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bioRxiv · 10.1101/2024.12.02.625901

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

Nakajima, S.·Kabahizi, A.·Aubailly, S.·Naili-Douaouda, S.·Tomita, A.·Bosson, A.·Murphy-Royal, C.·Fulton, S.
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Abstract

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.

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Nakajima, S., Kabahizi, A., Aubailly, S., Naili-Douaouda, S., Tomita, A., Bosson, A., Murphy-Royal, C., Fulton, S.. 2024-12-02. Microglial engulfing of glutamatergic inputs and diminished excitability of D1 medium spiny neurons of the nucleus accumbens by peripheral inflammatory insult. https://doi.org/10.1101/2024.12.02.625901

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