Neonatal immune challenge induces female-specific changes in social behavior and somatostatin cell number, independent of microglial inflammatory signaling

Abstract

Decreases in social behavior are a hallmark aspect of acute "sickness behavior" in response to infection.However, immune insults that occur during the perinatal period may have long-lasting consequences for adult social behavior by impacting the developmental organization of underlying neural circuits.Microglia, the resident immune cells of the central nervous system, are sensitive to immune stimulation and play a critical role in the developmental sculpting of neural circuits, making them likely mediators of this process. Here, we investigated the impact of a postnatal day (PND) 4 lipopolysaccharide (LPS) challenge on social behavior in adult mice. Somewhat surprisingly, neonatal LPS treatment decreased sociability in adult female, but not male mice. LPS-treated females also displayed reduced social interaction and social memory in a social discrimination task as compared to saline-treated females.Somatostatin (SST) interneurons within the anterior cingulate cortex (ACC) have recently been suggested to modulate a variety of social behaviors. Interestingly, the female-specific changes in social behavior observed here were accompanied by an increase in SST interneuron number in the ACC.Finally, these changes in social behavior and SST cell number do not appear to depend on microglial inflammatory signaling, because microglia-specific genetic knock-down of myeloid differentiation response protein 88 (MyD88; the removal of which prevents LPS from increasing proinflammatory cytokines such as TNFα and IL-1β) did not prevent these LPS-induced changes. This study provides novel evidence for enduring effects of neonatal immune activation on social behavior and SST interneurons in females, independent of microglial inflammatory signaling.

Oxytocin administration in neonates shapes the hippocampal circuitry and restores social behavior in a mouse model of autism

“…SST interneurons have recently been shown to play a role in the modulation of social behavior (64, 65) and a link between altered social memory and an increase in SST cell number has been recently suggested in LPS-treated female neonates (66). It is tempting to speculate that OXTR-transmission regulates the activity of SST hippocampal interneurons and the production/release of mature SST and impacts social memory.…”

“…Interestingly, OT modulates the activity of the SST+ neurons, increasing the excitability of SST interneurons (31) but no studies report an effect of OT on SST production.SST interneurons have recently been shown to play a role in the modulation of social behavior(73,74) and a reduction in the number of PV or SST interneurons has been reported to be associated with social deficits or ASD. Noticeably, a link between altered social memory and an increase in SST cell number has been recently reported in LPS-treated female neonates(75). It is tempting to speculate that OXTR-transmission regulates the activity of SST hippocampal interneurons and the production/release of mature SST and impacts social memory.…”