Neurobiology of Learning and Memory

Procedural memory facilitates the efficient processing of complex environmental stimuli and contributes to the acquisition of automatic behaviours and habits. Learning can occur intentionally or incidentally, yet, how the mode of learning affects procedural memory is still poorly understood. Importantly, procedural memory is a complex cognitive function composed of different subprocesses, including the acquisition and consolidation of statistical, frequency-based and sequential, order-based knowledge. Therefore, we tested how statistical and sequence knowledge develops during incidental versus intentional procedural memory formation and during consolidation. Seventy-four young adults performed either the uncued, incidental (N = 37) or the cued, intentional (N = 37) version of a probabilistic sequence learning task. Performance was retested after a 12-hour offline period, enabling us to test the effect of sleep on consolidation; therefore, half of the participants slept during the delay, while the other half had normal daily activity (PM-AM versus AM-PM design). The mode of learning (incidental versus intentional) had no effect on the acquisition of statistical knowledge, while intention to learn increased sequence learning performance. Consolidation was not affected by intention to learn: Both statistical and sequence knowledge was retained over the 12-hour delay, irrespective of the mode of learning and whether the delay included sleep or wake activity. These results suggest a time-dependent instead of sleep-dependent consolidation of both statistical and sequence knowledge. Our findings could contribute to a better understanding of how the mode of learning (intentional or incidental) affects procedural memory formation and consolidation.

Human memory for recent events is believed to undergo reactivation during sleep. This process is thought to be relevant for the consolidation of both individual episodic memories and gist extraction, the formation of generalized memory representations from multiple, related memories. Which kinds of gist are actually enhanced, however, is the subject of less consensus. To address this question, we focused our design on four types of gist: inferential gist (relations extracted across non-contiguous events), statistical learning (regularities extracted from a series), summary gist (a theme abstracted from a temporally contiguous series of items), and category gist (characterization of a stimulus at a higher level in the semantic hierarchy). Sixty-nine participants (30 men, 38 women, and 1 other) completed memory encoding tasks addressing these types of gist and corresponding retrieval tasks the same evening, the morning after, and one week later. Inferential gist was retained over a week, whereas memory for category gist, summary gist, and statistical learning decayed. Higher proportions of REM were associated with worse performance in a statistical learning task controlling for time. Our results support that REM sleep is involved in schema disintegration, which works against participants ability to identify regularities within temporal series.\n\nSIGNIFICANCE STATEMENTTo gain the most from our experiences, we extract from them the most important elements, or \"gist\", with sleep believed to facilitate this process. However, what is referred to as gist varies considerably across studies. We report categorically different mnemonic trajectories of two classes of gist. In particular, we show that gist involving synthesis across relational memories is retained over time, whereas other gists were subject to substantial decay. Moreover, our evidence supports the idea that REM works to discretize, rather than synthesize experiences. Future research should test similar constructs in different tasks to determine whether these findings are generalizable. Our research suggests that patients with reduced REM sleep may experience more interference between similar memories.

Accurate and efficient memory processing is essential for survival. Recent work in human subjects and animal models has suggested that memory processing may differ in meaningful ways between males and females. In mice, contextual fear memory (CFM) encoding, consolidation, and recall have been well studied, and the mouse hippocampus and amygdala have been implicated in these processes. The present study addresses how the specific contribution of these brain regions to each stage CFM processing in female vs. male mice. We find that male and female mice show no differences in CFM recall, nor in sleep behavior in the hours following single-trial contextual fear conditioning (CFC), which is essential for CFM consolidation. However, females - but not males - show significantly increased expression of cFos in dorsal hippocampal CA1 and CA2 neurons during CFM encoding. On the other hand, males - but not females - show increased cFos expression among DG granule cells during CFM consolidation. These findings highlight the fact that the neurobiological underpinnings of memory processing may differ between males and females, even when recall performance is identical. Scope statementHistorically, research on the neurobiological basis of memory processing has been carried out mainly in male subjects. Thus, our understanding of these mechanisms is biased towards male brain neurophysiology. Recent studies have variously reported performance differences for episodic memory tasks, in which male subjects perform better, worse, or the same as females. Here, we find that male and female mice perform similarly on a well-studied experimental memory task but nonetheless have differences in the relative activity of different brain structures during sequential stages of memory processing. This emphasizes the importance of including both males and females in memory studies, due to potential sex differences in the neurobiological substrates of memory.

