Microglial engulfing of glutamatergic inputs and diminished excitability of D1 medium spiny neurons of the nucleus accumbens by peripheral inflammatory insult

Neuroimmune responses to systemic inflammation can generate anxiodepressive behaviors and psychomotor slowing. The nucleus accumbens (NAc) is a neural hub encoding mood and motivation that contributes to the locomotor and mood dampening effects of neuroinflammation. Dopamine receptor 1 mediums spiny neurons (D1-MSNs) of the NAc regulate locomotor activity, motivated behavior and emotional states and are modulated by microglial reactivity. Here, we evaluated sickness- and anxiety-like behaviors along with D1-MSN activity and microglial responses in the NAc to systemic lipopolysaccharide (LPS) administration. LPS stimulated anxiety-like behavior, blunted locomotion and reduced cFos expression in D1-MSNs of the NAc core and shell of male mice. These effects associated with reduced excitatory inputs (EPSCs) onto D1-MSNs as measured by whole cell patch-clamp. To determine if microglia contribute to changes in MSN activity, Ca2+ imaging of primary cultures containing NAc neurons with or without primary NAc microglia was performed. The presence of microglia decreased the activity of LPS-treated MSNs in response to dopamine and glutamate application and LPS stimulated microglial phagocytosis of MSN processes in co-cultures. Immunohistochemical analyses revealed that in vivo LPS treatment enhanced morphological indices of microglia reactivity and engulfment of vesicular glutamate transporter 1 (VGLUT1) inputs in the NAc. Our results suggest that LPS reduces locomotion and stimulates anxiety via increasing microglia engulfment of excitatory inputs onto D1-MSNs, and highlight changes in NAc microglia phagocytic activity in the behavioral consequences of neuroinflammation.