Psilocybin and 4-Bromo-2,5-Dimethoxyphenethylamine (2C-B) at Encoding Distort Episodic Familiarity.

BACKGROUND: As research on psychedelics (hallucinogenic 5-HT2A agonists) progresses, it is important to delineate the reliability of supposedly unique effects across this drug class. One such effect is how psychedelics impair the formation (i.e., encoding) of hippocampal-dependent recollections (retrieval of specific details) while potentially enhancing the encoding of cortical-dependent familiarity (a feeling of knowing that a stimulus has been previously experienced). METHODS: In a double-blind, placebo-controlled, within-subjects study (N = 20), we tested the acute effects of two distinct psychedelics, psilocybin and 4-bromo-2,5-dimethoxyphenethylamine (2C-B), on the encoding of emotional episodic memories. During acute drug effects, participants viewed negative, neutral, and positive pictures. The following day (while sober), participants completed two separate memory tests for these pictures. RESULTS: Using computational models of memory confidence, we found trends for psilocybin and 2C-B at encoding to impair estimates of recollection that were supported by other measures/analyses. Surprisingly, psilocybin and 2C-B at encoding impaired estimates of familiarity, but these impairments were likely due to a misattribution of heightened familiarity, as both drugs at encoding selectively increased familiarity-based false alarms, especially for negative and positive stimuli. Psilocybin and 2C-B at encoding also tended to impair estimates of metamemory (understanding one's own memory) for negative and neutral memories but enhance estimates of metamemory for positive memories, though these effects were less reliable in additional analyses. CONCLUSIONS: Despite differences in their chemistry, pharmacology, and subjective effects, both psilocybin and 2C-B distort episodic familiarity, alluding to a common neurocognitive mechanism across psychedelics that may drive other phenomena.

The mechanistic divide in psychedelic neuroscience: An unbridgeable gap?

In recent years, psychedelics have generated considerable excitement and interest as potential novel therapeutics for an array of conditions, with the most advanced evidence base in the treatment of certain severe and/or treatment-resistant psychiatric disorders. An array of clinical and pre-clinical evidence has informed our current understanding of how psychedelics produce profound alterations in consciousness. Mechanisms of psychedelic action include receptor binding and downstream cellular and transcriptional pathways, with long-term impacts on brain structure and function-from the level of single neurons to large-scale circuits. In this perspective, we first briefly review and synthesize separate lines of research on potential mechanistic processes underlying the acute and long-term effects of psychedelic compounds, with a particular emphasis on highlighting current theoretical models of psychedelic drug action and their relationships to therapeutic benefits for psychiatric and brain-based disorders. We then highlight an existing area of ongoing controversy we argue is directly informed by theoretical models originating from disparate levels of inquiry, and we ultimately converge on the notion that bridging the current chasm in explanatory models of psychedelic drug action across levels of inquiry (molecular, cellular, circuit, and psychological/behavioral) through innovative methods and collaborative efforts will ultimately yield the comprehensive understanding needed to fully capitalize on the potential therapeutic properties of these compounds.

Unique effects of sedatives, dissociatives, psychedelics, stimulants, and cannabinoids on episodic memory: A review and reanalysis of acute drug effects on recollection, familiarity, and metamemory.

Despite distinct classes of psychoactive drugs producing putatively unique states of consciousness, there is surprising overlap in terms of their effects on episodic memory and cognition more generally. Episodic memory is supported by multiple subprocesses that have been mostly overlooked in psychopharmacology and could differentiate drug classes. Here, we reanalyzed episodic memory confidence ratings from 10 previously published data sets (28 drug conditions total) using signal detection models to estimate two conscious states involved in episodic memory and one consciously controlled metacognitive process of memory: autonoetic retrieval of specific details (recollection), noetic recognition absent of retrieved details (familiarity), and retrospective introspection of memory decisions (metamemory). Sedatives, dissociatives, psychedelics, stimulants, and cannabinoids had unique patterns of effects on these mnemonic processes dependent on whether they impacted encoding, consolidation, or retrieval (the formation, stabilization, and access to memory traces, respectively). Sedatives at encoding reliably impaired both recollection and familiarity but at consolidation enhanced recollection. Dissociatives and cannabinoids at encoding impaired recollection but less reliably impaired familiarity, and cannabinoids at retrieval increased false recollections. These drug-induced encoding impairments occasionally came with metamemory enhancements, perhaps because of less interstimulus interference. Psychedelics at encoding impaired recollection but tended to enhance familiarity and did not impact metamemory. Stimulants at encoding enhanced metamemory, at consolidation impaired metamemory, and at retrieval enhanced familiarity and metamemory. These findings allude to mechanisms underlying the idiosyncratic phenomena of drugs, such as blackouts from sedatives and presque vu from psychedelics. Finally, these findings converge on a model in which memory quantity and stability influence metamemory. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The acute effects of psychoactive drugs on emotional episodic memory encoding, consolidation, and retrieval: A comprehensive review.

