Neuropsychological and neurophysiological studies have emphasized the role of the prefrontal cortex (PFC) in maintaining information about the temporal order of events or items for upcoming actions. However, the medial temporal lobe (MTL) has also been considered critical to bind individual events or items to their temporal context in episodic memory. Here we characterize the contributions of these brain areas by comparing single-unit activity in the dorsal and ventral regions of macaque lateral PFC (d-PFC and v-PFC) with activity in MTL areas including the hippocampus (HPC), entorhinal cortex, and perirhinal cortex (PRC) as well as in area TE during the encoding phase of a temporal-order memory task. The v-PFC cells signaled specific items at particular time periods of the task. By contrast, MTL cortical cells signaled specific items across multiple time periods and discriminated the items between time periods by modulating their firing rates. Analysis of the temporal dynamics of these signals showed that the conjunctive signal of item and temporal-order information in PRC developed earlier than that seen in v-PFC. During the delay interval between the two cue stimuli, while v-PFC provided prominent stimulus-selective delay activity, MTL areas did not. Both regions of PFC and HPC exhibited an incremental timing signal that appeared to represent the continuous passage of time during the encoding phase. However, the incremental timing signal in HPC was more prominent than that observed in PFC. These results suggest that PFC and MTL contribute to the encoding of the integration of item and timing information in distinct ways.

Background: Orexin can facilitate emergence after general anaesthesia via multiple neural pathways. Dopaminergic neurones in the ventral tegmental area (VTA) participate in behavioural arousal from anaesthesia. We investigated the regulation of dopaminergic VTA neurones by orexinergic neurones during emergence from general anaesthesia. Methods: Orexins were microinjected into the VTA to determine the effects on isoflurane anaesthesia induction, emergence, and maintenance. Orexin receptors and dopaminergic neurones in the VTA were identified using immunofluorescence. Orexinergic terminals in the VTA were optogenetically regulated to detect the endogenous orexinmediated regulation of dopaminergic neurones during anaesthesia in Hcrt cre rats. Results: Injection of orexin-A (100 pmol) into the VTA reduced emergence time [from 949 (118) to 727 (101) s; P¼0.0058] and reduced the electroencephalographic burstesuppression ratio (BSR) (26.6 [10.2]% vs 44.3 [6.8]%; P¼0.0027) during isoflurane anaesthesia. The percentage of dopaminergic neurones that expressed either orexin-1 receptor or orexin-2 receptor was 73.4 (5.0)% and 74.4 (62.4)%, respectively. Optogenetic activation of orexinergic projections to the VTA reduced the BSR (from 40.5 [2.7]% to 22.4 [11.8]%; P¼0.0019) and facilitated emergence (915 [89] vs 685 [68] s; P¼0.0026), whereas optical inhibition prolonged the time to wakefulness (from 941 [92] to 1279 [250] s; P¼0.011). Dopaminergic neurones in the VTA showed increased firing frequency (387 [78]% of control, P¼0.005) after bath application of orexin-A. Conclusions: Orexin promotes emergence from isoflurane anaesthesia through activation of dopaminergic neurones in the VTA.

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