title: Neuropathic pain-induced depressive-like behavior and hippocampal neurogenesis and plasticity are dependent on TNFR1 signaling.
abstract: Patients suffering from neuropathic pain have a higher incidence of mood disorders such as depression. Increased expression of tumor necrosis factor (TNF) has been reported in neuropathic pain and depressive-like conditions and most of the pro-inflammatory effects of TNF are mediated by the TNF receptor 1 (TNFR1). Here we sought to investigate: (1) the occurrence of depressive-like behavior in chronic neuropathic pain and the associated forms of hippocampal plasticity, and (2) the involvement of TNFR1-mediated TNF signaling as a possible regulator of such events. Neuropathic pain was induced by chronic constriction injury of the sciatic nerve in wild-type and TNFR1(-/-) mice. Anhedonia, weight loss and physical state were measured as symptoms of depression. Hippocampal neurogenesis, neuroplasticity, myelin remodeling and TNF/TNFRs expression were analyzed by immunohistochemical analysis and western blot assay. We found that neuropathic pain resulted in the development of depressive symptoms in a time dependent manner and was associated with profound hippocampal alterations such as impaired neurogenesis, reduced expression of neuroplasticity markers and myelin proteins. The onset of depressive-like behavior also coincided with increased hippocampal levels of TNF, and decreased expression of TNF receptor 2 (TNFR2), which were all fully restored after mice spontaneously recovered from pain. Notably, TNFR1(-/-) mice did not develop depressive-like symptoms after injury, nor were there changes in hippocampal neurogenesis and plasticity. Our data show that neuropathic pain induces a cluster of depressive-like symptoms and profound hippocampal plasticity that are dependent on TNF signaling through TNFR1.
authors.affiliation: The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, United States.
authors.forename: Anna
authors.initials: A
authors.lastname: Dellarole
authors.affiliation: The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Morton
authors.affiliation: The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, United States.
authors.forename: Roberta
authors.initials: R
authors.lastname: Brambilla
authors.affiliation: The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, United States.
authors.forename: Winston
authors.initials: W
authors.lastname: Walters
authors.affiliation: The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, United States.
authors.forename: Spencer
authors.initials: S
authors.lastname: Summers
authors.affiliation: The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, United States; Núcleo de Neurociências (NNC), Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas (ICB), Universidade Federal de Minas Gerais (UFMG), Brazil.
authors.forename: Danielle
authors.initials: D
authors.lastname: Bernardes
authors.affiliation: Laboratory of Neuroplasticity and Pain, Department of Pharmaceutical Sciences, University of Piemonte Orientale "A. Avogadro", 28100 Novara, Italy.
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Grilli
authors.affiliation: The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, United States; The Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, United States; Department of Biology, Drexel University, Philadelphia, PA 19104, United States. Electronic address: jrb445@drexel.edu.
authors.forename: John R
authors.initials: JR
authors.lastname: Bethea
mesh_terms: D059445:Anhedonia / Q000502:physiology; D000818:Animals; D003345:Corticosterone / Q000097:blood; D003863:Depression / Q000209:etiology* / Q000503:physiopathology; D004327:Drinking Behavior / Q000502:physiology; D005106:Exploratory Behavior / Q000502:physiology; D005518:Food Preferences / Q000502:physiology; D006624:Hippocampus / Q000473:pathology*; D006358:Hot Temperature / Q000009:adverse effects; D006930:Hyperalgesia / Q000209:etiology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009437:Neuralgia / Q000473:pathology / Q000503:physiopathology* / Q000523:psychology; D055495:Neurogenesis / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D011312:Pressure / Q000009:adverse effects; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012584:Sciatic Nerve / Q000293:injuries; D012585:Sciatica / Q000473:pathology / Q000503:physiopathology* / Q000523:psychology; D015398:Signal Transduction / Q000502:physiology*; D016037:Single-Blind Method; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; C469948:Tnfrh2 protein, mouse; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D003345:Corticosterone
keywords: Cytokines; Depression; Myelin; Neurogenesis; Neuropathic pain; Plasticity; TNF; TNFR1