Psychoactive drugs modulate learning and emotional processes in ways that could impact their recreational and medical use. Recent work has revealed how drugs impact different stages of processing emotional episodic memories, specifically encoding (forming memories), consolidation (stabilizing memories), and retrieval (accessing memories). Drugs administered before encoding may preferentially impair (e.g., GABAA sedatives including alcohol and benzodiazepines, Δ9-tetrahydrocannabinol or THC, ketamine), enhance (e.g., dextroamphetamine and dextromethamphetamine), or both impair and enhance (i.e., ± 3,4-methylenedioxymethylamphetamine or MDMA) emotionally negative and positive compared to neutral memories. GABAA sedatives administered immediately post-encoding (during consolidation) can preferentially enhance emotional memories, though this selectivity may decline or even reverse (i.e., preferential enhancement of neutral memories) as the delay between encoding and retrieval increases. Finally, retrieving memories under the effects of THC, dextroamphetamine, MDMA, and perhaps GABAA sedatives distorts memory, with potentially greater selectively for emotional (especially positive) memories. We review these effects, propose neural mechanisms, discuss methodological considerations for future work, and speculate how drug effects on emotional episodic memory may contribute to drug use and abuse.

Skepticism about Recent Evidence That Psilocybin "Liberates" Depressed Minds.

A recent paper in Nature Medicine found that psilocybin therapy in patients with depression decreased brain network modularity (measured with task-free functional magnetic resonance imaging), an effect supposedly not found with the selective serotonin reuptake inhibitor S-citalopram. This decrease in network modularity also correlated with depression. Here, we raise several issues with this paper, including inconsistencies in reports of the primary clinical outcome, statistical flaws including a one-tailed test, nonsignificant interaction, and regression to the mean, the ambiguity and overinterpretation of "resting state" data, and a missing reference for a conceptually similar study that exemplifies why a one-tailed test cannot be justified. Together, these issues make us question the uniqueness and impact of these findings, as well as the unwarranted media hype that they generated.

Psychedelic resting-state neuroimaging: A review and perspective on balancing replication and novel analyses.

Clinical research into serotonergic psychedelics is expanding rapidly, showing promising efficacy across myriad disorders. Resting-state functional magnetic resonance imaging (rs-fMRI) is a commonly used strategy to identify psychedelic-induced changes in neural pathways in clinical and healthy populations. Here we, a large group of psychedelic imaging researchers, review the 42 research articles published to date, based on the 17 unique studies evaluating psychedelic effects on rs-fMRI, focusing on methodological variation. Prominently, we observe that nearly all studies vary in data processing and analysis methodology, two datasets are the foundation of over half of the published literature, and there is lexical ambiguity in common outcome metric terminology. We offer guidelines for future studies that encourage coherence in the field. Psychedelic rs-fMRI will benefit from the development of novel methods that expand our understanding of the brain mechanisms mediating its intriguing effects; yet, this field is at a crossroads where we must also consider the critical importance of consistency and replicability to effectively converge on stable representations of the neural effects of psychedelics.

Models of psychedelic drug action: modulation of cortical-subcortical circuits.

Classic psychedelic drugs such as psilocybin and lysergic acid diethylamide (LSD) have recaptured the imagination of both science and popular culture, and may have efficacy in treating a wide range of psychiatric disorders. Human and animal studies of psychedelic drug action in the brain have demonstrated the involvement of the serotonin 2A (5-HT2A) receptor and the cerebral cortex in acute psychedelic drug action, but different models have evolved to try to explain the impact of 5-HT2A activation on neural systems. Two prominent models of psychedelic drug action (the cortico-striatal thalamo-cortical, or CSTC, model and relaxed beliefs under psychedelics, or REBUS, model) have emphasized the role of different subcortical structures as crucial in mediating psychedelic drug effects. We describe these models and discuss gaps in knowledge, inconsistencies in the literature and extensions of both models. We then introduce a third circuit-level model involving the claustrum, a thin strip of grey matter between the insula and the external capsule that densely expresses 5-HT2A receptors (the cortico-claustro-cortical, or CCC, model). In this model, we propose that the claustrum entrains canonical cortical network states, and that psychedelic drugs disrupt 5-HT2A-mediated network coupling between the claustrum and the cortex, leading to attenuation of canonical cortical networks during psychedelic drug effects. Together, these three models may explain many phenomena of the psychedelic experience, and using this framework, future research may help to delineate the functional specificity of each circuit to the action of both serotonergic and non-serotonergic hallucinogens.

Psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder.

Psilocybin has shown promise for the treatment of mood disorders, which are often accompanied by cognitive dysfunction including cognitive rigidity. Recent studies have proposed neuropsychoplastogenic effects as mechanisms underlying the enduring therapeutic effects of psilocybin. In an open-label study of 24 patients with major depressive disorder, we tested the enduring effects of psilocybin therapy on cognitive flexibility (perseverative errors on a set-shifting task), neural flexibility (dynamics of functional connectivity or dFC via functional magnetic resonance imaging), and neurometabolite concentrations (via magnetic resonance spectroscopy) in brain regions supporting cognitive flexibility and implicated in acute psilocybin effects (e.g., the anterior cingulate cortex, or ACC). Psilocybin therapy increased cognitive flexibility for at least 4 weeks post-treatment, though these improvements were not correlated with the previously reported antidepressant effects. One week after psilocybin therapy, glutamate and N-acetylaspartate concentrations were decreased in the ACC, and dFC was increased between the ACC and the posterior cingulate cortex (PCC). Surprisingly, greater increases in dFC between the ACC and PCC were associated with less improvement in cognitive flexibility after psilocybin therapy. Connectome-based predictive modeling demonstrated that baseline dFC emanating from the ACC predicted improvements in cognitive flexibility. In these models, greater baseline dFC was associated with better baseline cognitive flexibility but less improvement in cognitive flexibility. These findings suggest a nuanced relationship between cognitive and neural flexibility. Whereas some enduring increases in neural dynamics may allow for shifting out of a maladaptively rigid state, larger persisting increases in neural dynamics may be of less benefit to psilocybin therapy.

Psychedelics and Consciousness: Distinctions, Demarcations, and Opportunities.

Psychedelic substances produce unusual and compelling changes in conscious experience that have prompted some to propose that psychedelics may provide unique insights explaining the nature of consciousness. At present, psychedelics, like other current scientific tools and methods, seem unlikely to provide information relevant to the so-called "hard problem of consciousness," which involves explaining how first-person experience can emerge. However, psychedelics bear on multiple "easy problems of consciousness," which involve relations between subjectivity, brain function, and behavior. In this review, we discuss common meanings of the term "consciousness" when used with regard to psychedelics and consider some models of the effects of psychedelics on the brain that have also been associated with explanatory claims about consciousness. We conclude by calling for epistemic humility regarding the potential for psychedelic research to aid in explaining the hard problem of consciousness while pointing to ways in which psychedelics may advance the study of many specific aspects of consciousness.

The Acute Effects of the Atypical Dissociative Hallucinogen Salvinorin A on Functional Connectivity in the Human Brain.

Salvinorin A (SA) is a κ-opioid receptor agonist and atypical dissociative hallucinogen found in Salvia divinorum. Despite the resurgence of hallucinogen studies, the effects of κ-opioid agonists on human brain function are not well-understood. This placebo-controlled, within-subject study used functional magnetic resonance imaging for the first time to explore the effects of inhaled SA on strength, variability, and entropy of functional connectivity (static, dynamic, and entropic functional connectivity, respectively, or sFC, dFC, and eFC). SA tended to decrease within-network sFC but increase between-network sFC, with the most prominent effect being attenuation of the default mode network (DMN) during the first half of a 20-min scan (i.e., during peak effects). SA reduced brainwide dFC but increased brainwide eFC, though only the former effect survived multiple comparison corrections. Finally, using connectome-based classification, most models trained on dFC network interactions could accurately classify the first half of SA scans. In contrast, few models trained on within- or between-network sFC and eFC performed above chance. Notably, models trained on within-DMN sFC and eFC performed better than models trained on other network interactions. This pattern of SA effects on human brain function is strikingly similar to that of other hallucinogens, necessitating studies of direct comparisons.