Sleep, especially slow-wave sleep (SWS), has been found to facilitate memory consolidation for many types of learning. Mathematical learning, however, has seldom been examined in this context. Solving multiplication problems involves multiple steps before problems can be mastered or answers memorized, and thus it can depend on both skill learning and fact learning. Here we aimed to test the hypothesis that memory reactivation during sleep contributes to multiplication learning. To do so, we used a technique known as targeted memory reactivation (TMR), or the pairing of newly learned information with specific stimuli that are later presented during sleep. With TMR, specific memories can be reactivated over a period of sleep without disrupting ongoing sleep. We applied TMR during an afternoon nap to reactivate half of the multiplication problems that had previously been practiced. Results showed no effect of TMR on response time or accuracy of multiplication problem solving. Because these results were unexpected, we also used a variation of this paradigm to examine results in subjects who remained awake. Comparisons between the wake and sleep groups showed no difference in response time or accuracy in either the initial test or the final test. Although neither TMR nor sleep differentially influenced multiplication performance, correlational analysis provided some clues about mathematical problem solving and sleep. On the basis of these findings, even though they did not provide convincing support for our hypotheses, we suggest future experiments that could help produce a better understanding of the relevance of sleep and memory reactivation for this type of learning.

The hippocampus is thought to combine "what" and "where" information from the cortex so that objects and events can be represented within the spatial context in which they occur. Surprisingly then, these distinct types of information remain partially segregated in the output region of the hippocampus, area CA1. In this region, objects preferentially activate neurons in the distal segment (adjacent to the subiculum) while spatial locations are precisely represented by neurons in the proximal segment (adjacent to CA2). This difference likely results from distinct anatomical connections; proximal CA1 receives direct input from the medial entorhinal cortex (which encodes spatial context) whereas distal CA1 has reciprocal connections with the lateral entorhinal cortex (which encodes objects and events). Based on these findings, it has been proposed that CA1 contains two distinct representations; one that encodes the animals spatial location and another that encodes objects that are present in the environment. The current study aimed to determine the role of distal CA1 in learning the location of objects in an environment. To do this, we first examined c-Fos expression in proximal and distal CA1 to see if we could replicate previous findings and confirm that neurons in these distinct segment are responsive to different stimuli. As previous studies indicate that catecholamines can regulate the activity of segments of CA1, we then investigate the role of catecholamines on learning object locations using 6-OHDA or SCH23390 to lesion catecholaminergic input and block D1/D5 receptors, respectively. Finally, we monitored calcium activity with fiber photometry while animals performed a hippocampal-dependent object location memory task.

Aversive associative learning paradigms such as inhibitory avoidance (IA) are frequently used to examine episodic-like memories in rodents. In IA, rodents learn to associate a context with a footshock, followed by testing for memory strength in the original training context and for memory precision in a similar yet distinct neutral context. The present work assessed the effects of different contextual exposure procedures on memory strength and precision in IA at both recent and remote time points using male and female Long-Evans rats. An initial experiment found that rats kept in the lit (non-shock) compartment of the IA apparatus for 60 s during training, as opposed to 10 s, displayed enhanced memory strength, with discrimination between both chambers at the recent retention test and generalization at the remote retention test. Subsequent experiments investigated the effects of contextual pre-exposure the day before training. The results indicate that pre-exposure to the neutral context promoted generalization without altering memory strength compared to the first experiment. In contrast, pre-exposure to the aversive chamber promoted discrimination and enhanced memory strength. Notably, the different procedures yielded similar effects in both sexes. However, the results also indicate an overall pattern of greater contextual discrimination in females compared to males. These findings provide evidence for how different contextual exposures influence the degree of encoding at the time of training and a behavioral foundation for future studies examining the neurobiological mechanisms underlying memory strength and precision in IA, while highlighting the importance of using both sexes in initial behavioral work. Significance StatementStrength and precision are two fundamental properties of memory that can be simultaneously measured using inhibitory avoidance (IA), a type of context-footshock association task. However, little is known about how different context exposures alter rats encoding of these memories, thereby influencing subsequent memory strength and precision. Here, we found that pre-exposure to the neutral IA chamber decreased memory precision, whereas pre-exposure to the aversive IA chamber promoted memory strength and precision. Additionally, females demonstrated overall enhanced memory precision compared to males. These results indicate that different types of contextual exposures influence initial IA encoding and add to a limited body of research examining memory strength and precision in IA in both sexes.

