Insulin induces long-term depression of ventral tegmental area dopamine neurons via endocannabinoids.
The prevalence of obesity has markedly increased over the past few decades. Exploration of how hunger and satiety signals influence the reward system can help us understand non-homeostatic feeding. Insulin may act in the ventral tegmental area (VTA), a critical site for reward-seeking behavior, to suppress feeding. However, the neural mechanisms underlying insulin effects in the VTA remain unknown. We demonstrate that insulin, a circulating catabolic peptide that inhibits feeding, can induce long-term depression (LTD) of mouse excitatory synapses onto VTA dopamine neurons. This effect requires endocannabinoid-mediated presynaptic inhibition of glutamate release. Furthermore, after a sweetened high-fat meal, which elevates endogenous insulin, insulin-induced LTD is occluded. Finally, insulin in the VTA reduces food anticipatory behavior in mice and conditioned place preference for food in rats. Taken together, these results suggest that insulin in the VTA suppresses excitatory synaptic transmission and reduces anticipatory activity and preference for food-related cues.
Department of Anesthesiology, Pharmacology and Therapeutics, The University of British Columbia, Vancouver, British Columbia, Canada.
Gwenaël
G
Labouèbe
Shuai
S
Liu
Carine
C
Dias
Haiyan
H
Zou
Jovi C Y
JC
Wong
Subashini
S
Karunakaran
Susanne M
SM
Clee
Anthony G
AG
Phillips
Benjamin
B
Boutrel
Stephanie L
SL
Borgland
D000818:Animals; D001245:Association Learning / Q000187:drug effects / Q000502:physiology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D004041:Dietary Fats / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D063388:Endocannabinoids / Q000378:metabolism*; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D036881:Long-Term Synaptic Depression / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects* / Q000502:physiology
D004041:Dietary Fats; D063388:Endocannabinoids; D007328:Insulin; D018698:Glutamic Acid; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases