Static and dynamic functional connectivity alterations in mice with LPS-induced depression: A 9.4T fMRI study using independent component and graph theory analyses.

Abstract

BACKGROUND: Systemic inflammation has emerged as a significant contributor to the pathophysiology of neuropsychiatric disorders, particularly depression. The lipopolysaccharide (LPS)-induced inflammation model in rodents is widely used to study inflammation-related behavioral and neural changes, with a strong emphasis on understanding the mechanisms of LPS-induced depression. However, the effects of systemic inflammation on the dynamic architecture of brain functional networks in the context of depression are not well understood. METHODS: Using high-field (9.4 T) resting-state functional magnetic resonance imaging (rs-fMRI), we investigated the impact of LPS-induced systemic inflammation on brain functional network organization in mice. Independent component analysis (ICA) was used to extract 15 functional brain networks. Static and dynamic functional network connectivity (sFNC and dFNC) were analyzed, and graph theory-based metrics were applied to evaluate global, local, and nodal efficiency. Behavioral tests (open field, elevated plus maze, tail suspension) and biochemical assays (serum IL-6, CXCL1, and brain regional ATP levels) were performed to assess emotional state, inflammation, and brain metabolism. RESULTS: LPS administration significantly increased anxiety- and depression-like behaviors, elevated peripheral inflammatory markers, and reduced ATP levels in multiple brain regions. ICA-based analysis revealed significant alterations in both static and dynamic connectivity across cortical, limbic, cerebellar, and basal ganglia networks. Graph theory analysis showed preserved global and local efficiency but a significant reduction in nodal efficiency within the basal ganglia. Moreover, dynamic metrics revealed reduced temporal variability of global and local efficiency following LPS treatment. Several brain network metrics were significantly correlated with behavioral outcomes, serum cytokine levels, and regional ATP concentrations. CONCLUSIONS: Our findings demonstrate that acute systemic inflammation disrupts both the static structure and dynamic regulation of brain functional networks in mice. These alterations are linked to emotional and metabolic disturbances and highlight the basal ganglia and cortical networks as key nodes of inflammation-related vulnerability. This study provides novel systems-level insights into the neural mechanisms underlying inflammation-associated neuropsychiatric symptoms.