Single-units were recorded in hippocampus, septum, and striatum while freely behaving rats (n=3) ran trials in a T-maze task, and rested in a holding bucket between trials. During periods of motor inactivity, SWRs triggered excitatory responses from 28% (64/226) and inhibitory responses from 14% (31/226) of septal neurons. By contrast, only 4% (14/378) of striatal neurons were excited and 6% (24/378) were inhibited during SWRs. In both structures, SWR-responsive neurons exhibited greater spike coherence with hippocampal theta rhythm than neurons that did not respond to SWRs. In septum, neurons that were excited by SWRs fired at late phases of the theta cycle, whereas neurons that were inhibited by SWRs fired at early phases of the theta cycle. By contrast, SWR-responsive striatal neurons did not show consistent phase preferences during the theta cycle. A subset of SWR-responsive neurons in septum (55/95) and striatum (26/38) behaved as speed cells, with firing rates that were positively or negatively modulated by the rats running speed. In both structures, firing rates of most SWR-excited speed cells were positively modulated by running speed, whereas firing rates of most SWR-inhibited speed cells were negatively modulated by running speed. These findings are consistent with a growing body of evidence that SWRs can activate subcortical representations of motor actions in conjunction with hippocampal representations of places and states, which may be important for storing and retrieving values of state-action pairs during reinforcement learning and memory consolidation.

Brown and Robertson (2007) revealed that skill learning interferes with the wakeful consolidation of episodic memories in young adults. This finding is commonly used as evidence that episodic and procedural memories should not be learned in close temporal proximity but has not been reproduced by an independent laboratory. Additionally, older adults experience episodic memory deficits, but it is unknown whether this group is also vulnerable to this type of interference. We aimed to reproduce Brown and Robertsons (2007) finding in younger adults, while also comparing the magnitude of interference between younger and older adults. Forty younger (18-40 years; n =20) and older adults ([≥]55 years; n = 20) visited the laboratory in the morning and acquired episodic memories (a list of words) immediately before a procedural finger-tapping (procedural) task. Half of all participants were exposed to a learnable sequential structure. In the afternoon of the same day, participants were asked to recall the episodic memories from the morning session. We found weak evidence of interference for both age groups and no statistical difference in interference between groups. Our results suggest that the interfering effects of these memory types may be negligible or overestimated, and that these memory types can be acquired together without interference.

The dentate gyrus is critical for spatial memory formation and shows task related activation of cellular ensembles considered as memory engrams. Semilunar granule cells (SGCs), a sparse dentate projection neuron subtype distinct from granule cells (GCs), were recently reported to be enriched among behaviorally activated neurons. However, the mechanisms governing SGC recruitment during memory formation and their role in engram refinement remains unresolved. By examining neurons labeled during contextual memory formation in TRAP2 mice, we empirically tested competing hypotheses for GC and SGC recruitment into memory ensembles. In support of the proposal that more excitable neurons are preferentially recruited into memory ensembles, SGCs showed greater sustained firing than GCs. Additionally, SGCs labeled during memory formation showed less adapting firing than unlabeled SGCs. Our recordings did not reveal glutamatergic connections between behaviorally labeled SGCs and GCs, providing evidence against SGC driven local circuit feedforward excitation in ensemble recruitment. Contrary to a leading hypothesis, there was little evidence for individual SGCs or labeled neuronal ensembles supporting lateral inhibition of unlabeled neurons. Instead, labeled GCs and SGCs received more spontaneous excitatory synaptic inputs than their unlabeled counterparts. Moreover, pairs of GCs and SGCs within labeled neuronal cohorts received more temporally correlated spontaneous excitatory synaptic inputs than labeled-unlabeled neuronal pairs, validating a role for correlated afferent inputs in neuronal ensemble selection. These findings challenge the proposal that SGCs drive dentate GC ensemble refinement, while supporting a role for intrinsic active properties and correlated inputs in preferential SGC recruitment to contextual memory engrams. Impact StatementEvaluation of semilunar granule cell involvement in dentate gyrus contextual memory processing supports recruitment based on intrinsic and input characteristics while revealing limited contribution to ensemble refinement. Major subject area, keywords and organismsSemilunar granule cell, inhibition, memory, engram, circuit, hippocampus

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. HighlightsO_LIDorsolateral striatum D1 receptor signaling during fear extinction reduces renewal C_LIO_LINeural activity in the dorsomedial striatum during fear extinction permits renewal C_LIO_LIDorsal striatum subregions have opposing roles in contextual gating of fear extinction C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=51 SRC="FIGDIR/small/576042v2_ufig1.gif" ALT="Figure 1"> View larger version (8K): org.highwire.dtl.DTLVardef@6d935org.highwire.dtl.DTLVardef@19e51acorg.highwire.dtl.DTLVardef@103fa30org.highwire.dtl.DTLVardef@1e7017_HPS_FORMAT_FIGEXP M_FIG C_FIG

Across sleep-based and retrieval-mediated consolidation, memories typically become generalised and less dependent on their episodic components for their recollection. However, memory transformations across sleep and retrieval training have not been directly compared. The current study aims to compare how sleep and retrieval training impact the endorsement of semantically similar and different lures, as well as their episodic recollection using the parietal old/new effect on the late positive component (LPC) in subjects EEG. Thirty subjects (27F, 18-34, M=22.17) attended four sessions where they learnt different sets of 104 object-word pairs and completed one of four 120-minute memory interventions: retrieval training (i.e., cued recall practice), restudy (i.e., pair re-exposure), a nap opportunity, or a wakeful rest. EEG was recorded while subjects were tested on their recognition accuracy in an old/new paradigm with similar- and different-object lures. Our results revealed that retrieval training, but not sleep, lead to greater accuracy for identifying old pairs, but worse similar-lure discrimination. Whilst the parietal old/new effect did not differ between conditions, retrieval had lower LPC amplitudes for similar- than different-object false alarms, whilst restudy demonstrated the opposite. Sleep and wake demonstrated no differences in LPC amplitudes between hits and different false alarm types. Together, our study demonstrates evidence for gist-abstraction across retrieval training, and a task-relevant selective maintenance of episodic details across sleep. These results challenge theories that retrieval training replicates sleep-based consolidation mechanisms, instead acting as a fast route to semanticization regardless of the context.

When faced with a familiar situation, we can use memory to make predictions about what will happen next. If such predictions turn out to be erroneous, the brain can adapt by differentiating the representations of the cues that generated the prediction from the mispredicted item itself, reducing the likelihood of future prediction errors. Prior work by Kim et al. (2017) found that violating a sequential association in a statistical learning paradigm triggered differentiation of the neural representations of the associated items in the hippocampus. Here, we used fMRI to test the preregistered hypothesis that this hippocampal differentiation occurs only when violations are followed by rapid eye movement (REM) sleep. In the morning, participants first learned that some items predict others (e.g., A predicts B) then encountered a violation in which a predicted item (B) failed to appear when expected after its associated item (A); the predicted item later appeared on its own after an unrelated item. Participants were then randomly assigned to one of three conditions: remain awake, take a nap containing non-REM sleep only, or take a nap with both non-REM and REM sleep. While the predicted results were not observed in the preregistered left CA2/3/DG ROI, we did observe evidence for our hypothesis in closely related hippocampal ROIs, uncorrected for multiple comparisons: In right CA2/3/DG, differentiation in the group with REM sleep was greater than in the groups without REM sleep (wake and non-REM nap); this differentiation was item-specific and concentrated in right DG. Differentiation effects were also greater in bilateral DG when the predicted item was more strongly reactivated during the violation. Overall, the results presented here provide initial evidence linking REM sleep to changes in the hippocampal representations of memories in humans.

Spatial memory in the hippocampus involves dynamic neural patterns that change over days, termed representational drift. While drift may aid memory updating, excessive drift could impede retrieval. Memory retrieval is influenced by reward expectation during encoding, so we hypothesized that diminished reward expectation would exacerbate representational drift. We found that high reward expectation limited drift, with CA1 representations on one day gradually re-emerging over successive trials the following day. Conversely, the absence of reward expectation resulted in increased drift, as the gradual re-emergence of the previous days representation did not occur. At the single cell level, lowering reward expectation caused an immediate increase in the proportion of place-fields with low trial-to-trial reliability. These place fields were less likely to be reinstated the following day, underlying increased drift in this condition. In conclusion, heightened reward expectation improves memory encoding and retrieval by maintaining reliable place fields that are gradually reinstated across days, thereby minimizing representational drift.

