Delta FosB-mediated alterations in dopamine signaling are normalized by a palatable high-fat diet.
BACKGROUND
Sensitivity to reward has been implicated as a predisposing factor for behaviors related to drug abuse as well as overeating. However, the underlying mechanisms contributing to reward sensitivity are unknown. We hypothesized that a dysregulation in dopamine signaling might be an underlying cause of heightened reward sensitivity whereby rewarding stimuli could act to normalize the system.


METHODS
We used a genetic mouse model of increased reward sensitivity, the Delta FosB-overexpressing mouse, to examine reward pathway changes in response to a palatable high-fat diet. Markers of reward signaling in these mice were examined both basally and following 6 weeks of palatable diet exposure. Mice were examined in a behavioral test following high-fat diet withdrawal to assess the vulnerability of this model to removal of rewarding stimuli.


RESULTS
Our results demonstrate altered reward pathway activation along the nucleus accumbens-hypothalamic-ventral tegmental area circuitry resulting from overexpression of Delta FosB in the nucleus accumbens and striatal regions. Levels of phosphorylated cyclic adenosine monophosphate (cAMP) response element binding protein (pCREB), brain-derived neurotrophic factor (BDNF), and dopamine and cyclic adenosine monophosphate regulated phosphoprotein with a molecular mass of 32 kDa (DARPP-32) in the nucleus accumbens were reduced in Delta FosB mice, suggestive of reduced dopamine signaling. Six weeks of high-fat diet exposure completely ameliorated these differences, revealing the potent rewarding capacity of a palatable diet. Delta FosB mice also showed a significant increase in locomotor activity and anxiety-related responses 24 hours following high-fat withdrawal.


CONCLUSIONS
These results establish an underlying sensitivity to changes in reward related to dysregulation of Delta FosB and dopamine signaling that can be normalized with palatable diets and may be a predisposing phenotype in some forms of obesity.
Teegarden
Sarah L
SL
Department of Animal Biology, University of Pennsylvania, Philadelphia, PA 19104-6046, USA.
Nestler
Eric J
EJ
Bale
Tracy L
TL
D000818:Animals; D001345:Autoradiography; D001835:Body Weight / Q000187:drug effects / Q000235:genetics; D050882:CREB-Binding Protein / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D004041:Dietary Fats / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D004435:Eating / Q000187:drug effects / Q000235:genetics; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009479:Neuropeptides / Q000378:metabolism; D009714:Nucleus Accumbens / Q000378:metabolism; D000068797:Orexins; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D012201:Reward; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism
D004041:Dietary Fats; D050483:Dopamine Plasma Membrane Transport Proteins; C483819:Fosb protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D016760:Proto-Oncogene Proteins c-fos; D014446:Tyrosine 3-Monooxygenase; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D004298:Dopamine