Adrenalectomy exacerbates stress-induced impairment in fear discrimination: A causal role for kynurenic acid?

Impaired activity of the hypothalamic-pituitary axis and reduced blood levels of glucocorticoids (GCs) are signature features of stress-related maladies. Recent evidence suggests a possible role of the tryptophan metabolite kynurenic acid (KYNA) in this context. Here we investigated possible causal relationships in adult male rats, using stress-induced fear discrimination as a translationally relevant behavioral outcome measure. One week following adrenalectomy (ADX) or sham surgery, animals were for 2 h either physically restrained or exposed to a predator odor, which caused a much milder stress response. Extracellular KYNA levels were determined before, during and after stress by in vivo microdialysis in the prefrontal cortex. Separate cohorts underwent a fear discrimination procedure starting immediately after stress termination. Different auditory conditioned stimuli (CS) were either paired with a foot shock (CS+) or non-reinforced (CS-). One week later, fear was assessed by re-exposing the animals to each CS. Separate groups of rats were treated with the KYNA synthesis inhibitor BFF-816 prior to stress initiation to test a causal role of KYNA in fear discrimination. Restraint stress raised extracellular KYNA levels by ∼85 % in ADX rats for several hours, and these animals were unable to discriminate between CS+ and CS-. Both effects were prevented by BFF-816 and were not observed after exposure to predator odor or in sham-operated rats. These findings suggest that a causal connection exists between adrenal function, stress-induced KYNA increases, and behavioral deficits. Pharmacological inhibition of KYNA synthesis may therefore be an attractive, novel option for the treatment of stress-related disorders.

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.

Contributions of the retrosplenial and posterior parietal cortices to cue-specific and contextual fear conditioning.

The retrosplenial cortex (RSP) and the posterior parietal cortex (PPC) are the primary sources of cortical sensory input to the postrhinal cortex (POR) in rodents. Together, these areas compose a major corticohippocampal circuit that is involved in processing visuospatial information. The POR has been implicated in contextual learning and memory, consistent with the type of information presumably being processed by this region. By comparison, little is known about the role of the RSP or the PPC in contextual learning. In the present study, rats were trained either before or after surgery in a standard signaled fear conditioning task in which an auditory cue was paired with foot shock. Contextual fear and tone-specific fear were assessed in subsequent test sessions. In Experiment 1, electrolytic damage to the RSP either before or immediately after training impaired the expression of contextual fear but not tone-specific fear. In contrast, electrolytic damage to the PPC had no effect on conditional fear to the context or the tone in Experiment 2. These findings indicate that the RSP, but not the PPC, contributes to the processing of contextual information by the POR corticohippocampal processing stream. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Physical exercise and catecholamine reuptake inhibitors affect orienting behavior and social interaction in a rat model of attention-deficit/hyperactivity disorder.

The effects of methylphenidate (MPH), atomoxetine (ATMX), and/or physical exercise (EX) on orienting behavior and social interaction were examined in spontaneously hypertensive rats (SHRs), a commonly used animal model of attention-deficit/hyperactivity disorder (ADHD). During the orienting procedure, rats received repeated presentations of a nonreinforced visual stimulus. As observed previously, orienting behavior (rearing up on the hind legs) habituated across trials in normo-active control rats (Wistars) but not in SHRs, suggesting that SHRs have difficulty ignoring irrelevant behavioral stimuli. Treatment with MPH (0.125 mg/kg), ATMX (0.125 mg/kg), or EX (3 weeks of access to a running wheel), alone or in combination, reduced rearing behavior in SHRs to the level observed in the Wistar control group. Similarly, drug treatment and/or EX reduced the number of social interactions exhibited by SHRs, while having no effects on locomotor activity. It is important to note that EX was just as effective as MPH or ATMX in reducing orienting behavior and social interaction. In contrast to the SHRs, neither MPH nor ATMX affected orienting or social behavior in Wistar rats. Together, these findings support the growing literature that EX may be useful as an adjunctive or replacement therapy in ADHD. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

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).

Contributions of postrhinal and perirhinal cortex to contextual information processing.

The role of the postrhinal cortex (POR) and the perirhinal cortex (PER) in processing relational or contextual information was examined with Pavlovian fear conditioning. Rats with electrolytic or neurotoxic lesions of the POR or PER were tested in 2 contextual fear conditioning paradigms. In Experiment 1, electrolytic lesions of the POR or PER produced impairments in contextual fear conditioning but not in conditioning to a phasic auditory conditioned stimulus. Neurotoxic lesions of the POR or PER likewise resulted in anterograde (Experiment 2) and retrograde (Experiment 3) deficits in fear conditioning to the training context in an unsignaled shock paradigm. The results suggest that operations performed on sensory information by the POR and PER are necessary to support contextual learning. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Dreadds: Use and application in behavioral neuroscience.

Technological advances over the last decade are changing the face of behavioral neuroscience research. Here we review recent work on the use of one such transformative tool in behavioral neuroscience research, chemogenetics (or Designer Receptors Exclusively Activated by Designer Drugs, DREADDS). As transformative technologies such as DREADDs are introduced, applied, and refined, their utility in addressing complex questions about behavior and cognition becomes clear and exciting. In the behavioral neuroscience field, remarkable new findings now regularly appear as a result of the ability to monitor and intervene in neural processes with high anatomical precision as animals behave in complex task environments. As these new tools are applied to behavioral questions, individualized procedures for their use find their way into diverse labs. Thus, "tips of the trade" become important for wide dissemination not only for laboratories that are using the tools but also for those who are interested in incorporating them into their own work. Our aim is to provide an up-to-date perspective on how the DREADD technique is being used for research on learning and memory, decision making, and goal-directed behavior, as well as to provide suggestions and considerations for current and future users based on our collective experience. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Spatial learning in male and female Long-Evans rats.