RationaleRecent research on habits and skills has produced a wave of new theories regarding the shift in control from medial to lateral regions of the dorsal striatum, and how these regions are implicated in the selected and executed of action sequences. ObjectivesTo examine the comparative effects of muscimol/baclofen inactivation and dopamine D1 and D2 receptor agents in the dorsomedial (DMS) and dorsolateral (DLS) striatum on the performance of skilled action sequences. MethodsInfusions were made in well-trained rats using the five-step nose poke task to isolate the effects on initiation, execution and termination components of skilled action sequences. ResultsDLS inactivation produced sequencing deficits like those observed with pre-training lesions, indicating that the DLS is critical for both the acquisition and performance of sequences. Behaviour was unchanged following DMS inactivation, consistent with models of DMS disengagement following training. Infusions of D1 and D2 antagonists did not alter behaviour, however the D2 receptor agonist quinpirole increased sequence errors at a low dose and reduced sequences at the high dose in the DLS. DLS manipulations impaired sequence initiation and termination as well as reward transitions, while the chunking ballistic response pattern was largely unaltered, indicating that between-but not within-sequence actions rely on the DLS. ConclusionsSkilled action sequencing, including chunk transitions was dependent on DLS and its modulation by D2 receptors, but not on DMS function. Using a novel sequencing task, these results support the dissociable and dopamine-dependent role of the dorsal striatum subregions in performing skilled motor actions.

Presentation of learning-related cues during NREM sleep has been shown to improve memory consolidation. Past studies suggest that REM sleep may contribute to the beneficial effect of reactivating memories during NREM sleep, but the relationship between REM sleep and induced reactivations in NREM remains unclear. We investigated whether a naturally ensuing episode of REM sleep is necessary for prior NREM targeted memory reactivation (TMR) to exert a beneficial effect on memory consolidation. Nineteen participants learned the association between prior or non-prior known objects and their names (pseudowords) in a within-subject multiple session experiment, in which TMR was subsequently performed either before (Pre-REM) or after (Post-REM) the final REM sleep episode of the night. While word-picture association recall measures did not differ between TMR conditions, we found better name recognition based on confidence ratings for words reactivated during Pre-REM TMR in contrast with associations cued during Post-REM TMR. In addition, we found distinct associations between cue-evoked sigma activity, subsequent REM theta power and TMR memory benefits which were contingent upon the level of relatedness with prior knowledge for the learned material. Although TMR may be less effective during the second half of the night, our findings suggest an interplay between NREM and REM sleep oscillatory activity for memory reactivation and consolidation processes.

Hippocampal place cells are the functional units of spatial navigation and are present in all subregions-CA1, CA2, CA3 and CA4. Recent studies on CA2 have indicated its role in social and contextual memory, but its contribution towards spatial novelty detection and consolidation remains largely unknown. The current study aims to uncover how CA1 and CA2 detect, process, assimilate and consolidate spatial novelty. Accordingly, a novel 3-day paradigm was designed where the animal was introduced to a completely new environment on the first day and to varying degrees of familiarity and novelty on subsequent days, as the track was extended in length and modified in shape, keeping other environmental constraints fixed. Detection of spatial novelty was found to be a dynamic and complex phenomenon, characterized by different responses from hippocampal place cells, depending on when novelty was introduced. Therefore, the study concludes that early novelty detection (the first time a novel space is introduced in a relatively familiar environment) and subsequent novelty detection are not processed in the same way. Additionally, while neuronal responses to spatial novelty detection (early and subsequent) were found to be the same in CA1 and CA2 ensembles, their responses differed in spatial consolidation mechanisms during subsequent sleep replays. For CA1, spatial coverage of prior behaviour was found to be closely reflected in subsequent sleep for that particular day, but CA2 showed no such coherent response, highlighting mnemonic processing differences between CA2 and CA1 with respect to spatial novelty.

