Fear renewal preferentially activates ventral hippocampal neurons projecting to both amygdala and prefrontal cortex in rats

Anxiety, trauma and stress-related disorders are often characterized by a loss of context-appropriate emotional responding. The contextual retrieval of emotional memory involves hippocampal projections to the medial prefrontal cortex and amygdala; however the relative contribution of these projections is unclear. To address this question, we characterized retrieval-induced Fos expression in ventral hippocampal (VH) neurons projecting to the prelimbic cortex (PL) and basal amygdala (BA) after the extinction of conditioned fear in rats. After extinction, freezing behavior (an index of learned fear) to the auditory conditioned stimulus was suppressed in the extinction context, but was “renewed” in another context. Hippocampal neurons projecting to either PL or BA exhibited similar degrees of context-dependent Fos expression; there were more Fos-positive neurons in each area after the renewal, as opposed, to suppression of fear. Importantly, however, VH neurons projecting to both PL and BA were more likely to express Fos during fear renewal than neurons projecting to either PL or BA alone. These data suggest that although projections from the hippocampus to PL and BA are similarly involved in the contextual retrieval of emotional memories, VH neurons with collaterals to both areas may be particularly important for synchronizing prefrontal-amygdala circuits during fear renewal

Ventral hippocampal muscimol disrupts context-specific fear memory retrieval after extinction in rats

Research aimed at understanding Pavlovian fear memory extinction has yielded considerable insight into the conditions under which fear memories may become inhibited. After extinction, Pavlovian fear memory retrieval is context-specific. Fear memories are not expressed in the extinction context, but they are expressed in every other context. Research indicates that the dorsal hippocampus mediates the context-specific expression of fear memory, but the role of the ventral hippocampus in mediating this process is unknown. Insofar as the ventral hippocampus is involved in the acquisition and expression of both context and tone fear, we asked whether GABA systems in the ventral hippocampus mediate context-specific fear memory retrieval after extinction. Experiment 1 showed that ventral hippocampal inactivation with muscimol disrupted context-specific fear memory retrieval. Experiment 2 showed that rats infused with muscimol can discriminate a context in which they were shocked from a neutral context. Nonetheless, they do appear to have a mild impairment in this task. Experiment 3 showed that ventral hippocampal muscimol did not disrupt locomotor activity, but did result in a slight increase in freezing and grooming, an effect that cannot explain the context-specific retrieval deficit demonstrated in experiment 1. These data are consistent with a role for the ventral hippocampus in mediating context-specific fear memory retrieval. © 2005 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/49533/1/20144_ftp.pd

Overtraining does not mitigate contextual fear conditioning deficits produced by neurotoxic lesions of the basolateral amygdala

The influence of overtraining on the magnitude of fear-conditioning deficits produced by neurotoxic lesions of the basolateral amygdala (BLA) was examined. Either 1 d before or 1 week after the administration of neurotoxic BLA lesions, rats received either 1 or 25 conditioning trials consisting of the delivery of unsignaled foot shock in a novel observation chamber; freezing served as the measure of conditional fear. In this conditioning paradigm, asymptotic performance is reached in five conditioning trials, and 25 conditioning trials constitutes an overtraining procedure. The results revealed that overtraining does not affect the magnitude of the contextual freezing deficits produced by post-training BLA lesions. Similarly, overtraining did not influence the level of reacquisition obtained by rats with post-training BLA lesions after 10 reacquisition trials. A similar pattern of results was observed in rats with pretraining BLA lesions. Neurotoxic BLA lesions did not alter either motor activity or shock reactivity. These results indicate that overtraining does not limit the important role of the BLA in the acquisition and expression of contextual fear conditioning.http://deepblue.lib.umich.edu/bitstream/2027.42/56227/1/marenJN98.pd

Neurotoxic basolateral amygdala lesions impair learning and memory but not the performance of conditional fear in rats

