Episodic memory is essential to navigate in a changing environment by recalling past events, creating new memories, and updating stored information from experience. Although the mechanisms for acquisition and consolidation have been profoundly studied, much less is known about memory retrieval. Hippocampal spatial representations are key for retrieval of contextually guided episodic memories. Indeed, hippocampal place cells exhibit stable location-specific activity which is thought to support contextual memory, but can also undergo remapping in response to environmental changes. It is unclear if remapping is directly related to the expression of different episodic memories. Here, using an incidental memory recognition task in rats, we showed that retrieval of a contextually guided memory is reflected by the levels of CA3 remapping, demonstrating a clear link between external cues, hippocampal remapping, and episodic memory retrieval that guides behavior. Furthermore, we describe NMDARs as key players in regulating the balance between retrieval and memory differentiation processes by controlling the reactivation of specific memory traces. While an increase in CA3 NMDAR activity boosts memory retrieval, dentate gyrus NMDAR activity enhances memory differentiation. Our results contribute to understanding how the hippocampal circuit sustains a flexible balance between memory formation and retrieval depending on the environmental cues and the internal representations of the individual. They also provide new insights into the molecular mechanisms underlying the contributions of hippocampal subregions to generate this balance.

The perirhinal cortex (PER) supports multimodal object recognition, but how multimodal information of objects is integrated within the PER remains unknown. Here, we recorded single units within the PER while rats performed a PER-dependent multimodal object-recognition task. In this task, audiovisual cues were presented simultaneously (multimodally) or separately (unimodally). We identified 2 types of object-selective neurons in the PER: crossmodal cells, showing constant firing patterns for an object irrespective of its modality, and unimodal cells, showing a preference for a specific modality. Unimodal cells further dissociated unimodal and multimodal versions of the object by modulating their firing rates according to the modality condition. A population-decoding analysis confirmed that the PER could perform both modality-invariant and modality-specific object decoding-the former for recognizing an object as the same in various conditions and the latter for remembering modality-specific experiences of the same object.

The blank comparison (BLC) task was developed to assess stimulus relations in discrimination learning; that is, are subjects learning to \"select\" the correct stimulus (S+) or \"reject\" the incorrect stimulus (S-) or both? This task has been used to study exclusion learning, mostly in humans and monkeys, and the present study extends the procedure to rats. The BLC task uses an ambiguous stimulus (BLC+/-) that replaces S+ (in the presence of S-) and replaces S- (in the presence of S+). In the current experiment, four rats were trained to remove session-novel scented lids from sand-filled cups in a two-choice, simultaneous presentation procedure called the Odor Span Task (OST) before being trained on the BLC procedure using odors as the discriminative stimuli. The BLC training procedure utilized simple discrimination training (S+ and S-) and added select (S+ and BLC-) and reject (BLC+ and S-) trial types. All rats demonstrated accurate performance in sessions with both select and reject type trials. Next, BLC probe trials were interspersed in standard OST sessions to assess the form of stimulus control in the OST. Rats performed accurately on select type probe trials (similar to baseline OST performance) and also showed above chance accuracy on reject type trials. Thus, we demonstrated that rats could acquire an odor-based version of the BLC task and that both select and exclusion-based (reject) relations were active in the OST. The finding of exclusion in rats under the rigorous BLC task conditions confirms that exclusion-based responding is not limited to humans and non-human primates.

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.

UNASSIGNED: Psilocybin and related tryptamines have come into the spotlight in recent years as potential therapeutics for depression. Research on the mechanisms of these effects has historically focused on the direct effects of these drugs on neural processes. However, in addition to such neural effects, alterations in peripheral physiology may also contribute to their therapeutic effects. In particular, substantial support exists for a gut microbiome-mediated pathway for the antidepressant efficacy of other drug classes, but no prior studies have determined the effects of tryptamines on microbiota.
UNASSIGNED: To address this gap, in this preliminary study, male Long Evans rats were treated with varying dosages of oral psilocybin (0.2 or 2 mg/kg), norbaeocystin (0.25 or 2.52 mg/kg), or vehicle and their fecal samples were collected 1 week and 3 weeks after exposure for microbiome analysis using integrated 16S ribosomal DNA sequencing to determine gut microbiome composition.
UNASSIGNED: We found that although treatment with neither psilocybin nor norbaeocystin significantly affected overall microbiome diversity, it did cause significant dose- and time-dependent changes in bacterial abundance at the phylum level, including increases in Verrucomicrobia and Actinobacteria, and decreases in Proteobacteria.
UNASSIGNED: These preliminary findings support the idea that psilocybin and other tryptamines may act on the gut microbiome in a dose- and time-dependent manner, potentially identifying a novel peripheral mechanism for their antidepressant activity. The results from this preliminary study also suggest that norbaeocystin may warrant further investigation as a potential antidepressant, given the similarity of its effects to psilocybin.

The retrosplenial cortex (RSC) is a hub of diverse afferent and efferent projections thought to be involved in associative learning. RSC shows early pathology in mild cognitive impairment and Alzheimer\'s disease (AD), which impairs associative learning. To understand and develop therapies for diseases such as AD, animal models are essential. Given the importance of human RSC in object-location associative learning and the success of object-location associative paradigms in human studies and in the clinic, it would be of considerable value to establish a translational model of object-location learning for the rodent. For this reason, we sought to test the role of RSC in object-location learning in male rats using the object-location paired-associates learning (PAL) touchscreen task. First, increased cFos immunoreactivity was observed in granular RSC following PAL training when compared with extended pretraining controls. Following this, RSC lesions following PAL acquisition were used to explore the necessity of the RSC in object-location associative learning and memory and two tasks involving only one modality: trial-unique nonmatching-to-location for spatial working memory and pairwise visual discrimination/reversal. RSC lesions impaired both memory for learned paired-associates and learning of new object-location associations but did not affect performance in either the spatial or visual single-modality tasks. These findings provide evidence that RSC is necessary for object-location learning and less so for learning and memory involving the individual modalities therein.

