title: TNF-α-mediated anxiety in a mouse model of multiple sclerosis.
abstract: Multiple sclerosis (MS) causes a variety of motor and sensory deficits and it is also associated with mood disturbances. It is unclear if anxiety and depression in MS entirely reflect a subjective reaction to a chronic disease causing motor disability or rather depend on specific effects of neuroinflammation in neuronal circuits. To answer this question, behavioral, electrophysiological, and immunofluorescence experiments were performed in mice with experimental autoimmune encephalomyelitis (EAE), which models MS in mice. First, we observed high anxiety indexes in EAE mice, preceding the appearance of motor defects. Then, we demonstrated that tumor necrosis factor α (TNF-α) has a crucial role in anxiety associated with neuroinflammation. In fact, intracerebroventricular (icv) administration of etanercept, an inhibitor of TNF-α signaling, resulted in anxiolytic-like effects in EAE-mice. Accordingly, icv injection of TNF-α induced per se overt anxious behavior in control mice. Moreover, we propose the striatum as one of the brain regions potentially involved in EAE anxious behavior. We observed that before disease onset EAE striatum presents elevated TNF-α levels and strong activated microglia, early signs of inflammation associated with alterations of striatal excitatory postsynaptic currents (EPSCs). Interestingly, etanercept corrected the synaptic defects of pre-symptomatic EAE mice while icv injection of TNF-α in non-EAE mice altered EPSCs, thus mimicking the synaptic effects of EAE. In conclusion, anxiety characterizes EAE course since the very early phases of the disease. TNF-α released from activated microglia mediates this effect likely through the modulation of striatal excitatory synaptic transmission.
authors: Fondazione Santa Lucia/Centro Europeo per la Ricerca sul Cervello-CERC, Rome, Italy.
authors: Nabila
authors: N
authors: Haji
authors: Georgia
authors: G
authors: Mandolesi
authors: Antonietta
authors: A
authors: Gentile
authors: Lucia
authors: L
authors: Sacchetti
authors: Diego
authors: D
authors: Fresegna
authors: Silvia
authors: S
authors: Rossi
authors: Alessandra
authors: A
authors: Musella
authors: Helena
authors: H
authors: Sepman
authors: Caterina
authors: C
authors: Motta
authors: Valeria
authors: V
authors: Studer
authors: Valentina
authors: V
authors: De Chiara
authors: Giorgio
authors: G
authors: Bernardi
authors: Piergiorgio
authors: P
authors: Strata
authors: Diego
authors: D
authors: Centonze
mesh_terms: D000818:Animals; D001007:Anxiety / Q000209:etiology* / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism* / Q000503:physiopathology / Q000523:psychology*; D004797:Enzyme-Linked Immunosorbent Assay; D000068800:Etanercept; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D005455:Fluorescent Antibody Technique; D007074:Immunoglobulin G / Q000494:pharmacology; D007155:Immunologic Factors / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009103:Multiple Sclerosis / Q000378:metabolism / Q000523:psychology; D018408:Patch-Clamp Techniques; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D007074:Immunoglobulin G; D007155:Immunologic Factors; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept