Mental time travel in the rat.

I outline the perspective that searching the contents of memory is a form of mental time travel (MTT) in non-humans that is relatively tractable because it focuses on the contents of memory. I propose that an animal model of MTT requires three elements: (i) the animal remembers multiple events using episodic memory, (ii) the order of events in time is included in the representation, and (iii) the sequence of events can be searched to find a target that occurred at a particular time. I review experiments suggesting that rats represent multiple items in episodic memory (element 1) in order of occurrence (element 2) and engage in memory replay to search representations in episodic memory in sequential order to find information at particular points in the sequence (element 3). The cognitive building blocks needed for MTT may be quite old in the evolutionary timescale.This article is part of the theme issue 'Elements of episodic memory: lessons from 40 years of research'.

Negative allosteric modulation of CB1 cannabinoid receptor signalling decreases intravenous morphine self-administration and relapse in mice.

The endocannabinoid system interacts with the reward system to modulate responsiveness to natural reinforcers, as well as drugs of abuse. Previous preclinical studies suggested that direct blockade of CB1 cannabinoid receptors (CB1R) could be leveraged as a potential pharmacological approach to treat substance use disorder, but this strategy failed during clinical trials due to severe psychiatric side effects. Alternative strategies have emerged to circumvent the side effects of direct CB1 binding through the development of allosteric modulators. We hypothesized that negative allosteric modulation of CB1R signalling would reduce the reinforcing properties of morphine and decrease behaviours associated with opioid misuse. By employing intravenous self-administration in mice, we studied the effects of GAT358, a functionally-biased CB1R negative allosteric modulator (NAM), on morphine intake, relapse-like behaviour and motivation to work for morphine infusions. GAT358 reduced morphine infusion intake during the maintenance phase of morphine self-administration under a fixed ratio 1 schedule of reinforcement. GAT358 also decreased morphine-seeking behaviour after forced abstinence. Moreover, GAT358 dose dependently decreased the motivation to obtain morphine infusions under a progressive ratio schedule of reinforcement. Strikingly, GAT358 did not affect the motivation to work for food rewards in an identical progressive ratio task, suggesting that the effect of GAT358 in decreasing opioid self-administration was reward specific. Furthermore, GAT58 did not produce motor ataxia in the rotarod test. Our results suggest that CB1R NAMs reduced the reinforcing properties of morphine and could represent a viable therapeutic route to safely decrease misuse of opioids.

Comparative cognition: Free-living birds remember things past.

New research suggests that free-living blue and great tits remember foraging, including food type, location, and time since eating, even when event details were not known to be relevant for a subsequent assessment of memory, implicating the use of episodic memory in natural behavior.

Validation of a rodent model of episodic memory replay.

Vivid episodic memories in humans have been described as the replay of the flow of past events in sequential order. Recently, Panoz-Brown et al. Current Biology, 28, 1628-1634, (2018) developed an olfactory memory task in which rats were presented with a list of trial-unique odors in an encoding context; next, in a distinctive memory assessment context, the rats were rewarded for choosing the second to last item from the list while avoiding other items from the list. In a different memory assessment context, the fourth to last item was rewarded. According to the episodic memory replay hypothesis, the rat remembers the list items and searches these items to find the item at the targeted locations in the list. However, events presented sequentially differ in memory trace strength, allowing a rat to use the relative familiarity of the memory traces, instead of episodic memory replay, to solve the task. Here, we directly manipulated memory trace strength by manipulating the odor intensity of target odors in both the list presentation and memory assessment. The rats relied on episodic memory replay to solve the memory assessment in conditions in which reliance on memory trace strength is ruled out. We conclude that rats are able to replay episodic memories.

Animal cognition: Time mapping in the wild.

Foraging involves searching for resources distributed in space and time with varying nutritional values. New research suggests that free-ranging wild fruit bats track tree phenology, implicating the use of spatio-temporal mental maps.

Replay of incidentally encoded novel odors in the rat.