Δ9-Tetrahydrocannabinol (THC) impairs visual working memory performance: a randomized crossover trial.

With the increasing prevalence of legal cannabis use and availability, there is an urgent need to identify cognitive impairments related to its use. It is widely believed that cannabis, or its main psychoactive component Δ9-tetrahydrocannabinol (THC), impairs working memory, i.e., the ability to temporarily hold information in mind. However, our review of the literature yielded surprisingly little empirical support for an effect of THC or cannabis on working memory. We thus conducted a study with three main goals: (1) quantify the effect of THC on visual working memory in a well-powered sample, (2) test the potential role of cognitive effects (mind wandering and metacognition) in disrupting working memory, and (3) demonstrate how insufficient sample size and task duration reduce the likelihood of detecting a drug effect. We conducted two double-blind, randomized crossover experiments in which healthy adults (N = 23, 23) performed a reliable and validated visual working memory task (the "Discrete Whole Report task", 90 trials) after administration of THC (7.5 and/or 15 mg oral) or placebo. We also assessed self-reported "mind wandering" (Exp 1) and metacognitive accuracy about ongoing task performance (Exp 2). THC impaired working memory performance (d = 0.65), increased mind wandering (Exp 1), and decreased metacognitive accuracy about task performance (Exp 2). Thus, our findings indicate that THC does impair visual working memory, and that this impairment may be related to both increased mind wandering and decreased monitoring of task performance. Finally, we used a down-sampling procedure to illustrate the effects of task length and sample size on power to detect the acute effect of THC on working memory.

Emotions and brain function are altered up to one month after a single high dose of psilocybin.

Psilocybin is a classic psychedelic compound that may have efficacy for the treatment of mood and substance use disorders. Acute psilocybin effects include reduced negative mood, increased positive mood, and reduced amygdala response to negative affective stimuli. However, no study has investigated the long-term, enduring impact of psilocybin on negative affect and associated brain function. Twelve healthy volunteers (7F/5M) completed an open-label pilot study including assessments 1-day before, 1-week after, and 1-month after receiving a 25 mg/70 kg dose of psilocybin to test the hypothesis that psilocybin administration leads to enduring changes in affect and neural correlates of affect. One-week post-psilocybin, negative affect and amygdala response to facial affect stimuli were reduced, whereas positive affect and dorsal lateral prefrontal and medial orbitofrontal cortex responses to emotionally-conflicting stimuli were increased. One-month post-psilocybin, negative affective and amygdala response to facial affect stimuli returned to baseline levels while positive affect remained elevated, and trait anxiety was reduced. Finally, the number of significant resting-state functional connections across the brain increased from baseline to 1-week and 1-month post-psilocybin. These preliminary findings suggest that psilocybin may increase emotional and brain plasticity, and the reported findings support the hypothesis that negative affect may be a therapeutic target for psilocybin.

Creating emotional false recollections: Perceptual recombination and conceptual fluency mechanisms.

We investigated the impact of 2 hypothetical mechanisms of episodic memory reconstruction-perceptual recombination and conceptual fluency-on objectively measured recollection accuracy and false recollections of neutral and emotional stimuli. Participants encoded negative, neutral, and positive pictures depicting objects and scenes (i.e., target pictures), each accompanied with a descriptive verbal label (e.g., "boy crying at funeral," "wooden basket on floor," "four chimpanzees laughing together"). Next, they encoded fragmented pictures of some of the scenes they did and did not earlier see (perceptual misinformation), or they received multiple presentations of the corresponding verbal labels (conceptual misinformation). Recollection of target pictures was then tested, using labels as retrieval cues. We had three key findings in each of two experiments. First, as in our prior work, both perceptual and conceptual misinformation significantly increased false recollection judgments of nonstudied pictures, including high-confidence errors. These effects implicate perceptual recombination and conceptual fluency mechanisms. Second, these misinformation effects generalized across all emotional categories, implicating separable roles of these two mechanisms on emotional recollections. Finally, conceptual misinformation was less likely to influence negative than neutral recollection errors, providing new evidence that emotion can improve retrieval monitoring accuracy and reduce false memories based on conceptual fluency (i.e., an emotional distinctiveness heuristic). (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Δ9-Tetrahydrocannabinol During Encoding Impairs Perceptual Details yet Spares Context Effects on Episodic Memory.

