the preparation of this manuscript, used a similar approach to address this issue (Nelson and Lenz, 2016). Our findings expand on those, as we used a behavioral battery to assess the appropriate acquisition and development of pups’ motor reflexes, strength, and coordination with the aim of identifying early markers of dysfunction.…”

A novel herbal treatment reduces depressive-like behaviors and increases brain-derived neurotrophic factor levels in the brain of type 2 diabetic rats

“…The FST was conducted to assess behavioral despair in a sound-attenuated room, which was dimly illuminated 14. Rats were placed individually in a clear plastic cylinder (height =40 cm; diameter =30 cm) filled with water to 21.5±1.5 cm high at 24°C±0.5°C for 5 min.…”

Neuroimmunology and neuroepigenetics in the establishment of sex differences in the brain

“…Furthermore, masculinization of copulatory behaviour in females by neonatal oestradiol treatment can be prevented by co-treatment with minocycline 43 . Even brief microglial ablation from the neonatal brain of males leads to complete loss of male typical copulatory behaviour in adulthood 52 , along with other sex-specific effects 53 .…”