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).

Effects of sex and retention interval on the retrieval and extinction of auditory fear conditioning.

Fear memory retrieval is relevant to psychiatric disorders such as post-traumatic stress disorder (PTSD). One of the hallmark symptoms of PTSD is the repeated retrieval and re-experiencing of the initial fear memory even long after the traumatic event has occurred. Women are nearly twice as likely to develop PTSD following a trauma than men, thus sex differences in the retrieval of fear memories is highly relevant for understanding the development and maintenance of PTSD. In the current study, we aimed to examine sex differences in the retrieval and extinction of either recent or remote fear memories. To do so, we conditioned male and female rats either 1 day (recent) or 28 days (remote) prior to testing retrieval and extinction. While there was no effect of sex or retention interval on initial retrieval, we found that remotely conditioned females exhibited higher rates of freezing than remotely conditioned males in later retrieval/extinction sessions, suggesting a sex difference in the retrieval and/or extinction of remote, but not recent, fear memories. Overall, these results are the first to demonstrate a sex difference in the extinction of remote fear memory, and this may contribute to the differential expression of fear-related disorders like PTSD in men and women.

How common is a common error term? The rules that govern associative learning in sensory preconditioning and second-order conditioning.

In standard (first-order) Pavlovian conditioning protocols, pairings of an initially neutral conditioned stimulus (CS) and a biologically significant unconditioned stimulus (US) result in the formation of a CS-US association. The strength of this association is theoretically regulated by prediction error: specifically, the difference between the total level of conditioning supported by the US and the degree to which it is predicted by all stimuli present (i.e., a common error term). In higher-order conditioning protocols (e.g., sensory preconditioning and second-order conditioning), a Pavlovian CS is used to condition responses to other stimuli with which it is paired. At present, it is unknown whether error-correction processes regulate associative learning in higher-order conditioning and, if so, whether these processes are the same as those that regulate formation of a CS-US association in first-order conditioning. Here we review studies that have provided findings relevant to this question: specifically, studies that have examined blocking and/or inhibitory learning in sensory preconditioning and second-order conditioning. These studies show that: (1) animals can form inhibitory associations between relatively neutral sensory stimuli; (2) the learning that occurs in sensory preconditioning and second-order conditioning can be blocked; and, finally, (3) a first-order CS can block conditioning to a second-order CS, and vice versa. The findings are taken to imply that a common error term regulates associative learning in higher-order conditioning, just as it regulates associative learning in first-order conditioning. They are discussed with respect to the nature of the error signal that underlies conditioning and future work that is needed to advance our understanding of the rules that govern different types of learning.

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.

Retrograde amnesia of contextual fear conditioning: Evidence for retrosplenial cortex involvement in configural processing.

It has been suggested that contextual fear conditioning can be supported by either an elemental system, where individual features of the environment are associated with shock, or a configural system, where environmental features are bound together and associated with shock. Although the retrosplenial cortex (RSC) is known to be involved in contextual fear conditioning, it is not clear whether it contributes to the elemental or configural system. To isolate the role of the RSC in contextual fear conditioning, the current experiments examined the influence of RSC lesions on the context preexposure facilitation effect, a procedure known to produce conditioning to a configural representation of context. In Experiment 1, rats that were preexposed to the conditioning context froze more compared to rats that were not, replicating the context preexposure facilitation effect. Although pretraining lesions of the RSC had no impact on the context preexposure facilitation effect (Experiment 2a), posttraining lesions attenuated the effect (Experiment 2b), suggesting that the RSC normally contributes to a configural context representation. Retrohippocampal contributions to contextual fear conditioning are discussed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Cortical Contributions to Higher-Order Conditioning: A Review of Retrosplenial Cortex Function.

