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REM sleep is proposed to create an
REM sleep is proposed to create an environment to facilitate plasticity processes that create a generalized downregulation of synaptic strength (Grosmark et al., 2012; Tononi and Cirelli, 2014), while synapses are upregulated specifically by the reactivation of neuronal firing sequences experienced during salient events found in REM and NREM sleep episodes (Atherton et al., 2015; Lee and Wilson, 2002; Louie and Wilson, 2001). Our findings for the release of IT-901 only during some periods of REM sleep, and not during NREM sleep, suggest that acetylcholine may enable the dual processes of generalized synaptic downregulation and specific synaptic potentiation to occur in different phases of sleep and, therefore, facilitate efficient memory consolidation. The importance of phasic acetylcholine release to attention and cue detection has been demonstrated by the lack of cue detection in the absence of phasic cholinergic events in the prefrontal cortex (Gritton et al., 2016; Parikh et al., 2007) and a reduction in attentional performance in animals with reduced cholinergic innervation, which may be rescued by cholinergic agonists (Paolone et al., 2013). Further evidence suggests that phasic acetylcholine release in the mPFC shifts the behavioral state from cue monitoring to activation of response rules and subsequent responses (Howe et al., 2013). However, this view is challenged by data showing that BF non-cholinergic, but not cholinergic, neuron activity is correlated with performance accuracy (Hangya et al., 2015). We found that coordinated phasic acetylcholine release between the mPFC and dHPC occurs only during maze performance. This suggests that phasic acetylcholine release is important for task performance and shows that phasic release is not limited spatially to the mPFC but also occurs in the dHPC. In our study, the occurrence of phasic acetylcholine release events in the reward-delivery areas, regardless of reward delivery and independent of successful task completion, indicates a response to reward or the expectation of reward. This supports previous theories for the role of acetylcholine release as a reinforcement signal to guide learned behavior in response to salient cues and the dependence of cholinergic activation on outcome expectation (Hangya et al., 2015), thus suggesting a role for coordinated phasic release of acetylcholine in the mPFC and dHPC for the accessing of retained place-reward associations (internal cues) necessary for successful task completion. Thus, the coordinated phasic release of acetylcholine may be important for the processing of both externally and internally stored cues relevant to salient events (Baddeley, 2003), enabling the assessment of uncertainty (Yu and Dayan, 2005). Furthermore, the release of acetylcholine in the mPFC and dHPC in the same spatial locations implies that place-reward association requires coordinated reorganization of network function in these interconnected structures. The PFC and HPC are both required for the successful learning of spatial working memory tasks, including delayed non-match to place tasks such as the T-maze task used in this study. The direct synaptic connection between the ventral HPC and mPFC is required for the acquisition phase of working memory potentially by synchronizing the two brain areas within the gamma frequency range (Spellman et al., 2015). Equally, synchronization of the mPFC and dHPC within the theta frequency range at the choice point and, therefore, retrieval phase of the task is also important (Jones and Wilson, 2005; Kucewicz et al., 2011) and is disrupted in an animal model of schizophrenia with poor working memory performance (Sigurdsson et al., 2010). Acetylcholine release amplifies both theta and gamma frequency oscillations (Fisahn et al., 1998; Lee et al., 1994); therefore, its coordinated release in the mPFC and HPC is predicted to contribute to the transient increases in mPFC-HPC theta and gamma coherence that underlie successful trial performance. Although our experiments are not designed to test this hypothesis directly, our observation that phasic release of acetylcholine is coordinated in the mPFC and dHPC suggests that it may play a role in controlling mPFC-HPC theta and gamma coherence.