Postrhinal cortex contributions to the expression of auditory fear conditioning.

The postrhinal cortex (POR), the rodent homologue of the primate parahippocampal cortex (PHC), has been implicated in contextual and spatial processing. For instance, prior studies have demonstrated that permanent lesions of POR impair contextual fear conditioning. In contrast, permanent lesions of POR, specifically prior to training, do not impact auditory fear conditioning. In the current experiments, we examined the role of POR in the expression of auditory fear conditioning by using chemogenetics to silence neural activity in POR at the time of retrieval testing. Considering that extinction is context-dependent, and POR contributes to contextual memory, we hypothesized that POR would be necessary for expression of auditory fear conditioning following extinction. We found that POR inactivation during retrieval impaired freezing to an auditory cue that was tested in the conditioning context (A) after it had been extinguished in a different context (B). However, the involvement of POR was not specific to extinction. POR inactivation also impaired freezing to an auditory fear cue that had not undergone extinction. Thus, while prior studies have identified a role for POR in contextual fear conditioning, the current findings extend the functional role of POR to include the expression of auditory fear conditioning.

Retrosplenial cortex inactivation during retrieval, but not encoding, impairs remotely acquired auditory fear conditioning in male rats.

Prior studies with permanent lesion methods have demonstrated a role for the retrosplenial cortex (RSC) in the retrieval of remotely, but not recently, acquired delay fear conditioning. To extend the generalizability of these prior findings, the present experiments used chemogenetics to temporarily inactivate the RSC during either retrieval or encoding of delay auditory fear conditioning. Inactivation of the RSC at the time of test impaired retrieval of a remotely conditioned auditory cue, but not a recently conditioned one. In addition, inactivation of the RSC during encoding had no impact on freezing during later retrieval testing for both a remotely and recently conditioned auditory cue. These findings indicate that the RSC contributes to the retrieval, but not encoding, of remotely acquired auditory fear conditioning, and suggest it has less of a role in both retrieval and encoding of recently acquired auditory fear conditioning.

Permanent damage or temporary silencing of retrosplenial cortex impairs the expression of a negative patterning discrimination.

The retrosplenial cortex (RSC) is positioned at the interface between cortical sensory regions and the hippocampal/parahippocampal memory system. As such, it has been theorized that RSC may have a fundamental role in linking sensory stimuli together in the service of forming complex representations. To test this, three experiments were carried out to determine the effects of RSC damage or temporary inactivation on learning or performing a negative patterning discrimination. In this procedure, two conditioned stimuli are reinforced when they are presented individually (i.e., stimulus elements) but are non-reinforced when they are presented simultaneously as a compound stimulus. Normal rats successfully discriminate between the two types of trials as evidenced by more responding to the elements compared to the compound stimulus. This is thought to reflect the formation of a configural representation of the compound stimulus; that is, the two cues are linked together in such a fashion that the compound stimulus is a wholly different, unique stimulus. Permanent lesions of RSC made prior to training (Experiment 1) had no effect on learning the discrimination. However, lesions (Experiment 2) or temporary chemogenetic inactivation (Experiment 3) of RSC made after training impaired subsequent performance of the discrimination. We argue that this pattern of results indicates that RSC may normally be involved in forming the configural representations manifested in negative patterning, but that absent the RSC, other brain systems or structures can compensate sufficiently to result in normal behavior.

Paradoxical accentuation of motivation following accumbens-pallidum disconnection.

The nucleus accumbens (NAc) and ventral pallidum (VP) are reciprocally connected, and activity within this circuit is thought to promote reward learning. Inconsistent with this notion, we find that disconnecting NAc medial shell and VP greatly enhances the attribution of value to a cue that is paired with reward. This result suggests that medial NAc shell and VP are both needed for attributing value to cues yet can also oppose one-another's functional contribution.

Intertrial unconditioned stimuli differentially impact trace conditioning.