In higher-order conditioning paradigms, such as sensory preconditioning or second-order conditioning, discrete (e.g., phasic) or contextual (e.g., static) stimuli can gain the ability to elicit learned responses despite never being directly paired with reinforcement. The purpose of this mini-review is to examine the neuroanatomical basis of high-order conditioning, by selectively reviewing research that has examined the role of the retrosplenial cortex (RSC) in sensory preconditioning and second-order conditioning. For both forms of higher-order conditioning, we first discuss the types of associations that may occur and then review findings from RSC lesion/inactivation experiments. These experiments demonstrate a role for the RSC in sensory preconditioning, suggesting that this cortical region might contribute to higher-order conditioning via the encoding of neutral stimulus-stimulus associations. In addition, we address knowledge gaps, avenues for future research, and consider the contribution of the RSC to higher-order conditioning in relation to related brain structures.

Reduced renewal of conditioned suppression following lesions of the dorsal hippocampus in male rats.

Extinguished responding will renew when the conditioned stimulus occurs outside the extinction context. Although studies of conditioned freezing have consistently demonstrated a role for the hippocampus in renewal, several studies have demonstrated intact renewal of conditioned suppression despite damage to the hippocampus (Frohardt, Guarraci, & Bouton, 2000; Todd, Jiang, DeAngeli, & Bucci, 2017; Wilson, Brooks, & Bouton, 1995). Because these prior studies have examined renewal when testing occurred in the original conditioning context ("Context A"), the present conditioned suppression experiments examined the role of the hippocampus when testing occurred in a context not associated with prior conditioning ("Context C"). In Experiments 1 and 2, conditioning occurred in Context A, and extinction in Context B. Renewal of conditioned suppression was observed when the extinguished conditioned stimulus (CS) was tested in Context C. However, renewal was attenuated in rats with lesions of the dorsal hippocampus (DH). Summation testing failed to detect conditioned inhibition in the extinction context, suggesting instead that the context acquired negative occasion-setting properties. Attenuated renewal was not due to an inability of DH lesioned rats to discriminate contexts (Experiment 3). These experiments thus demonstrate a role for the DH in renewal of conditioned suppression when testing occurs in a neutral context. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Effects of conditioned stimulus (CS) duration, intertrial interval, and I/T ratio on appetitive Pavlovian conditioning.

Pavlovian learning is influenced by at least 2 temporal variables: The time between the onset of the conditioned stimulus (CS) and presentation of the unconditioned stimulus (US), and the time between successive conditioning trials (the intertrial interval [ITI]). Wagner's Sometimes Opponent Process (SOP) model (e.g., 1981) provides a rich account of the effects of varying the absolute durations of CS and ITI. However, other theories have contrastingly emphasized the role of the relative durations of CS (T) and ITI (I). Three experiments with rats used an appetitive conditioning preparation to separate the two approaches. They manipulated absolute values of I and T over a factor of 6 and compared the effect of varying T and I/T by the same factor. Conditioning was indexed by the rate of foodcup entry during training, during common tests conducted later with different combinations of I and T, and with a reinforcers-to-criterion measure. Experiment 1 found that learning with a 10-s CS was superior to that with a 60-s CS when the I/T ratio was the same. There was little evidence of learning with the 60-s CS. Experiment 2 replicated that result and extended it to show that a 60-s CS still supported little conditioned responding when I/T was increased from 12 to 72. Experiment 3 then examined intermediate CS durations between 10-s and 60-s while I/T was controlled. The results support a role for absolute CS duration rather than the I/T ratio. Explanations based on SOP and behavior systems theory are explored. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Retrosplenial cortex damage impairs unimodal sensory preconditioning.

The retrosplenial cortex (RSC) is positioned at the interface between cortical sensory regions and the structures that compose the medial temporal lobe memory system. It has recently been suggested that 1 functional role of the RSC involves the formation of associations between cues in the environment (stimulus-stimulus [S-S] learning; Bucci & Robinson, 2014). This suggestion is based, in part, on the finding that lesions or temporary inactivation of the RSC impair sensory preconditioning. However, all prior studies examining the role of the RSC in sensory preconditioning have used cues from multiple modalities (both visual and auditory stimuli). The purpose of the present experiment was to determine whether the RSC contributes to unimodal sensory preconditioning. In the present study we found that both electrolytic and neurotoxic lesions of the RSC impaired sensory preconditioning with auditory cues. Together with previous experiments, these findings indicate that the RSC contributes to both multisensory and unimodal sensory integration, which suggests a general role for the RSC in linking sensory cues in the environment. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

A sense of space in postrhinal cortex.