Although events are not always known to be important when they occur, people can remember details about such incidentally encoded information using episodic memory. Sheridan et al. (2024) argued that rats replayed episodic memories of incidentally encoded information in an unexpected assessment of memory. In one task, rats reported the third-last item in an explicitly encoded list of trial-unique odors. In a second task, rats foraged in a radial maze in the absence of odors. On a critical test, rats foraged in the maze, but scented lids covered the food. Next, memory of the third-last odor was assessed. The rats correctly answered the unexpected question. Because the odors used in the critical test were the same as those used during training, automatically encoding odors for the purpose of taking an upcoming test of memory (stimulus generalization) may have been encouraged. Here, we provided an opportunity for incidental encoding of novel odors. Previously trained rats foraged in the radial maze with entirely novel odors covering the food. Next, memory of the third-last odor was assessed. The rats correctly answered the unexpected question. High accuracy when confronted with novel odors provides evidence that the rats did not automatically encode odors for the purpose of taking an upcoming test, ruling out stimulus generalization. We conclude that rats encode multiple pieces of putatively unimportant information, and later replayed a stream of novel episodic memories when that information was needed to solve an unexpected problem.

Replay of incidentally encoded episodic memories in the rat.

Although events are not always known to be important when they occur, people can remember details about such incidentally encoded information using episodic memory. Importantly, when information is explicitly encoded for use in an expected test of retention (as in most assessments in animals), it is possible that it is used to generate a planned action1,2,3; thus, the remembered action can occur without remembering the earlier episode. By contrast, when a test is unexpected, transforming information into an action plan is unlikely because the importance of the information and the nature of the test are not yet known. Thus, accurate performance in an unexpected test after incidental encoding documents episodic memory.1,2,3,4,5,6,7,8 Here, we present evidence that rats replay episodic memories of incidentally encoded information in an unexpected assessment of memory. In one task,9 rats reported the third-last item in an explicitly encoded list of trial-unique odors. In a second task,10 rats foraged in a radial maze in the absence of odors. On a critical test, rats foraged in the radial maze, but scented lids covered the food. Next, memory of the third-last odor was assessed. All participating rats correctly answered the unexpected question. These results suggest that rats encoded multiple pieces of putatively unimportant information, and later they replayed a stream of episodic memories when that information was needed to solve an unexpected problem. We propose that rats replay episodic memories of incidentally encoded information, which documents a critical aspect of human episodic memory in a non-human animal.

Negative allosteric modulation of CB1 cannabinoid receptor signaling decreases intravenous morphine self-administration and relapse in mice.

The endocannabinoid system interacts with the reward system to modulate responsiveness to natural reinforcers, as well as drugs of abuse. Previous preclinical studies suggested that direct blockade of CB1 cannabinoid receptors (CB1R) could be leveraged as a potential pharmacological approach to treat substance use disorder, but this strategy failed during clinical trials due to severe psychiatric side effects. Alternative strategies have emerged to circumvent the side effects of direct CB1 binding through the development of allosteric modulators. We hypothesized that pharmacological inhibition of CB1R signaling through negative allosteric modulation (NAM) would reduce the reinforcing properties of morphine and decrease opioid addictive behaviors. By employing i.v. self-administration in mice, we studied the effects of the CB1-biased NAM GAT358 on morphine intake, relapse-like behavior, and motivation to work for morphine infusions. Our data revealed that GAT358 reduced morphine infusion intake during the maintenance phase of morphine self-administration under fixed ratio 1 schedule of reinforcement. GAT358 decreased morphine-seeking behavior after forced abstinence. Moreover, GAT358 dose-dependently decreased the motivation to obtain morphine infusions in a progressive ratio schedule of reinforcement. Strikingly, GAT358 did not affect the motivation to work for food rewards in an identical progressive ratio task, suggesting that the effect of GAT358 in decreasing opioid self-administration is reward specific. Furthermore, GAT58 did not produce motor ataxia in the rota-rod test. Our results suggest that CB1R NAMs reduced the reinforcing properties of morphine and could represent a viable therapeutic route to safely decrease opioid-addicted behaviors.

The timing database: An open-access, live repository for interval timing studies.