Three experiments assessed how appetitive conditioning in rats changes over the duration of a trace conditioned stimulus (CS) when unsignaled unconditioned stimuli (USs) are introduced into the intertrial interval. In Experiment 1, a target US occurred at a fixed time either shortly before (embedded), shortly after (trace), or at the same time (delay) as the offset of a 120-s CS. During the CS, responding was most suppressed by intertrial USs in the trace group, less so in the delay group, and least in the embedded group. Unreinforced probe trials revealed a bell-shaped curve centered on the normal US arrival time during the trace interval, suggesting that temporally specific learning occurred both with and without intertrial USs. Experiments 2a and 2b confirmed that the bulk of the trace CS became inhibitory when intertrial USs were scheduled, as measured by summation and retardation tests, even though CS offset evoked a temporally precise conditioned response. Thus, an inhibitory CS may give rise to new stimuli specifically linked to its termination, which are excitatory. A modification to the microstimulus temporal difference model is offered to account for the data.

Retrosplenial cortex is required for the retrieval of remote memory for auditory cues.

The restrosplenial cortex (RSC) has a well-established role in contextual and spatial learning and memory, consistent with its known connectivity with visuo-spatial association areas. In contrast, RSC appears to have little involvement with delay fear conditioning to an auditory cue. However, all previous studies have examined the contribution of the RSC to recently acquired auditory fear memories. Since neocortical regions have been implicated in the permanent storage of remote memories, we examined the contribution of the RSC to remotely acquired auditory fear memories. In Experiment 1, retrieval of a remotely acquired auditory fear memory was impaired when permanent lesions (either electrolytic or neurotoxic) were made several weeks after initial conditioning. In Experiment 2, using a chemogenetic approach, we observed impairments in the retrieval of remote memory for an auditory cue when the RSC was temporarily inactivated during testing. In Experiment 3, after injection of a retrograde tracer into the RSC, we observed labeled cells in primary and secondary auditory cortices, as well as the claustrum, indicating that the RSC receives direct projections from auditory regions. Overall our results indicate the RSC has a critical role in the retrieval of remotely acquired auditory fear memories, and we suggest this is related to the quality of the memory, with less precise memories being RSC dependent.

Higher-order conditioning and the retrosplenial cortex.

The retrosplenial cortex (RSC) is known to contribute to contextual and spatial learning and memory. This is consistent with its well-established connectivity; the RSC is located at the interface of visuo-spatial association areas and the parahippocampal-hippocampal memory system. However, the RSC also contributes to learning and memory for discrete cues. For example, both permanent lesions and temporary inactivation of the RSC have been shown to impair sensory preconditioning, a form of higher-order conditioning. The purpose of the present experiment was to examine the role of the RSC in a closely related higher-order conditioning paradigm: second-order conditioning. Sham and RSC lesioned rats received first-order conditioning in which one visual stimulus (V1) was paired with footshock and one visual stimulus (V2) was not. Following first-order conditioning, one auditory stimulus (A1) was then paired with V1 and a second auditory stimulus (A2) was paired with V2. Although lesions of the RSC impaired the first-order discrimination, they had no impact on the acquisition of second-order conditioning. Thus, the RSC does not appear necessary for acquisition/expression of second-order fear conditioning. The role of the RSC in higher-order conditioning, as well as a possible dissociation from the hippocampus, is discussed.

Medial prefrontal cortex involvement in the expression of extinction and ABA renewal of instrumental behavior for a food reinforcer.

Instrumental renewal, the return of extinguished instrumental responding after removal from the extinction context, is an important model of behavioral relapse that is poorly understood at the neural level. In two experiments, we examined the role of the dorsomedial prefrontal cortex (dmPFC) and the ventromedial prefrontal cortex (vmPFC) in extinction and ABA renewal of instrumental responding for a sucrose reinforcer. Previous work, exclusively using drug reinforcers, has suggested that the roles of the dmPFC and vmPFC in expression of extinction and ABA renewal may depend at least in part on the type of drug reinforcer used. The current experiments used a food reinforcer because the behavioral mechanisms underlying the extinction and renewal of instrumental responding are especially well worked out in this paradigm. After instrumental conditioning in context A and extinction in context B, we inactivated dmPFC, vmPFC, or a more ventral medial prefrontal cortex region by infusing baclofen/muscimol (B/M) just prior to testing in both contexts. In rats with inactivated dmPFC, ABA renewal was still present (i.e., responding increased when returned to context A); however responding was lower (less renewal) than controls. Inactivation of vmPFC increased responding in context B (the extinction context) and decreased responding in context A, indicating no renewal in these animals. There was no effect of B/M infusion on rats with cannula placements ventral to the vmPFC. Fluorophore-conjugated muscimol was infused in a subset of rats following test to visualize infusion spread. Imaging suggested that the infusion spread was minimal and mainly constrained to the targeted area. Together, these experiments suggest that there is a region of medial prefrontal cortex encompassing both dmPFC and vmPFC that is important for ABA renewal of extinguished instrumental responding for a food reinforcer. In addition, vmPFC, but not dmPFC, is important for expression of extinction of responding for a food reinforcer. The role of the medial prefrontal cortex in renewal in the original conditioning context may depend in part on control over excitatory context-response or context-(response-outcome) relations that might be learned in acquisition. The role of the vmPFC in expression of extinction may depend on its control over inhibitory context-response or context-(response-outcome) relations that are learned in extinction.

