EARLY NETWORK AND BEHAVIORAL DYSFUNCTION IN EXPERIMENTAL NEUROINFLAMMATION: THE ROLE OF IFN-GAMMA

Background: Depressive symptoms are linked to alterations in the brain’s structural connectome and reduced network efficiency, particularly within mood-regulating circuits. In multiple sclerosis, chronic neuroinflammation induces widespread network dysfunction beyond focal demyelinating lesions, contributing to the discomfort and observed heightened risk of depression. The hippocampus, a key hub for emotional and cognitive processing, is vulnerable to inflammatory insults, yet the mechanisms linking neuroinflammation to affective alterations remain unclear. This study investigated early depressive-like behaviors and their association with hippocampal circuit dysfunction, focusing on the potential mechanistic role played by the cytokine interferon-gamma (IFN-γ).
Methods: Experiments were conducted during the early phase of the experimental autoimmune encephalomyelitis (EAE) mouse model. Affective behavior was assessed using the nesting and Crawley tests. Hippocampal circuit function was evaluated through electrophysiological recordings in the CA1 region. IFN-γ knockout mice were used to determine the contribution of this cytokine to behavioral and synaptic alterations.
Results: EAE mice displayed depressive like-behavior and impaired social preference, alongside increased excitability and enhanced long-term potentiation in CA1 neurons. Hippocampal network dysfunction resolved at 50 days post-induction, suggesting that these alterations were transient. The lack of IFN-γ prevented both functional and clinical alterations.
Conclusions: Mood-related behavioral alterations emerge early during neuroinflammation and are associated with transient dysfunction of the hippocampal network. IFN-γ plays a key role in mediating these effects, highlighting it as a potential therapeutic target for affective disorders in neuroinflammatory diseases.
Acknowledgements: LB is supported by a research fellowship FISM - Fondazione Italiana Sclerosi Multipla (cod. 2023/BR/005).