Male and female Long-Evans rats were tested in the Morris water maze at 6 months of age. A place training procedure, in which rats learned the position of a camouflaged platform, was followed by cue training, in which rats escaped to a visible platform. No sex difference was found in place learning ability. Search accuracy on probe trials, when the platform was unavailable, was also equivalent for the male and female groups. These results contrast with previous studies of rodents at younger ages, which have reported a male advantage in spatial learning. It is suggested that the age at which rats are assessed may be an important factor, possibly reflecting a different course in the relatively protracted maturation of the hippocampus in male and female rats. The results of this investigation are also discussed with reference to studies of sex differences for spatial abilities in humans. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

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).

Stress-induced impairment in fear discrimination is causally related to increased kynurenic acid formation in the prefrontal cortex.

RATIONALE: Stress is related to cognitive impairments which are observed in most major brain diseases. Prior studies showed that the brain concentration of the tryptophan metabolite kynurenic acid (KYNA) is modulated by stress, and that changes in cerebral KYNA levels impact cognition. However, the link between these phenomena has not been tested directly so far. OBJECTIVES: To investigate a possible causal relationship between acute stress, KYNA, and fear discrimination. METHODS: Adult rats were exposed to one of three acute stressors-predator odor, restraint, or inescapable foot shocks (ISS)-and KYNA in the prefrontal cortex was measured using microdialysis. Corticosterone was analyzed in a subset of rats. Another cohort underwent a fear discrimination procedure immediately after experiencing stress. Different auditory conditioned stimuli (CSs) were either paired with foot shock (CS+) or were non-reinforced (CS-). One week later, fear was assessed by re-exposing rats to each CS. Finally, to test whether stress-induced changes in KYNA causally impacted fear discrimination, a group of rats that received ISS were pre-treated with the selective KYNA synthesis inhibitor PF-04859989. RESULTS: ISS caused the greatest increase in circulating corticosterone levels and raised extracellular KYNA levels by ~ 85%. The two other stressors affected KYNA much less (< 25% increase). Moreover, only rats that received ISS were unable to discriminate between CS+ and CS-. PF-04859989 abolished the stress-induced KYNA increase and also prevented the impairment in fear discrimination in animals that experienced ISS. CONCLUSIONS: These findings demonstrate a causal connection between stress-induced KYNA increases and cognitive deficits. Pharmacological manipulation of KYNA synthesis therefore offers a novel approach to modulate cognitive processes in stress-related disorders.

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).

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 damage produces retrograde and anterograde context amnesia using strong fear conditioning procedures.

Contextual fear conditioning relies upon a network of cortical and subcortical structures, including the hippocampus and the retrosplenial cortex (RSC). However, the contribution of the hippocampus is parameter-dependent. For example, with "weak" training procedures, lesions of the hippocampus produce both retrograde and anterograde context amnesia. However, with "strong" training procedures (e.g., more trials and/or higher levels of footshock), lesions of the hippocampus produce retrograde context amnesia but not anterograde amnesia (Wiltgen et al., 2006). Likewise, prior studies have shown that with weak training, RSC lesions produce both retrograde and anterograde context amnesia (Keene & Bucci, 2008). The purpose of the current study was to examine the effects of RSC damage on contextual fear conditioning following strong training. In Experiment 1, lesions of the RSC resulted in both retrograde and anterograde context amnesia following strong training using the same unsignaled fear conditioning procedures described by Wiltgen et al. (2006). In Experiment 2, using a signaled fear conditioning procedure, we replicated these effects on context memory observing both retrograde and anterograde context amnesia. In contrast, there were no lesion effects on tone-fear memory. Thus, unlike lesions of the hippocampus, lesions of RSC produce both retrograde and anterograde context amnesia even when rats undergo strong fear conditioning. These findings suggest that the RSC has an essential role in contextual fear conditioning and that other systems or pathways are unable to compensate for the loss of RSC function.

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.

Introduction to the special issue on the cognitive functions of the retrosplenial cortex.

This special issue on the cognitive functions of the retrosplenial cortex highlights progress that has been made in recent years in understanding the anatomy and function of the retrosplenial cortex in both animals and humans. The articles in this issue of Behavioral Neuroscience use a number of different approaches that together provide an up-to-date account of recent progress in understanding how the retrosplenial cortex contributes to cognition, with an emphasis on its functional role in spatial navigation and learning and memory. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

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).

Increased sign-tracking behavior in adolescent rats.

An autoshaping procedure was used to test the notion that conditioned stimuli (CSs) gain greater incentive salience during adolescence than young adulthood under conditions of social isolation rearing and food restriction. Rats were single-housed and placed on food restriction during 10 daily training sessions in which a lever (CS+ ) was presented then followed immediately by a food unconditioned stimulus (US). A second lever (CS- ) was presented on intermixed trials and was not reinforced. Despite the fact that food delivery was not contingent on the rats' behavior, all rats exhibited behaviors directed towards the lever (i.e., sign-tracking). In the adolescent group, the rate of lever pressing and the percentage of trials with a lever press were higher than in young adults. Initially, group differences were observed when rats were retrained when the adolescents had reached young adulthood. These findings support the hypothesis that cues that come to predict reward become imbued with excessive motivational value in adolescents, perhaps contributing to the hyper-responsiveness to reward-related stimuli typically observed during this period of development.

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