Chemogenetic silencing of neurons in retrosplenial cortex disrupts sensory preconditioning.

An essential aspect of episodic memory is the formation of associations between neutral sensory cues in the environment. In light of recent evidence that this critical aspect of learning does not require the hippocampus, we tested the involvement of the retrosplenial cortex (RSC) in this process using a chemogenetic approach that allowed us to temporarily silence neurons along the entire rostrocaudal extent of the RSC. A viral vector containing the gene for a synthetic inhibitory G-protein-coupled receptor (hM4Di) was infused into RSC. When the receptor was later activated by systemic injection of clozapine-N-oxide, neural activity in RSC was transiently silenced (confirmed using a patch-clamp procedure). Rats expressing hM4Di and control rats were trained in a sensory preconditioning procedure in which a tone and light were paired on some trials and a white noise stimulus was presented alone on the other trials during the Preconditioning phase. Thus, rats were given the opportunity to form an association between a tone and a light in the absence of reinforcement. Later, the light was paired with food. During the test phase when the auditory cues were presented alone, controls exhibited more conditioned responding during presentation of the tone compared with the white noise reflecting the prior formation of a tone-light association. Silencing RSC neurons during the Preconditioning phase prevented the formation of an association between the tone and light and eliminated the sensory preconditioning effect. These findings indicate that RSC may contribute to episodic memory formation by linking essential sensory stimuli during learning.

Contribution of the retrosplenial cortex to temporal discrimination learning.

The retrosplenial cortex (RSC) has an important role in contextual learning and memory. While the majority of experiments have focused on the physical context, the present study asked whether the RSC is involved in processing the temporal context. Rats were trained in a temporal discrimination procedure where the duration of the intertrial interval (ITI) signaled whether or not the next tone conditioned stimulus would be paired with food pellet reinforcement. When the tone was presented after a 16-min ITI it was reinforced, but when it was presented after a 4-min ITI it was not. Rats demonstrated successful discrimination in this procedure by responding more to the tone on reinforced trials than on non-reinforced trials. Pre-training electrolytic lesions of the RSC attenuated acquisition of the temporal discrimination. The results are the first to demonstrate a role for the RSC in processing temporal information and in turn extend the role of the RSC beyond the physical context to now include the temporal context.

Chemogenetic manipulation of ventral pallidal neurons impairs acquisition of sign-tracking in rats.

Cues associated with rewarding events acquire value themselves as a result of the incentive value of the reward being transferred to the cue. Consequently, presentation of a reward-paired cue can trigger reward-seeking behaviours towards the cue itself (i.e. sign-tracking). The ventral pallidum (VP) has been demonstrated to be involved in a number of motivated behaviours, both conditioned and unconditioned. However, its contribution to the acquisition of incentive value is unknown. Using a discriminative autoshaping procedure with levers, the effects of disrupting VP activity in rats on the emergence of sign-tracking was investigated using chemogenetics, i.e. Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Transient disruption of VP neurons [activation of the inhibitory hM4D(Gi) DREADD through systemic injections of clozapine N-oxide (CNO) prior to each autoshaping session] impaired acquisition of sign-tracking (lever press rate) without having any effect on approach to the site of reward delivery (i.e. goal-tracking) or on the expression of sign-tracking after it was acquired. In addition, electrophysiological recordings were conducted in freely behaving rats following VP DREADD activation. The majority of VP units that were responsive to CNO injections exhibited rapid inhibition relative to baseline, a subset of CNO-responsive units showed delayed excitation, and a smaller subset displayed a mixed response of inhibition and excitation following CNO injections. It is argued that disruption of VP during autoshaping specifically disrupted the transfer of incentive value that was attributed to the lever cue, suggesting a surprisingly fundamental role for the VP in acquiring, compared with expressing, Pavlovian incentive values.

