title: A sphingolipid mechanism for behavioral extinction.
abstract: Reward-dependent instrumental behavior must continuously be re-adjusted according to environmental conditions. Failure to adapt to changes in reward contingencies may incur psychiatric disorders like anxiety and depression. When an expected reward is omitted, behavior undergoes extinction. While extinction involves active re-learning, it is also accompanied by emotional behaviors indicative of frustration, anxiety, and despair (extinction-induced depression). Here, we report evidence for a sphingolipid mechanism in the extinction of behavior. Rapid extinction, indicating efficient re-learning, coincided with a decrease in the activity of the enzyme acid sphingomyelinase (ASM), which catalyzes turnover of sphingomyelin to ceramide, in the dorsal hippocampus of rats. The stronger the decline in ASM activity, the more rapid was the extinction. Sphingolipid-focused lipidomic analysis showed that this results in a decline of local ceramide species in the dorsal hippocampus. Ceramides shape the fluidity of lipid rafts in synaptic membranes and by that way can control neural plasticity. We also found that aging modifies activity of enzymes and ceramide levels in selective brain regions. Aging also changed how the chronic treatment with corticosterone (stress) or intranasal dopamine modified regional enzyme activity and ceramide levels, coinciding with rate of extinction. These data provide first evidence for a functional ASM-ceramide pathway in the brain involved in the extinction of learned behavior. This finding extends the known cellular mechanisms underlying behavioral plasticity to a new class of membrane-located molecules, the sphingolipids, and their regulatory enzymes, and may offer new treatment targets for extinction- and learning-related psychopathological conditions. Sphingolipids are common lipids in the brain which form lipid domains at pre- and postsynaptic membrane compartments. Here we show a decline in dorsal hippocampus ceramide species together with a reduction of acid sphingomyelinase activity during extinction of conditioned behavior in rats. This reduction was associated with expression of re-learning-related behavior, but not with emotional behaviors. Read the Editorial Highlight for this article on page 485.
authors.affiliation: Center for Behavioral Neuroscience, Institute of Experimental Psychology, Heinrich-Heine-University of Dusseldorf, Düsseldorf, Germany.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Huston
authors.affiliation: Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Kornhuber
authors.affiliation: Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Mühle
authors.affiliation: Institute of Nutritional Science, Faculty of Mathematics and Natural Science, University of Potsdam, Nuthetal, Germany.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Japtok
authors.affiliation: Center for Behavioral Neuroscience, Institute of Experimental Psychology, Heinrich-Heine-University of Dusseldorf, Düsseldorf, Germany.
authors.forename: Mara
authors.initials: M
authors.lastname: Komorowski
authors.affiliation: M et P Pharma AG, Emmetten, Switzerland.|Oceanographic Center, Nova Southeastern University, Fort Lauderdale, Florida, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Mattern
authors.affiliation: Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Reichel
authors.affiliation: Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.|Department of Surgery, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
authors.affiliation: Institute of Nutritional Science, Faculty of Mathematics and Natural Science, University of Potsdam, Nuthetal, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kleuser
authors.affiliation: Center for Behavioral Neuroscience, Institute of Experimental Psychology, Heinrich-Heine-University of Dusseldorf, Düsseldorf, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Topic
authors.affiliation: Center for Behavioral Neuroscience, Institute of Experimental Psychology, Heinrich-Heine-University of Dusseldorf, Düsseldorf, Germany.
authors.forename: Maria A
authors.initials: MA
authors.lastname: De Souza Silva
authors.affiliation: Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Müller
mesh_terms: D000818:Animals; D002518:Ceramides / Q000378:metabolism*; D003216:Conditioning, Operant / Q000502:physiology*; D005108:Extinction, Psychological / Q000502:physiology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000502:physiology; D013107:Sphingolipids / Q000378:metabolism*; D013109:Sphingomyelins / Q000378:metabolism
chemical_list: D002518:Ceramides; D013107:Sphingolipids; D013109:Sphingomyelins
keywords: acid sphingomyelinase; ceramide; extinction; hippocampus; operant behavior; sphingomyelin