title: A novel role for brain interleukin-6: facilitation of cognitive flexibility in rat orbitofrontal cortex.
abstract: Cytokines, small proteins released by the immune system to combat infection, are typically studied under inflammatory conditions. However, these molecules are also expressed in the brain in basal, nonpathological states, where they can regulate neuronal processes, such as learning and memory. However, little is known about how cytokine signaling in the brain may influence higher-order cognitive functions. Cognitive flexibility is one such executive process, mediated by the prefrontal cortex, which requires an adaptive modification of learned behaviors in response to environmental change. We explored the role of basal IL-6 signaling in the orbitofrontal cortex (OFC) in reversal learning, a form of cognitive flexibility that can be measured in the rat using the attentional set-shifting test. We found that inhibiting IL-6 or its downstream JAK/STAT signaling pathway in the OFC impaired reversal learning, suggesting that basal IL-6 and JAK/STAT signaling facilitate cognitive flexibility. Further, we demonstrated that elevating IL-6 in the OFC by adeno-associated virus-mediated gene delivery reversed a cognitive deficit induced by chronic stress, thus identifying IL-6 and the downstream JAK/STAT signaling pathway as potentially novel therapeutic targets for the treatment of stress-related psychiatric diseases associated with cognitive dysfunction.
authors.affiliation: Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, and Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Donegan
authors.forename: Milena
authors.initials: M
authors.lastname: Girotti
authors.forename: Marc S
authors.initials: MS
authors.lastname: Weinberg
authors.forename: David A
authors.initials: DA
authors.lastname: Morilak
mesh_terms: D000818:Animals; D003071:Cognition / Q000502:physiology*; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D008297:Male; D017397:Prefrontal Cortex / Q000502:physiology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D000093242:Interleukin-6 Inhibitors
chemical_list: D015850:Interleukin-6; D000093242:Interleukin-6 Inhibitors
keywords: JAK/STAT; cognitive flexibility; depression; interleukin-6; orbitofrontal cortex; reversal learning