Interval timing refers to the ability to perceive and remember intervals in the seconds to minutes range. Our contemporary understanding of interval timing is derived from relatively small-scale, isolated studies that investigate a limited range of intervals with a small sample size, usually based on a single task. Consequently, the conclusions drawn from individual studies are not readily generalizable to other tasks, conditions, and task parameters. The current paper presents a live database that presents raw data from interval timing studies (currently composed of 68 datasets from eight different tasks incorporating various interval and temporal order judgments) with an online graphical user interface to easily select, compile, and download the data organized in a standard format. The Timing Database aims to promote and cultivate key and novel analyses of our timing ability by making published and future datasets accessible as open-source resources for the entire research community. In the current paper, we showcase the use of the database by testing various core ideas based on data compiled across studies (i.e., temporal accuracy, scalar property, location of the point of subjective equality, malleability of timing precision). The Timing Database will serve as the repository for interval timing studies through the submission of new datasets.

Temporal foundations of episodic memory.

A fundamental question in the development of animal models of episodic memory concerns the role of temporal processes in episodic memory. Gallistel, (1990) developed a framework in which animals remember specific features about an event, including the time of occurrence of the event and its location in space. Gallistel proposed that timing is based on a series of biological oscillators, spanning a wide range of periods. Accordingly, a snapshot of the phases of multiple oscillators provides a representation of the time of occurrence of the event. I review research on basic timing mechanisms that may support memory for times of occurrence. These studies suggest that animals use biological oscillators to represent time. Next, I describe recently developed animal models of episodic memory that highlight the importance of temporal representations in memory. One line of research suggests that an oscillator representation of time supports episodic memory. A second line of research highlights the flow of events in time in episodic memory. Investigations that integrate time and memory may advance the development of animal models of episodic memory.

Negative allosteric modulation of CB1 cannabinoid receptor signaling suppresses opioid-mediated reward.

Blockade of cannabinoid type 1 (CB1)-receptor signaling decreases the rewarding properties of many drugs of abuse and has been proposed as an anti-addiction strategy. However, psychiatric side-effects limit the clinical potential of orthosteric CB1 antagonists. Negative allosteric modulators (NAMs) represent a novel and indirect approach to attenuate CB1 signaling by decreasing affinity and/or efficacy of CB1 ligands. We hypothesized that a CB1-NAM would block opioid reward while avoiding the unwanted effects of orthosteric CB1 antagonists. GAT358, a CB1-NAM, failed to elicit cardinal signs of direct CB1 activation or inactivation when administered by itself. GAT358 decreased catalepsy and hypothermia but not antinociception produced by the orthosteric CB1 agonist CP55,940, suggesting that a CB1-NAM blocked cardinal signs of CB1 activation. Next, GAT358 was evaluated using in vivo assays of opioid-induced dopamine release and reward in male rodents. In the nucleus accumbens shell, a key component of the mesocorticolimbic reward pathway, morphine increased electrically-evoked dopamine efflux and this effect was blocked by a dose of GAT358 that lacked intrinsic effects on evoked dopamine efflux. Moreover, GAT358 blocked morphine-induced reward in a conditioned place preference (CPP) assay without producing reward or aversion alone. GAT358-induced blockade of morphine CPP was also occluded by GAT229, a CB1 positive allosteric modulator (CB1-PAM), and absent in CB1-knockout mice. Finally, GAT358 also reduced oral oxycodone (but not water) consumption in a two-bottle choice paradigm. Our results support the therapeutic potential of CB1-NAMs as novel drug candidates aimed at preventing opioid reward and treating opioid abuse while avoiding unwanted side-effects.

Memory: Dolphins remember incidental events.

A fundamental problem in the evolution of cognition is the search for complex memory systems given the longstanding belief that complex cognition is unique to humans. Along these lines, new research suggests that bottlenose dolphins can answer unexpected questions after encoding information that was seemingly unimportant when it was encountered.

Inhibition of PSD95-nNOS protein-protein interactions decreases morphine reward and relapse vulnerability in rats.

