TY  - JOUR
A1  - Huston, Joseph P.
A1  - Kornhuber, Johannes
A1  - Muehle, Christiane
A1  - Japtok, Lukasz
A1  - Komorowski, Mara
A1  - Mattern, Claudia
A1  - Reichel, Martin
A1  - Gulbins, Erich
A1  - Kleuser, Burkhard
A1  - Topic, Bianca
A1  - Silva, Maria A. De Souza
A1  - Mueller, Christian P.
T1  - A sphingolipid mechanism for behavioral extinction
JF  - Journal of neurochemistry
N2  - 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.
KW  - acid sphingomyelinase
KW  - ceramide
KW  - extinction
KW  - hippocampus
KW  - operant behavior
KW  - sphingomyelin
Y1  - 2016
U6  - https://doi.org/10.1111/jnc.13537
SN  - 0022-3042
SN  - 1471-4159
VL  - 137
SP  - 589
EP  - 603
PB  - Wiley-Blackwell
CY  - Hoboken
ER  -