Habituation, latent inhibition, and extinction.

In two conditioned suppression experiments with a latent inhibition (LI) design, we measured the habituation of rats in preexposure, their LI during conditioning, and then extinction over days. In the first experiment, lick suppression, the preexposed group (PE) showed a significant initial unconditioned response (UR) to the target stimulus and significant long-term habituation (LTH) of that response over days. The significant difference between the PE and nonpreexposed (NPE) groups on the first conditioning trial was due solely to the difference in their URs to the conditioned stimulus (CS)-a habituated response (PE) and an unhabituated response (NPE). In the second experiment, bar-press suppression, little UR to the target stimulus was apparent during preexposure, and no detectable LTH. Thus, there was no difference between the PE and NPE groups on the first conditioning trial. Whether the UR to the CS confounds the interpretation of LI (Exp. 1) or not (Exp. 2) can only be known if the UR is measured. In both experiments, LI was observed in acquisition. Also in both experiments, rats that were preexposed and then conditioned to asymptote were significantly more resistant to extinction than were the rats not preexposed. This result contrasts with the consistently reported finding that preexposure either produces less resistance to extinction or has no effect on extinction. The effect of stimulus preexposure survived conditioning to asymptote and was reflected directly in extinction. These two experiments provide a cautionary procedural note for LI experiments and have shown an unexpected extinction effect that may provide new insights into the interpretation of LI.

Retrosplenial Cortex and Long-Term Memory: Molecules to Behavior.

The retrosplenial cortex (RSC) is reciprocally connected with the hippocampus and various parahippocampal cortical regions, suggesting that RSC is well-positioned to contribute to hippocampal-dependent memory. Consistent with this, substantial behavioral evidence indicates that RSC is essential for consolidating and/or retrieving contextual and spatial memories. In addition, there is growing evidence that RSC neurons undergo activity-dependent plastic changes during memory formation and retrieval. In this paper we review both the behavioral and cellular/molecular data and posit that the RSC has a particularly important role in the storage and retrieval of spatial and contextual memories perhaps due its involvement in binding together multiple cues in the environment. We identify remaining questions and avenues for future research that take advantage of emerging methods to selectively manipulate RSC neurons both spatially and temporally and to image the RSC in awake, behaving animals.

Behavioral and neurobiological mechanisms of extinction in Pavlovian and instrumental learning.

This article reviews research on the behavioral and neural mechanisms of extinction as it is represented in both Pavlovian and instrumental learning. In Pavlovian extinction, repeated presentation of a signal without its reinforcer weakens behavior evoked by the signal; in instrumental extinction, repeated occurrence of a voluntary action without its reinforcer weakens the strength of the action. In either case, contemporary research at both the behavioral and neural levels of analysis has been guided by a set of extinction principles that were first generated by research conducted at the behavioral level. The review discusses these principles and illustrates how they have informed the study of both Pavlovian and instrumental extinction. It shows that behavioral and neurobiological research efforts have been tightly linked and that their results are readily integrated. Pavlovian and instrumental extinction are also controlled by compatible behavioral and neural processes. Since many behavioral effects observed in extinction can be multiply determined, we suggest that the current close connection between behavioral-level and neural-level analyses will need to continue.

Retrosplenial cortex and aversive conditioning.

The retrosplenial cortex (RSC) is well-known for its contribution to episodic memory, as well as contextual and spatial learning and memory. However, two literatures have also emerged examining the role of the RSC in aversive conditioning. The purpose of this manuscript is to review, and attempt to integrate, these two literatures. We focus on studies in which discrete cues, such as tones, predict the occurrence of aversive outcomes, such as mild shocks. Using both electrophysiological recordings and lesion methods, the first literature has examined RSC contributions to discriminative avoidance conditioning. The second, and more recent literature, has focused on the role of the RSC in Pavlovian fear conditioning. We discuss both literatures in terms of the type of information processed by the RSC, the role of the RSC in memory storage, and how the aversive conditioning literature might be consistent with a role for the RSC in contextual learning and memory.