Vasopressin (AVP) regulates various social behaviors, often in sex-specific ways, including social play behavior, a rewarding behavior displayed primarily by juveniles. Here, we examined whether and how AVP acting in the brain\'s reward system regulates social play behavior in juvenile rats. Specifically, we focused on AVP signaling in the ventral pallidum (VP), a brain region that is a part of the reward system. First, we examined the organization of the VP-AVP system in juvenile rats and found sex differences, with higher density of both AVP-immunoreactive fibers and AVP V1a receptor (V1aR) binding in males compared to females while females show a greater number of V1aR-expressing cells compared to males. We further found that, in both sexes, V1aR-expressing cells co-express a GABA marker to a much greater extent (approx. 10 times) than a marker for glutamate. Next, we examined the functional involvement of V1aR-expressing VP cells in social play behavior. We found that exposure to social play enhanced the proportion of activated V1aR-expressing VP cells in males only. Finally, we showed that infusion of a specific V1aR antagonist into the VP increased social play behaviors in juvenile male rats while decreasing these behaviors in juvenile female rats. Overall, these findings reveal structural and functional sex differences in the AVP-V1aR system in the VP that are associated with the sex-specific regulation of social play behavior.

Systemic manipulations that enhance dopamine (DA) transmission around the time of fear extinction can strengthen fear extinction and reduce conditioned fear relapse. Prior studies investigating the brain regions where DA augments fear extinction focus on targets of mesolimbic and mesocortical DA systems originating in the ventral tegmental area, given the role of these DA neurons in prediction error. The dorsal striatum (DS), a primary target of the nigrostriatal DA system originating in the substantia nigra (SN), is implicated in behaviors beyond its canonical role in movement, such as reward and punishment, goal-directed action, and stimulus-response associations, but whether DS DA contributes to fear extinction is unknown. We have observed that chemogenetic stimulation of SN DA neurons during fear extinction prevents the return of fear in contexts different from the extinction context, a form of relapse called renewal. This effect of SN DA stimulation is mimicked by a DA D1 receptor (D1R) agonist injected into the DS, thus implicating DS DA in fear extinction. Different DS subregions subserve unique functions of the DS, but it is unclear where in the DS D1R agonist acts during fear extinction to reduce renewal. Furthermore, although fear extinction increases neural activity in DS subregions, whether neural activity in DS subregions is causally involved in fear extinction is unknown. To explore the role of DS subregions in fear extinction, adult, male Long-Evans rats received microinjections of either the D1R agonist SKF38393 or a cocktail consisting of GABAA/GABAB receptor agonists muscimol/baclofen selectively into either dorsomedial (DMS) or dorsolateral (DLS) DS subregions immediately prior to fear extinction, and extinction retention and renewal were subsequently assessed drug-free. While increasing D1R signaling in the DMS during fear extinction did not impact fear extinction retention or renewal, DMS inactivation reduced later renewal. In contrast, DLS inactivation had no effect on fear extinction retention or renewal but increasing D1R signaling in the DLS during extinction reduced fear renewal. These data suggest that DMS and DLS activity during fear extinction can have opposing effects on later fear renewal, with the DMS promoting renewal and the DLS opposing renewal. Mechanisms through which the DS could influence the contextual gating of fear extinction are discussed.

Current theories of decision-making propose that decisions arise through competition between choice options. Computational models of the decision process estimate how quickly information about choice options is integrated and how much information is needed to trigger a choice. Experiments using this approach typically report data from well-trained participants. As such, we do not know how the decision process evolves as a decision-making task is learned for the first time. To address this gap, we used a behavioral design separating learning the value of choice options from learning to make choices. We trained male rats to respond to single visual stimuli with different reward values. Then, we trained them to make choices between pairs of stimuli. Initially, the rats responded more slowly when presented with choices. However, as they gained experience in making choices, this slowing reduced. Response slowing on choice trials persisted throughout the testing period. We found that it was specifically associated with increased exponential variability when the rats chose the higher value stimulus. Additionally, our analysis using drift diffusion modeling revealed that the rats required less information to make choices over time. These reductions in the decision threshold occurred after just a single session of choice learning. These findings provide new insights into the learning process of decision-making tasks. They suggest that the value of choice options and the ability to make choices are learned separately and that experience plays a crucial role in improving decision-making performance.

Historically, the orbitofrontal cortex (OFC) has been implicated in a variety of behaviors ranging from reversal learning and inhibitory control to more complex representations of reward value and task space. While modern interpretations of the OFC\'s function have focused on a role in outcome evaluation, these cognitive processes often require an organism to inhibit a maladaptive response or strategy. Single-unit recordings from the OFC in rats performing a stop-change task show that the OFC responds strongly to STOP trials. To investigate the role that the OFC plays in stop-change performance, we expressed halorhodopsin (eNpHR3.0) in excitatory neurons in the OFC and tested rats on the stop-change task. Previous work suggests that the OFC differentiates between STOP trials based on trial sequence (i.e., gS trials: STOP trials preceded by a GO vs sS trials: STOP trials preceded by a STOP). We found that yellow light activation of the eNpHR3.0-expressing neurons significantly decreased accuracy only on STOP trials that followed GO trials (gS trials). Further, optogenetic inhibition of the OFC speeded reaction times on error trials. This suggests that the OFC plays a role in inhibitory control processes and that this role needs to be accounted for in modern interpretations of OFC function.