BACKGROUND: With the growing acceptance of cannabis use, it is crucial to understand the drug's effects on episodic memory accuracy and distortion. We investigated the impact of the administration of Δ9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, on a context-based memory illusion. METHODS: In a double-blind, placebo-controlled, within-subjects design, healthy infrequent cannabis users (N = 24) memorized object pictures that were superimposed over scenes (e.g., gray cat on beach) after pretreatment with placebo or THC (15 mg oral). Two days later under sober conditions, memory for the object pictures was tested by asking participants to discriminate between previously seen objects or perceptually similar lures (e.g., different gray cat). Context reinstatement was manipulated by presenting objects on their original or different scenes (e.g., beach or forest). RESULTS: THC impaired memory for perceptual details of objects compared with placebo, and the context illusion was obtained in each condition: context reinstatement increased high-confidence false recognition along with correct recognition of previously seen objects. Although THC did not interact with these context effects overall, post hoc analyses showed that THC magnified the context illusion when objects were semantically congruent with their encoding contexts but abolished the context illusion when objects were incongruent with their encoding contexts. CONCLUSIONS: These results are consistent with the hypothesis that THC impairs the encoding of specific object information more than item-context associations. As a result, THC may spare the distorting effects of context reinstatement on memory. In fact, THC may increase these distorting effects under conditions when objects are semantically congruent with context.

Alcohol and pharmacologically similar sedatives impair encoding and facilitate consolidation of both recollection and familiarity in episodic memory.

Alcohol and other pharmacologically similar sedatives (i.e., GABAA positive allosteric modulators or PAMs) impair the encoding of new episodic memories but retroactively facilitate the consolidation of recently encoded memories. These effects are consistent for recollection (i.e., the retrieval of details) but some mixed results have been reported for familiarity (i.e., a feeling of knowing a stimulus was presented). Here, with dual-process models, we reanalyzed prior work testing the effects of GABAA PAMs at encoding or consolidation. Contrary to previous conclusions, we show that GABAA PAMs at encoding consistently impair both recollection and familiarity when an independence correction is applied to familiarity-based responses. These findings were further confirmed and extended in a dual-process signal detection analysis of a recent study on the effects of alcohol during encoding or consolidation: Alcohol at encoding impaired both recollection and familiarity, whereas alcohol at consolidation enhanced both recollection and familiarity. These findings speak to the ability of alcohol and other GABAA PAMs to induce 'blackouts,' highlighting the importance of dual-process approaches when analyzing drug manipulations at different phases of episodic memory.

Δ9-Tetrahydrocannabinol at Retrieval Drives False Recollection of Neutral and Emotional Memories.

BACKGROUND: It is well established that the main psychoactive constituent of cannabis, Δ9-tetrahydrocannabinol (THC), impairs episodic memory encoding and modulates emotional processing, but little is known about the impact of THC during the retrieval of emotional episodic memories. With the rise of cannabis to treat medical conditions, including those characterized by emotional and episodic memory disturbances, there is an urgent need to determine the effects of THC on memory accuracy and distortion. Here, we report the first study investigating the effects of THC during retrieval of neutral and emotional episodic memories. METHODS: Using a double-blind, placebo-controlled, within-subjects design, healthy volunteers (N = 23) viewed negative, neutral, and positive pictures (emotional memory task) and lists of semantically related words (false memory task). Forty-eight hours later, participants ingested a capsule containing either THC (15 mg) or placebo and completed tasks to test their memories for the previously studied pictures and words. RESULTS: THC during retrieval did not reduce the number of correct responses to studied items. Instead, it robustly increased false recollection on both the emotional memory and false memory tasks. This effect was found for both neutral and emotional items. CONCLUSIONS: These findings show that THC has adverse effects during memory retrieval, distorting both neutral and emotional memories. Coupled with THC's known effects during encoding, these new retrieval findings are important in light of the spreading acceptance of cannabis.

The Dark Side of Context: Context Reinstatement Can Distort Memory.