Renewal of conditioned fear in male and female rats.

Pavlovian extinction reduces the performance of conditioned responses and occurs when the conditioned stimulus (CS) is repeatedly presented in the absence of the unconditioned stimulus (US). However, when the CS is experienced in a context that is different from the extinction context, there is a recovery of the conditioned response, a phenomenon known as renewal. There is some evidence that the renewal of appetitive conditioning is influenced by sex, with females failing to exhibit renewed responding. Further, there is recent evidence that renewal of fear might also not occur in female rats. In both appetitive and fear preparations, the lack of renewal in females has been postulated to be related to cycling ovarian hormones. Therefore, in Experiments 1 and 2, we directly compared fear renewal in males and females (Experiment 1) as well as ovariectomized (OVX) females (Experiment 2) when conditioning occurred in Context A, extinction in B, and testing in A (ABA renewal). Experiments 3 and 4 examined renewal when conditioning and extinction occurred in A and testing occurred in B (AAB renewal). In all experiments, renewal was not significantly different between male and female rats. Further, in Experiments 2 and 4, renewal did not differ between males, intact females, and OVX females. Additionally, in each experiment, there was no evidence that context excitation and/or inhibition contributed to renewal; instead suggesting that renewal was controlled by an occasion-setting mechanism. Overall, these results suggest little evidence for the role of sex in renewal of conditioned freezing and also indicate that cycling ovarian hormones have little role in the strength of renewal in female rats. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Within- and between-session variety effects in a food-seeking habituation paradigm.

Appetitive behavior is stronger when organisms are given a variety of foods than when they are repeatedly given the same food (the variety effect). Two experiments examined the variety effect in an operant food-seeking task. In both experiments, rats received a 45-mg food pellet for every 4th lever press over a series of daily 30-min sessions. The rats responded at a high rate early in the session, but the rate declined systematically over time within the session. In Experiment 1, alternating unpredictably between grain and sucrose pellets caused a higher level of responding, and a slower within-session decline in responding, than presenting either type of pellet consistently. In groups receiving one pellet consistently, a switch to the alternate pellet caused lawful changes in response rate that reflected both habituation and incentive contrast processes. In Experiment 2, an experimental group received grain only and sucrose only in daily alternating sessions. In sucrose sessions, they responded more than controls that always received either sucrose or grain (a type of variety effect); in grain sessions, they responded less than the controls. The results indicated a within-session variety effect that was controlled by habituation processes and a between-session variety effect that was controlled by incentive contrast. Both types of processes can come into play when organisms are exposed to food variety.

Effects of the amount of acquisition and contextual generalization on the renewal of instrumental behavior after extinction.

Four experiments with rat subjects examined the role of context during the extinction of instrumental (free-operant) behavior. In all experiments, leverpressing was first reinforced on a variable-interval 30-s schedule and then extinguished before being tested in the extinction and renewal contexts. The results identified three important variables affecting the renewal effect after instrumental extinction. First, ABA and ABC forms of renewal were strengthened by increasing the amount of acquisition training. This suggests that the strength of the association learned during acquisition, or the final level of performance, influences the degree of renewal after extinction. The effect of the amount of training was modulated by the second factor, the degrees of generalization from the acquisition and extinction contexts to the test context. The third variable was acquisition training in multiple contexts, which was shown to strengthen ABC renewal. Methodological, theoretical, and practical implications are discussed.

Contextual control of appetite. Renewal of inhibited food-seeking behavior in sated rats after extinction.

Obesity and overeating have become fundamental problems in modern society. This article studies the inhibition of food-seeking behavior, and how contextual cues can control it. Rats that had free food in the home cage nevertheless learned to lever press for sucrose or high-fat pellets in a distinctive context (a Skinner box). Lever pressing was then inhibited by extinction, in which lever presses no longer produced food. After extinction, inhibited responding was "renewed" when the rats were switched to a different context: in the new context, the rats lever-pressed again, and worked more for food when food was made available. These effects were observed when conditioning, extinction and testing occurred in contexts A, B, and A (respectively) or in A, A, and B. Thus, mere removal from the context in which food-seeking was inhibited initiated a return to food-seeking. The contextual control of extinction may help explain why food seeking and consumption seem so persistent.