We examined the influence of extensive overtraining (75 trials) on the impact of neurotoxic basolateral amygdala (BLA) lesions on Pavlovian fear conditioning in rats. As we have shown previously, pretraining BLA lesions yielded severe deficits in the acquisition of conditional freezing in rats trained with either 1 or 25 conditioning trials. However, extensive overtraining (50 or 75 trials) mitigated deficits in conditional freezing. Under these conditions the rats with BLA lesions expressed normal and robust freezing behavior, although they required at least 10 times as much training as control rats to reach this level of performance. The ability of rats with BLA lesions to acquire and express conditional freezing after extensive overtraining was modality-specific; conditional freezing in individual rats was acquired to contextual, but not acoustic, conditional stimuli. These results suggest that neural circuitry outside of the amygdala can mediate contextual fear conditioning under some conditions. In contrast to pretraining lesions, post-training BLA lesions eradicated the memory for Pavlovian fear in rats trained with either 1 or 75 trials; this deficit was not modality-specific. Together, these results reveal that impairments in the acquisition and expression of conditional fear in rats with BLA lesions are not attributable to deficits in the performance of the freezing response but are attributable to disruptions in the learning and memory of Pavlovian fear conditioning.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/56236/1/marenJN99.pd

The Role of the Medial Prefrontal Cortex in the Conditioning and Extinction of Fear

Once acquired, a fearful memory can persist for a lifetime. Although learned fear can be extinguished, extinction memories are fragile. The resilience of fear memories to extinction may contribute to the maintenance of disorders of fear and anxiety, including post-traumatic stress disorder (PTSD). As such, considerable effort has been placed on understanding the neural circuitry underlying the acquisition, expression, and extinction of emotional memories in rodent models as well as in humans. A triad of brain regions, including the prefrontal cortex, hippocampus, and amygdala, form an essential brain circuit involved in fear conditioning and extinction. Within this circuit, the prefrontal cortex is thought to exert top-down control over subcortical structures to regulate appropriate behavioral responses. Importantly, a division of labor has been proposed in which the prelimbic (PL) and infralimbic (IL) subdivisions of the medial prefrontal cortex (mPFC) regulate the expression and suppression of fear in rodents, respectively. Here we critically review the anatomical and physiological evidence that has led to this proposed dichotomy of function within mPFC. We propose that under some conditions, the PL and IL act in concert, exhibiting similar patterns of neural activity in response to aversive conditioned stimuli and during the expression or inhibition of conditioned fear. This may stem from common synaptic inputs, parallel downstream outputs, or cortico-cortical interactions. Despite this functional covariation, these mPFC subdivisions may still be coding for largely opposing behavioral outcomes, with PL biased towards fear expression and IL towards suppression

Muscimol inactivation of the dorsal hippocampus impairs contextual retrieval of fear memory

Some models of hippocampal function have suggested a role of the hippocampus in contextual memory retrieval. We have examined this hypothesis by assessing the impact of reversible inactivation of the dorsal hippocampus (DH) on the context-specific expression of latent inhibition, a decrement in conditional responding produced by preexposure to a to-be-conditional stimulus. In Experiment 1, rats received tone preexposure either in the context that would later be used for extinction testing (context A) or in a different context (context C); a third group of rats did not receive tone preexposure. All rats then received fear conditioning, which consisted of tone-footshock pairings, in a third distinct context (context B). The following day conditional fear to the tone was assessed in one of the preexposure contexts (context A) by measuring freezing during a tone extinction test. Rats preexposed and tested in the same context exhibited less freezing to the tone than either rats preexposed and tested in different contexts or non-preexposed rats. These results indicate that the expression of latent inhibition is context specific. In Experiment 2, DH inactivation eliminated the context-specific expression of latent inhibition. Compared with saline-infused rats, rats infused with muscimol into the DH exhibited low levels of tone freezing independent of whether they had received tone preexposure in the test context or in a different context. Experiment 3 revealed normal contextual discrimination in rats after DH inactivation. These results suggest the DH is required for contextual memory retrieval in a latent inhibition paradigm.http://deepblue.lib.umich.edu/bitstream/2027.42/56237/1/holtJN99.pd