It is widely assumed that context reinstatement benefits memory, but our experiments revealed that context reinstatement can systematically distort memory. Participants viewed pictures of objects superimposed over scenes, and we later tested their ability to differentiate these old objects from similar new objects. Context reinstatement was manipulated by presenting objects on the reinstated or switched scene at test. Not only did context reinstatement increase correct recognition of old objects, but it also consistently increased incorrect recognition of similar objects as old ones. This false recognition effect was robust, as it was found in several experiments, occurred after both immediate and delayed testing, and persisted with high confidence even after participants were warned to avoid the distorting effects of context. To explain this memory illusion, we propose that context reinstatement increases the likelihood of confusing conceptual and perceptual information, potentially in medial temporal brain regions that integrate this information.

MDMA Impairs Both the Encoding and Retrieval of Emotional Recollections.

The psychoactive drug ±3,4-methylenedioxymethamphetamine (MDMA) is increasingly used for its perceived emotional effects (eg, prosociality, empathy, psychotherapy), but surprisingly little research has been aimed at identifying the effect of the drug on emotional episodic memory in humans. Here, we report the first double-blind placebo-controlled study to examine the effects of MDMA on emotional memory separately during encoding and retrieval in healthy participants. Participants viewed emotionally negative, neutral, and positive pictures and their labels. Forty-eight hours later, they were given cued recollection and recognition memory tests designed to assess recollection and familiarity for the studied pictures. Participants were randomly assigned to one of three groups who received MDMA (1 mg/kg) either during encoding (Encoding group; N=20), retrieval (Retrieval group; N=20), or neither (Placebo group; N=20). Although MDMA administered at either phase did not affect overall memory accuracy, it did alter the recollection of details associated specifically with emotional memories as estimated using a dual process signal detection analysis of confidence judgments and subjective 'remember' judgments. In the Encoding group, MDMA reduced recollection estimates for negative and positive pictures but had little to no effect on neutral items or familiarity estimates. There was evidence for similar trends in the Retrieval group. These findings indicate that MDMA attenuates the encoding and retrieval of salient details from emotional events, consistent with the idea that its potential therapeutic effects for treating posttraumatic stress disorder are related to altering emotional memory.

Two mechanisms of constructive recollection: Perceptual recombination and conceptual fluency.

Recollection is constructive and prone to distortion, but the mechanisms through which recollections can become embellished with rich yet illusory details are still debated. According to the conceptual fluency hypothesis, abstract semantic or conceptual activation increases the familiarity of a nonstudied event, causing one to falsely attribute imagined features to actual perception. In contrast, according to the perceptual recombination hypothesis, details from actually perceived events are partially recollected and become erroneously bound to a nonstudied event, again causing a detailed yet false recollection. Here, we report the first experiments aimed at disentangling these 2 mechanisms. Participants imagined pictures of common objects, and then they saw an actual picture of some of the imagined objects. We next presented misinformation associated with these studied items, designed to increase conceptual fluency (i.e., semantically related words) or perceptual recombination (i.e., perceptually similar picture fragments). Finally, we tested recollection for the originally seen pictures using verbal labels as retrieval cues. Consistent with conceptual fluency, processing-related words increased false recollection of pictures that were never seen, and consistent with perceptual recombination, processing picture fragments further increased false recollection. We also found that conceptual fluency was more short-lived than perceptual recombination, further dissociating these 2 mechanisms. These experiments provide strong evidence that conceptual fluency and perceptual recombination independently contribute to the constructive aspects of recollection. (PsycINFO Database Record

Post-learning Hippocampal Dynamics Promote Preferential Retention of Rewarding Events.

Reward motivation is known to modulate memory encoding, and this effect depends on interactions between the substantia nigra/ventral tegmental area complex (SN/VTA) and the hippocampus. It is unknown, however, whether these interactions influence offline neural activity in the human brain that is thought to promote memory consolidation. Here we used fMRI to test the effect of reward motivation on post-learning neural dynamics and subsequent memory for objects that were learned in high- and low-reward motivation contexts. We found that post-learning increases in resting-state functional connectivity between the SN/VTA and hippocampus predicted preferential retention of objects that were learned in high-reward contexts. In addition, multivariate pattern classification revealed that hippocampal representations of high-reward contexts were preferentially reactivated during post-learning rest, and the number of hippocampal reactivations was predictive of preferential retention of items learned in high-reward contexts. These findings indicate that reward motivation alters offline post-learning dynamics between the SN/VTA and hippocampus, providing novel evidence for a potential mechanism by which reward could influence memory consolidation.