Glutamate signalling through the N-methyl-d-aspartate receptor (NMDAR) activates the enzyme neuronal nitric oxide synthase (nNOS) to produce the signalling molecule nitric oxide (NO). We hypothesized that disruption of the protein-protein interaction between nNOS and the scaffolding protein postsynaptic density 95 kDa (PSD95) would block NMDAR-dependent NO signalling and represent a viable therapeutic route to decrease opioid reward and relapse-like behaviour without the unwanted side effects of NMDAR antagonists. We used a conditioned place preference (CPP) paradigm to evaluate the impact of two small-molecule PSD95-nNOS inhibitors, IC87201 and ZL006, on the rewarding effects of morphine. Both IC87201 and ZL006 blocked morphine-induced CPP at doses that lacked intrinsic rewarding or aversive properties. Furthermore, in vivo fast-scan cyclic voltammetry (FSCV) was used to ascertain the impact of ZL006 on morphine-induced increases in dopamine (DA) efflux in the nucleus accumbens shell (NAc shell) evoked by electrical stimulation of the medial forebrain bundle (MFB). ZL006 attenuated morphine-induced increases in DA efflux at a dose that did not have intrinsic effects on DA transmission. We also employed multiple intravenous drug self-administration approaches to examine the impact of ZL006 on the reinforcing effects of morphine. Interestingly, ZL006 did not alter acquisition or maintenance of morphine self-administration, but reduced lever pressing in a morphine relapse test after forced abstinence. Our results provide behavioural and neurochemical support for the hypothesis that inhibition of PSD95-nNOS protein-protein interactions decreases morphine reward and relapse-like behaviour, highlighting a previously unreported application for these novel therapeutics in the treatment of opioid addiction.

An adolescent rat model of vincristine-induced peripheral neuropathy.

Childhood acute lymphoblastic leukemia (ALL) is a significant clinical problem that can be effectively treated with vincristine, a vinca alkaloid-based chemotherapeutic agent. However, nearly all children receiving vincristine treatment develop vincristine-induced peripheral neuropathy (VIPN). The impact of adolescent vincristine treatment across the lifespan remains poorly understood. We, consequently, developed an adolescent rodent model of VIPN which can be utilized to study possible long term consequences of vincristine treatment in the developing rat. We also evaluated the therapeutic efficacy of voluntary exercise and potential impact of obesity as a genetic risk factor in this model on the development and maintenance of VIPN. Out of all the dosing regimens we evaluated, the most potent VIPN was produced by fifteen consecutive daily intraperitoneal (i.p.) vincristine injections at 100 µg/kg/day, throughout the critical period of adolescence from postnatal day 35 to 49. With this treatment, vincristine-treated animals developed hypersensitivity to mechanical and cold stimulation of the plantar hind paw surface, which outlasted the period of vincristine treatment and resolved within two weeks following the cessation of vincristine injection. By contrast, impairment in grip strength gain was delayed by vincristine treatment, emerging shortly following the termination of vincristine dosing, and persisted into early adulthood without diminishing. Interestingly, voluntary wheel running exercise prevented the development of vincristine-induced hypersensitivities to mechanical and cold stimulation. However, Zucker fa/fa obese animals did not exhibit higher risk of developing VIPN compared to lean rats. Our studies identify sensory and motor impairments produced by vincristine in adolescent animals and support the therapeutic efficacy of voluntary exercise for suppressing VIPN in developing rats.

Evaluating evidence from animal models of episodic memory.

A fundamental question in comparative cognition concerns the ability to remember back in time to an earlier event or episode. This ability is referred to as episodic memory. Whether nonhumans can be used to model human episodic memory has engendered much interest and debate for over 2 decades. The central hypothesis of an animal model of episodic memory is that, at the moment of the memory assessment, the animal remembers back in time to a specific earlier event or episode. I describe (a) an approach for evaluating evidence of episodic memory in animal models (b) what aspects of episodic memory are being modeled in animals (c) what standards ought to be applied to a candidate model of episodic memory in nonhumans (d) the first evidence of episodic memory in nonhumans, and (e) a brief overview of the diversity of approaches that are now available. The remainder of the article focuses on the development of a robust model of episodic memory in rats. Converging lines of evidence suggest that rats provide a good model for exploring episodic memory. This evidence includes studies that focus on (a) what-where-when memory (b) source memory (c) binding of episodic memories (d) memory of multiple Items in context using episodic memory (e) replay of episodic memories (f), recollection, and (g) answering an unexpected question after incidental encoding. In each of these domains, I describe evidence for episodic memory in the absence of nonepisodic judgments of familiarity. I end with some consideration of future directions. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Extraordinary claims, extraordinary evidence? A discussion.