A topographic representation of local space is critical for navigation and spatial memory. In humans, topographic spatial learning relies upon the parahippocampal cortex, damage to which renders patients unable to navigate their surroundings or develop new spatial representations. Stable spatial signals have not yet been observed in its rat homolog, the postrhinal cortex. We recorded from single neurons in the rat postrhinal cortex whose firing reflects an animal's egocentric relationship to the geometric center of the local environment, as well as the animal's head direction in an allocentric reference frame. Combining these firing correlates revealed a population code for a stable topographic map of local space. This may form the basis for higher-order spatial maps such as those seen in the hippocampus and entorhinal cortex.

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.

Retrosplenial cortex and its role in cue-specific learning and memory.

The retrosplenial cortex (RSC) contributes to spatial navigation, as well as contextual learning and memory. However, a growing body of research suggests that the RSC also contributes to learning and memory for discrete cues, such as auditory or visual stimuli. In this review, we summarize and assess the Pavlovian and instrumental conditioning experiments that have examined the role of the RSC in cue-specific learning and memory. We use the term cue-specific to refer to these putatively non-spatial conditioning paradigms that involve discrete cues. Although these paradigms emphasize behavior related to cue presentations, we note that cue-specific learning and memory always takes place against a background of contextual stimuli. We review multiple ways by which contexts can influence responding to discrete cues and suggest that RSC contributions to cue-specific learning and memory are intimately tied to contextual learning and memory. Indeed, although the RSC is involved in several forms of cue-specific learning and memory, we suggest that many of these can be linked to processing of contextual stimuli.

A functional circuit for the retrieval of remote cued fear memory.

Although the retrosplenial cortex (RSC) is necessary for the retrieval of remotely acquired fear to a discrete auditory cue, it is not necessary for the retrieval of recently acquired cued-fear memories. Thus, the RSC's role in memory retrieval for discrete cues is time-dependent. The purpose of the current experiment was to identify the larger cortical circuit involved in the retrieval of remotely-acquired auditory fear memories. One candidate circuit involves the RSC and secondary auditory cortex; the secondary auditory cortex is also necessary for the retrieval of remotely acquired auditory fear memories (Sacco & Sacchetti, 2010), and sends direct projections to the RSC. To test this possibility, we assessed retrieval of remote memory following functional disconnection of the RSC and secondary auditory cortex. Complete disconnection of these regions produced a larger impairment in fear expression to a remotely acquired auditory cue compared to partial disconnection of these regions. These results are consistent with the notion that RSC and secondary auditory cortex form a functional circuit involved in the retrieval of remotely acquired fear to a discrete auditory cue. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Retrosplenial cortex has a time-dependent role in memory for visual stimuli.

Although the retrosplenial cortex (RSC) is critically involved in spatial learning and memory, it appears to have more selective contributions to learning and memory for discrete cues. For example, damage to the RSC does not impair Pavlovian delay fear conditioning to a discrete auditory cue (e.g., tone), when RSC manipulation occurs just prior to, or shortly after, conditioning. In contrast, when lesions of the RSC occur following a substantial retention interval (e.g., 28 days), the RSC is necessary for retrieval of fear to the tone. Thus, the RSC makes time-dependent contributions to memory retrieval for discrete auditory cues. The purpose of the current experiment was to assess if the time-dependent involvement of the RSC in cue-specific fear memory extended to cues of other sensory modalities. Rats firsts underwent fear conditioning to a visual stimulus, and lesions of the RSC subsequently occurred 1 or 28 days later. Lesions of the RSC impaired fear expression when made 28 days after conditioning, but not when made 1 day following conditioning. Coupled with previous findings, the current results suggest the RSC is necessary for retrieval of remotely acquired cued fear memories across multiple modalities. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

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.

