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.
Highlights
Ventral tegmental area (VTA) dopamine neurons are involved in motivated survival behaviours and their activity can influence positive and negative reinforcement, incentive salience, and aversion [1,2,3,4]
Neurons can be reliably activated by photostimulation (Supple-Pavlovian conditioning Orexin-Cre ChR2 (n = 8) or mCherry (n = 10) mice implanted with bilateral optical fibres targeted at the VTA were used for both mentary Fig. 1A–D)
We identified the frequency of optical stimulation of lateral hypothalamic (LH) orexin/dynorphin inputs that would influence firing activity of VTA dopamine neurons (Supplementary Fig. 1E)
Summary
Ventral tegmental area (VTA) dopamine neurons are involved in motivated survival behaviours and their activity can influence positive and negative reinforcement, incentive salience, and aversion [1,2,3,4]. Application of intra-VTA norBNI inhibits actions of dynorphin from all sources, it is unknown what the direct contribution of dynorphin from the LH input is to reward-seeking behaviour It is unknown if endogenous LH orexin/dynorphin action in the VTA can influence mesolimbic dopamine neuro-. Recording (targeted at right NAc core) and NAc dopamine release, reward-seeking behaviours, and/or stimulating (combined with optical fibre; targeted at VTA) were increases the incentive value of food. FSCV data were collected in 120 s files, with stimulation onset occurring 5 s into the recording using TarHeel CV and High-Definition Cyclic Voltammetry (HDCV)
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