Roberts (2020, Learning & Behavior, 48[2], 191-192) discussed research claiming honeybees can do arithmetic. Some readers of this research might regard such claims as unlikely. The present authors used this example as a basis for a debate on the criterion that ought to be used for publication of results or conclusions that could be viewed as unlikely by a significant number of readers, editors, or reviewers.

Comparative cognition: Perspectives, challenges, and prospects.

The publication of the centennial year of the Journal of Comparative Psychology is an occasion to reflect on the state of our discipline. In this article, I focus on one aspect of comparative psychology, namely, comparative cognition. This focus stems from my long-standing interest in comparative cognition. The trends and challenges in comparative cognition share many of the trends and challenges in the broader field of comparative psychology. In the first part of this article, I outline my perspective on the field. Next, I consider challenges. I end with a section on prospects for the future. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Peripheral nerve injury promotes morphine-seeking behavior in rats during extinction.

Chronic neuropathic pain and prescription opioid abuse represent highly interconnected societal problems. We used a rat model of spared nerve injury (SNI) and an intravenous drug self-administration paradigm to investigate the impact of a neuropathic pain state on morphine-seeking behavior in extinction (i.e. when morphine is withheld). SNI, sham-operated and naive groups exhibited similar levels of active lever presses for morphine infusions on a fixed ratio 1 (FR1) schedule. Self-administration of morphine, but not vehicle, attenuated nerve injury-induced mechanical allodynia in SNI rats. Under these same conditions, mechanical paw withdrawal thresholds in sham-operated and naive groups were largely unaltered. However, SNI rats showed higher levels of morphine-seeking behavior compared to sham-operated or naïve groups in extinction (i.e. when vehicle was substituted for morphine). Interestingly, the perseveration of morphine-seeking behavior observed during extinction was only present in the SNI group despite the fact that all groups had a similar history of morphine self-administration intake. Our results suggest that different motivational states associated with neuropathic pain promote morphine-seeking behavior in extinction. Drug self-administration paradigms may be useful for evaluating analgesic efficacy and motivational properties associated with opioid reinforcers in pathological pain states.

The cannabinoid CB2 receptor agonist LY2828360 synergizes with morphine to suppress neuropathic nociception and attenuates morphine reward and physical dependence.

The opioid crisis has underscored the urgent need to identify safe and effective therapeutic strategies to overcome opioid-induced liabilities. We recently reported that LY2828360, a slowly signaling G protein-biased cannabinoid CB2 receptor agonist, suppresses neuropathic nociception and attenuates the development of tolerance to the opioid analgesic morphine in paclitaxel-treated mice. Whether beneficial effects of LY2828360 are dependent upon the presence of a pathological pain state are unknown and its impact on unwanted opioid-induced side-effects have never been investigated. Here, we asked whether LY2828360 would produce synergistic anti-allodynic effects with morphine in a paclitaxel model of chemotherapy-induced neuropathic pain and characterized its impact on opioid-induced reward and other unwanted side-effects associated with chronic opioid administration. Isobolographic analysis revealed that combinations of LY2828360 and morphine produced synergistic anti-allodynic effects in suppressing paclitaxel-induced mechanical allodynia. In wildtype (WT) mice, LY2828360 blocked morphine-induced reward in a conditioned place preference assay without producing reward or aversion when administered alone. The LY2828360-induced attenuation of morphine-induced reward was absent in CB2 knockout (CB2KO) mice. In the absence of a neuropathic pain state, LY2828360 partially attenuated naloxone-precipitated opioid withdrawal in morphine-dependent WT mice, and this withdrawal was itself markedly exacerbated in CB2KO mice. Moreover, LY2828360 did not reliably alter morphine-induced slowing of colonic transit or attenuate tolerance to morphine antinociceptive efficacy in the hot plate test of acute nociception. Our results suggest that cannabinoid CB2 receptor activation enhances the therapeutic properties of opioids while attenuating unwanted side-effects such as reward and dependence that occur with sustained opioid treatment.

Memory: Amyloid Beta Is Good Before It Is Bad.

A fundamental mystery in the biology of memory is to understand the pathway from normal memory to later dysfunctional memory. Some insight on this problem comes from new research suggesting that amyloid beta helps memory consolidation, before it impairs memory.