Acute stress suppresses pain by activating brain pathways that engage opioid or non-opioid mechanisms. Here we show that an opioid-independent form of this phenomenon, termed stressinduced analgesia 1 , is mediated by the release of endogenous marijuana-like (cannabinoid) compounds in the brain. Blockade of cannabinoid CB 1 receptors in the periaqueductal grey matter of the midbrain prevents non-opioid stress-induced analgesia. In this region, stress elicits the rapid formation of two endogenous cannabinoids, the lipids 2-arachidonoylglycerol 2 (2-AG) and anandamide 3 . A newly developed inhibitor of the 2-AG-deactivating enzyme, monoacylglycerol lipase 4,5 , selectively increases 2-AG concentrations and, when injected into the periaqueductal grey matter, enhances stress-induced analgesia in a CB 1 -dependent manner. Inhibitors of the anandamide-deactivating enzyme fatty-acid amide hydrolase 6 , which selectively elevate anandamide concentrations, exert similar effects. Our results indicate that the coordinated release of 2-AG and anandamide in the periaqueductal grey matter might mediate opioid-independent stress-induced analgesia. These studies also identify monoacylglycerol lipase as a previously unrecognized therapeutic target.Stress activates neural systems that inhibit pain sensation. This adaptive response, referred to as stress-induced analgesia (SIA), depends on the recruitment of brain pathways that project from the amygdala to the midbrain periaqueductal grey matter (PAG) and descend to the brainstem rostroventromedial medulla and dorsal horn of the spinal cord 7 . Endogenous opioid peptides have key functions in this process 1,8 , but other as yet unidentified neurotransmitters are also known to be involved 1 . We proposed that endocannabinoids might be implicated in stress analgesia for two reasons. First, agonists of CB 1 receptors-the predominant cannabinoid receptor subtype present in the brain 9,10 -exert profound antinociceptive effects 7 and suppress activity in nociceptive neurons 11-14 . Second, CB 1 antagonists increase the activity of nociceptive rostroventromedial medulla neurons 14 and enhance sensitivity to noxious stimuli 15 , indicating that an intrinsic endocannabinoid tone might regulate descending antinociceptive pathways 7 . To study non-opioid SIA we delivered brief, continuous electric foot shock to rats and quantified their sensitivity to pain after stress by using the tail-flick test. As demonstrated previously 1,16 , this stimulation protocol caused a profound antinociceptive effect that was not affected by intraperitoneal (i.p.) injection of the opiate antagonist naltrexone (14 mg kg 21 ) (Fig. 1a). However, the response was almost abolished by administration of the CB 1 antagonist rimonabant (SR141617A, 5 mg kg

The ability to reflect on one's own mental processes, termed metacognition, is a defining feature of human existence [1, 2]. Consequently, a fundamental question in comparative cognition is whether nonhuman animals have knowledge of their own cognitive states [3]. Recent evidence suggests that people and nonhuman primates [4-8] but not less "cognitively sophisticated" species [3, 9, 10] are capable of metacognition. Here, we demonstrate for the first time that rats are capable of metacognition--i.e., they know when they do not know the answer in a duration-discrimination test. Before taking the duration test, rats were given the opportunity to decline the test. On other trials, they were not given the option to decline the test. Accurate performance on the duration test yielded a large reward, whereas inaccurate performance resulted in no reward. Declining a test yielded a small but guaranteed reward. If rats possess knowledge regarding whether they know the answer to the test, they would be expected to decline most frequently on difficult tests and show lowest accuracy on difficult tests that cannot be declined [4]. Our data provide evidence for both predictions and suggest that a nonprimate has knowledge of its own cognitive state.

A fundamental question in comparative cognition is whether animals remember unique, personal past experiences. It has long been argued that memories for specific events (referred to as episodic memory) are unique to humans. Recently, considerable evidence has accumulated to show that food-storing birds possess critical behavioral elements of episodic memory, referred to as episodic-like memory in acknowledgment of the fact that behavioral criteria do not assess subjective experiences. Here we show that rats have a detailed representation of remembered events and meet behavioral criteria for episodic-like memory. We provided rats with access to locations baited with distinctive (e.g., grape and raspberry) or nondistinctive (regular chow) flavors. Locations with a distinctive flavor replenished after a long but not a short delay, and locations with the nondistinctive flavor never replenished. One distinctive flavor was devalued after encoding its location by prefeeding that flavor (satiation) or by pairing it with lithium chloride (acquired taste aversion), while the other distinctive flavor was not devalued. The rats selectively decreased revisits to the devalued distinctive flavor but not to the nondevalued distinctive flavor. The present studies demonstrate that rats selectively encode the content of episodic-like memories.