Behavioral predictors of alcohol drinking in a neurodevelopmental rat model of schizophrenia and co-occurring alcohol use disorder.

Alcohol use disorder commonly occurs in patients with schizophrenia and contributes greatly to its morbidity. Unfortunately, the neural and behavioral underpinnings of alcohol drinking in these patients are not well understood. In order to begin to understand the cognitive and reward-related changes that may contribute to alcohol drinking, this study was designed to address: 1) latent inhibition; 2) conditioning; and 3) extinction of autoshaping in a neurodevelopmental rat model with relevance to co-occurring schizophrenia and alcohol use disorders, the neonatal ventral hippocampal lesioned (NVHL) rat. NVHL lesions (or sham surgeries) were performed on post-natal day 7 (PND7) and animals were given brief exposure to alcohol during adolescent (PND 28-42). Latent inhibition of autoshaping, conditioning and extinction were assessed between PND 72-90. On PND90 animals were given alcohol again and allowed to establish stable drinking. Latent inhibition of autoshaping was found to be prolonged in the NVHL rats; the NVHL rats pre-exposed to the lever stimulus were slower to acquire autoshaping than sham pre-exposed rats. NVHL rats that were not pre-exposed to the lever stimulus did not differ during conditioning, but were slower to extinguish conditioned responding compared to sham controls. Finally, the NVHL rats from both groups drank significantly more alcohol than sham rats, and the extent of latent inhibition predicted future alcohol intake in the pre-exposed animals. These findings suggest that the latent inhibition of autoshaping procedure can be used to model cognitive- and reward-related dysfunctions in schizophrenia, and these dysfunctions may contribute to the development of co-occurring alcohol use.

Retrograde amnesia of contextual fear conditioning: Evidence for retrosplenial cortex involvement in configural processing.

It has been suggested that contextual fear conditioning can be supported by either an elemental system, where individual features of the environment are associated with shock, or a configural system, where environmental features are bound together and associated with shock. Although the retrosplenial cortex (RSC) is known to be involved in contextual fear conditioning, it is not clear whether it contributes to the elemental or configural system. To isolate the role of the RSC in contextual fear conditioning, the current experiments examined the influence of RSC lesions on the context preexposure facilitation effect, a procedure known to produce conditioning to a configural representation of context. In Experiment 1, rats that were preexposed to the conditioning context froze more compared to rats that were not, replicating the context preexposure facilitation effect. Although pretraining lesions of the RSC had no impact on the context preexposure facilitation effect (Experiment 2a), posttraining lesions attenuated the effect (Experiment 2b), suggesting that the RSC normally contributes to a configural context representation. Retrohippocampal contributions to contextual fear conditioning are discussed. (PsycINFO Database Record

Intact renewal after extinction of conditioned suppression with lesions of either the retrosplenial cortex or dorsal hippocampus.

Extinction of fear to a Pavlovian conditioned stimulus (CS) is known to be context-specific. When the CS is tested outside the context of extinction, fear returns, or renews. Several studies have demonstrated that renewal depends upon the hippocampus, although there are also studies where renewal was not impacted by hippocampal damage, suggesting that under some conditions context encoding and/or retrieval of extinction depends upon other regions. One candidate region is the retrosplenial cortex (RSC), which is known to contribute to contextual and spatial learning and memory. Using a conditioned-suppression paradigm, Experiment 1 tested the impact of pre-training RSC lesions on renewal of extinguished fear. Consistent with previous studies, lesions of the RSC did not impact acquisition or extinction of conditioned fear to the CS. Further, there was no evidence that RSC lesions impaired renewal, indicating that contextual encoding and/or retrieval of extinction does not depend upon the RSC. In Experiment 2, post-extinction lesions of either the RSC or dorsal hippocampus (DH) also had no impact on renewal. However, in Experiment 3, both RSC and DH lesions did impair performance in an object-in-place procedure, an index of place memory. RSC and DH contributions to extinction and renewal are discussed.