Optogenetic stimulation of lateral hypothalamic orexin/dynorphin inputs in the ventral tegmental area potentiates mesolimbic dopamine neurotransmission and promotes reward-seeking behaviours
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ABSTRACT Reward and reinforcement processes are critical for survival and propagation of genes. While numerous brain systems underlie these processes, a cardinal role is ascribed to mesolimbic dopamine. However, ventral tegmental area (VTA) dopamine neurons receive complex innervation and various neuromodulatory factors, including input from lateral hypothalamic (LH) orexin/hypocretin neurons which also express and co-release the neuropeptide, dynorphin. Dynorphin in the VTA induces aversive conditioning through the Kappa opioid receptor (KOR) and decreases dopamine when administered intra-VTA. Exogenous application of orexin or orexin 1 receptor (oxR1) antagonists in the VTA bidirectionally modulates dopamine-driven motivation and reward-seeking behaviours, including the attribution of motivational value to primary rewards and associated conditioned stimuli. However, the effect of endogenous stimulation of LH orexin/dynorphin-containing projections to the VTA and the potential contribution of co-released dynorphin on mesolimbic dopamine and reward related processes remains uncharacterised. We combined optogenetic, electrochemical, and behavioural approaches to examine this. We found that optical stimulation of LH orexin/dynorphin inputs in the VTA potentiates mesolimbic dopamine neurotransmission in the nucleus accumbens (NAc) core, produces real time and conditioned place preference, and increases the food cue-directed orientation in a Pavlovian conditioning procedure. LH orexin/dynorphin potentiation of NAc dopamine release and real time place preference was blocked by an oxR1, but not KOR antagonist. Thus, rewarding effects associated with optical stimulation of LH orexin/dynorphin inputs in the VTA are predominantly driven by orexin rather than dynorphin.Keywords:
Dynorphin
Conditioned place preference
Lateral hypothalamus
Mesolimbic pathway
Orexin-A
Brain stimulation reward
Orexin-A
Lateral hypothalamus
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Orexin-A
Lateral hypothalamus
Retrograde tracing
Orexin receptor
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Reward is a strong behavioral cue. It is argued that a sense of reward must be strictly controlled in time and magnitude to be functional. Central to the reward system is the mesolimbic dopamine pathway which is titillated by addictive drugs and alcohol. Rat lines or strains that voluntarily drink alcohol have lower dynorphin levels in relevant brain areas than those which avoid alcohol. Reward control may be a protective factor against addiction.
Dynorphin
Reward system
Brain stimulation reward
Mesolimbic pathway
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Orexin-A
Lateral hypothalamus
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Orexin-A
Lateral hypothalamus
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Orexins (also called hypocretins) are peptide neurotransmitters expressed in neurons of the lateral hypothalamic area (LHA).Mice lacking the orexin peptides develop narcolepsy-like symptoms, whereas mice with a selective loss of the orexin neurons develop hypophagia and severe obesity in addition to the narcolepsy phenotype.These different phenotypes suggest that orexin neurons may contain neurotransmitters besides orexin that regulate feeding and energy balance.Dynorphin neurons are common in the LHA, and dynorphin has been shown to influence feeding; hence, we studied whether dynorphin and orexin are colocalized.In rats, double-label in situ hybridization revealed that nearly all (94%) neurons expressing prepro-orexin mRNA also expressed prodynorphin mRNA.The converse was also true: 96% of neurons in the LHA containing prodynorphin mRNA also expressed prepro-orexin mRNA.Double-label immunohistochemistry confirmed that orexin-A and dynorphin-A peptides were highly colocalized in the LHA.Wild-type mice and orexin knock-out mice showed abundant prodynorphin mRNA-expressing neurons in the LHA, but orexin/ataxin-3 mice with a selective loss of the orexin neurons completely lacked prodynorphin mRNA in this area, further confirming that within the LHA, dynorphin expression is restricted to the orexin neurons.These findings suggest that dynorphin-A may play an important role in the function of the orexin neurons.
Dynorphin
Orexin-A
Lateral hypothalamus
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Dynorphin
κ-opioid receptor
Brain stimulation reward
Ventral striatum
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Lateral hypothalamus
Brain stimulation reward
Orexin-A
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Orexin receptor
Orexin-A
Lateral hypothalamus
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Medial forebrain bundle
Brain stimulation reward
Lateral hypothalamus
Zona incerta
Ventral striatum
Forebrain
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