Summary People remember an event as a coherent scene [1-4]. Memory of such an episode is thought to reflect binding of a fully integrated representation, rather than memory of unconnected features [4-7]. However, it is not known if rodents form bound representations. Here we show that rats remember episodes as bound representations. Rats were presented with multiple features of unique episodes at memory encoding: what (food flavor), where (maze location), source (self-generated food seeking–running to the food site– or experimenter-generated food seeking –placement by the experimenter at the food site), and context (spatial cues in the room where the event occurred). After a delay, the trial continued with a memory assessment in which one flavor replenished at the self-generated- but not at experimenter-generated-locations. We presented rats with multiple overlapping features, in rapid succession, to ensure that successful memory retrieval required them to disambiguate multiple study episodes (using two rooms). We found that binding is resistant to interference from highly similar episodes and survives long retention intervals (~1 week). Our results suggest that multiple episodic memories are each structured as bound representations, which suggests that nonhumans represent episodic memories using a structure similar to that of people. This finding enhances the translational potential for utilizing animal models of episodic memory to explore the biological mechanisms of memory and validate therapeutic approaches for treating disorders of memory.

Summary A fundamental aspect of episodic memory is that retrieval of information can occur when encoding is incidental and memory assessment is unexpected [1–4]. These features are difficult to model in animals because behavioral training likely gives rise to well-learned expectations about the sequence of events. Thus, the possibility remains that animals may solve an episodic-memory test by using well-learned semantic rules without remembering the episode at memory assessment. Here we show that rats can answer an unexpected question after incidental encoding in a hippocampal-dependent manner, consistent with the use of episodic memory. Rats were initially trained to report about a recent event (food vs. no-food) and separately searched for food where there was no expectation of being asked about the presence of food. To test episodic memory, rats were given the opportunity to incidentally encode the presence or absence of food and were unexpectedly asked to report about the recent event. Temporary inactivation of the CA3 region of the hippocampus with bilateral infusions of lidocaine selectively eliminated the ability of rats to answer the unexpected, but not the expected, question. Our studies suggest that rats remember an earlier episode after incidental encoding based upon hippocampal-dependent episodic memory.

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The content of episodic memory consists of representations of unique past events. Episodic memories are grounded in a temporal framework (i.e., we remember when an event occurred). It has recently been argued that episodic-like memory in rats is qualitatively different from human episodic memory because, rather than remembering when an earlier past event occurred, rats used the cue of how long ago it occurred. We asked, therefore, whether rats remember the time of day at which they encountered a distinctive event, in addition to what occurred and where it happened. Rats were tested in the morning and afternoon, on separate days. A distinctive flavor (chocolate) was replenished at a daily-unique location at only one of these times. The interval between first and second daily opportunities to eat (study and test, respectively) was constant. Rats adjusted their revisits to the chocolate location at different times of day by using time of day rather than the cue of how long ago an event occurred. Two lines of evidence suggest that rats remembered the time at which the distinctive event occurred. First, under conditions in which the time of test (but not time of study) was novel, rats immediately transferred their knowledge of the chocolate contingency to the new test time. Second, under conditions in which predictions for study and test times were put in conflict, rats again used study time. Our results suggest that, at the time of memory assessment, rats remember when a recent episode occurred, similar to human episodic memory. P eople remember when a past event occurred within the time frame of hours, days, or years (1). It has been argued that retrieval of episodic memories is analogous to traveling back in time to experience specific events from one's personal past (2-4). An earlier definition focused on the content of episodic memory, that is, answering 3 questions about a specific event: what happened, where did it take place, and when did it transpire (5)? We refer to this type of content as what-where-when memory. Clayton and Dickinson (6) introduced the term episodic-like memory to emphasize that behavioral studies in animals evaluate the content of episodic memory rather than subjective experiences.Recent studies with nonhuman animals (6-18) suggest that animals remember specific episodes from their past (i.e., whatwhere-when memories). However, controversy has emerged about the comparability of episodic-like memory in rodents and episodic memory in humans (17). Roberts et al. (2,17) suggested that memory for when an event occurred suggests an ability akin to mentally traveling in time to locate an event within a temporal framework; such an ability would be similar to human episodic memory, in which people reconstruct past experiences using an absolute temporal dimension (1,19,20). By contrast, a judgment of how long ago an event occurred is quite different from human episodic memory. Such a judgment could also be solved by simpler alternative mechanisms (e.g., timing an interval since a distinctive event ...

Metacognition is thinking about thinking. There is considerable interest in developing animal models of metacognition to provide insight about the evolution of mind and a basis for investigating neurobiological mechanisms of cognitive impairments in people. Formal modeling of low-level (i.e., alternative) mechanisms has recently demonstrated that prevailing standards for documenting metacognition are inadequate. Indeed, low-level mechanisms are sufficient to explain data from existing methods. Consequently, an assessment of what is ‘lost’ (in terms of existing methods and data) necessitates the development of new, innovative methods for metacognition. Development of new methods may prompt the establishment of new standards for documenting metacognition.