(Re)mapping of different environments by hippocampal place cells is thought to reflect incidental learning. Rat "head scanning" is a spontaneous and presumed investigatory behavior that can trigger the onset of firing locations in place cells. This behavior was studied on (quasi-)circular tracks, and it was speculated that off-track head scans might have been overlooked or inadvertently discouraged in studies employing more common apparatus. To better understand the general prevalence and significance of off-track scanning, we investigated it in rats running laps on linear tracks in rooms featuring visual landmarks. Scanning spanned the length of the track, even in highly familiar conditions and in rats rewarded only at the two ends of the track. Thus, co-localized rewards are not necessary for the occurrence of this behavior. Scanning rate increased markedly in a novel room and then declined steeply during each daily session in this room over 3 days. Transient increases at the beginning of each daily session partially counteracted this decline, producing a "seesaw" profile that is reminiscent of previous observations on place cell plasticity. Therefore, the remapping that place cells are known to undergo in similar contextual changes could conceivably be facilitated by the putative surge of new place fields induced by increased scanning. Investigatory behaviors could thus be causally involved in the representational and dynamic properties of hippocampal representations. Addressing these possibilities offers insight into the incidental creation and update of a cognitive map. HIGHLIGHTSO_LIRat head scanning is known to trigger the onset of firing locations in place cells C_LIO_LIOff-track scanning occurs on linear tracks in familiar and novel conditions C_LIO_LICo-localized rewards are not necessary for scanning events C_LIO_LIResponse to a novel room resembles that seen in place cell dynamics C_LIO_LIRelationships between head scanning and place field formation could help uncover the incidental process of map making C_LI

BackgroundVisceral feedback from the body is often subconscious, but plays an important role in guiding motivated behaviors. Vagal sensory neurons relay "gut feelings" to noradrenergic (NA) neurons in the caudal nucleus of the solitary tract (cNTS), which in turn project to the anterior ventrolateral bed nucleus of the stria terminalis (vlBNST) and other hypothalamic-limbic forebrain regions. Prior work supports a role for these circuits in modulating memory consolidation and extinction, but a potential role in retrieval of conditioned avoidance remains untested. ResultsTo examine this, adult male rats underwent passive avoidance conditioning. We then lesioned gut-sensing vagal afferents by injecting cholecystokinin-conjugated saporin toxin (CSAP) into the vagal nodose ganglia (Experiment 1), or lesioned NA inputs to the vlBNST by injecting saporin toxin conjugated to an antibody against dopamine-beta hydroxylase (DSAP) into the vlBNST (Experiment 2). When avoidance behavior was later assessed, rats with vagal CSAP lesions or NA DSAP lesions displayed significantly increased conditioned passive avoidance. ConclusionsThese new findings support the view that a gut vagal afferent-to-cNTSNA-to-vlBNST circuit plays a role in modulating the expression/retrieval of learned passive avoidance. Overall, our data suggest a dynamic modulatory role of vagal sensory feedback to the limbic forebrain in integrating interoceptive signals with contextual cues that elicit conditioned avoidance behavior.

Although the role of striatal dopamine in Pavlovian conditioning and in habits has been reasonably well described, relatively little is known about its function in goal-directed action. In this study we trained hungry rats on two lever press actions for distinct food outcomes and recorded dopamine release in the dorsomedial striatum as these action-outcome associations were encoded and subsequently degraded. During initial training the lever press actions generated bilateral dopamine release that was found to reflect the predicted action value. This value was updated by the prediction error generated by the feedback produced by contact with the outcome, or its absence, after the press. Importantly, hemispheric dopamine release became increasingly lateralized across the course of training, with greater release in the hemisphere contralateral to the press. Using video analysis and multiple different measures, we could find no evidence that the degree of lateralized release was associated with movement; rather, we found that it tracked the strength of the action-outcome association, increasing and decreasing with increments and decrements in the contingency between specific actions and their consequences. Similar results emerged whether the rewards were delivered on ratio or interval schedules of reinforcement and whether we used unpaired outcome delivery or outcome-identity reversal to modify the specific contingencies. These findings suggest that, whereas moment-to-moment fluctuations in action value are reflected in bilateral dopamine release, a second signal broadcasts the overall strength of specific action-outcome relationships via the difference between contralateral and ipsilateral release during actions.

Theta and gamma rhythms temporally coordinate sequences of hippocampal place cell ensembles during active behaviors, while sharp wave-ripples coordinate place cell sequences during rest. We used a delayed match-to-place memory task to investigate whether such coordination of hippocampal place cell sequences is disrupted when memory errors occur. As rats approached a learned reward location, place cell sequences represented paths extending toward the reward location during correct trials. During error trials, paths coded by place cell sequences were significantly shorter as rats approached incorrect stop locations, with place cell sequences starting at a significantly delayed phase of the theta cycle. During rest, place cell sequences replayed representations of paths that were highly likely to end at the correct reward location during correct but not error trials. The relationship between place cell sequences and gamma rhythms, however, did not differ between correct and error trials. These results suggest that coordination of place cell sequences by theta rhythms and sharp wave-ripples is important for successful spatial memory.