Orexin A/hypocretin-1 (oxA/hcrt-1) is known to be a modulator of dopamine-dependent neuronal activity and behaviors. However, the role of this system in driving motivated behaviors remains poorly understood. Here, we show that orexin/hypocretin receptor-1 (ox/hcrt-1R) signaling is important for motivation for highly salient, positive reinforcement. Blockade of ox/hcrt-1R selectively reduced work to self-administer cocaine or high fat food pellets. Moreover, oxA/hcrt-1 strengthened presynaptic glutamatergic inputs to the ventral tegmental area (VTA) only in cocaine or high fat self-administering rats. Finally, oxA/hcrt-1-mediated excitatory synaptic transmission onto VTA neurons was not potentiated following an arousing, aversive stimulus, suggesting that oxA/hcrt-1-mediated glutamatergic synaptic transmission was potentiated selectively with highly salient positive reinforcers. These experiments provide evidence for a selective role of oxA/hcrt-1 signaling in motivation for highly salient reinforcers and may represent a unique opportunity to design novel therapies that selectively reduce excessive drive to consume positive reinforcers of high salience.
One of the most intriguing aspects of adaptive behavior involves the inference of regularities and rules in ever-changing environments. Rules are often deduced through evidence-based learning which relies on the prefrontal cortex (PFC). This is a highly dynamic process, evolving trial by trial and therefore may not be adequately captured by averaging single-unit responses over numerous repetitions. Here, we employed advanced statistical techniques to visualize the trajectories of ensembles of simultaneously recorded medial PFC neurons on a trial-by-trial basis as rats deduced a novel rule in a set-shifting task. Neural populations formed clearly distinct and lasting representations of familiar and novel rules by entering unique network states. During rule acquisition, the recorded ensembles often exhibited abrupt transitions, rather than evolving continuously, in tight temporal relation to behavioral performance shifts. These results support the idea that rule learning is an evidence-based decision process, perhaps accompanied by moments of sudden insight.
