Specific brain circuits have been classically linked to dedicated functions. However, compensation following brain damage suggests that these circuits are capable of dynamic adaptation. Such compensation is exemplified by Pavlovian fear conditioning following damage to the dorsal hippocampus (DH). Although the DH normally underlies contextual fear and fear renewal after extinction, both can be learned in the absence of the DH, although the mechanisms and nature of this compensation are currently unknown. Here, we report that recruitment of alternate structures, specifically the infralimbic and prelimbic prefrontal cortices, is required for compensation following damage to the hippocampus. Disconnection of these cortices in DH-compromised animals and immediate early gene induction profiles for amygdala-projecting prefrontal cells revealed that communication and dynamic rebalancing within this prefrontal microcircuit is critical. Additionally, the infralimbic cortex normally plays a role in limiting generalization of contextual fear. These discoveries reveal that plasticity through recruitment of alternate circuits allows the brain to compensate following damage, offering promise for targeted treatment of memory disorders.anxiety | recovery of function | amnesia | medial prefrontal cortex A widely accepted view is that the brain is comprised of multiple independent circuits dedicated to performing specific functions and encoding specific information. This view is exemplified in the field of learning and memory, where it is held that different circuits specialize in integrating and storing different classes of memories (1). However, studies looking at learning following brain damage clearly demonstrate that the brain can also behave dynamically. For example, in Pavlovian fear conditioning, contextual memories can be formed in the absence of circuits classically thought to underpin integration and storage of information about an animal's environment or context (2).In fear conditioning, contexts play two key roles in controlling fear learning and expression. First, a context can act as a conditional stimulus (CS), to which fear can be directly conditioned when an aversive experience, such as a foot shock [unconditional stimulus (US)] is signaled by the context. Second, contexts can modulate responding to a discrete cue, such as a tone-CS, which has acquired multiple meanings. For example, in extinction, a tone previously conditioned to elicit fear is presented in the absence of the aversive foot shock US, such that the conditional fear response begins to extinguish. However, because extinction is not an erasure of the original fear but rather new learning that interferes with retrieval of the original fear memory, an extinguished cue has multiple meanings (shock/no shock), which compete for behavioral expression (3). This competition is mediated by context, as fear renewal occurs when an extinguished stimulus is presented outside of the extinction context (4).These context-sensitive effects provide excellent models t...

Background Fears that are maladaptive or inappropriate can be reduced through extinction training. However, extinction is highly context-sensitive, resulting in the renewal of fear following shifts in context, and limiting the clinical efficacy of extinction training. Lesion and inactivation studies have shown that the contextualization of extinction depends on the hippocampus. Parallel studies have found that intrahippocampal scopolamine blocks contextual fear conditioning. Importantly, this effect was replicated using a non-invasive technique in which a low dose of scopolamine was administered systemically. We aimed to transfer the effects of this non-invasive approach to block the contextualization of fear extinction. Methods Rats were tone fear conditioned and extinguished under various systemic doses of scopolamine or the saline vehicle. They were subsequently tested (off drug) for tone fear in a context that was the same (controls) or shifted (renewal group) with respect to the extinction context. Results The lowest dose of scopolamine produced a significant attenuation of fear renewal when renewal was tested either in the original training context or a novel context. The drug also slowed the rate of long-term extinction memory formation, which was readily overcome by extending extinction training. Scopolamine only gave this effect when it was administered during, but not after extinction training. Higher doses of scopolamine severely disrupted extinction learning. Conclusions We discovered that disrupting contextual processing during extinction with the cholinergic antagonist scopolamine blocked subsequent fear renewal. Low doses of scopolamine may be a clinically promising adjunct to exposure therapy by making extinction more relapse-resistant.