Prefrontal microcircuit underlies contextual learning after hippocampal loss

Abstract

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...

Activity in prelimbic cortex subserves fear memory reconsolidation over time

“…Of note, the AC cortex has also been shown to have a corresponding role with the PL cortex in contextual memory reconsolidation over time (Einarsson and Nader 2012). Moreover, both the PL and AC cortices are alternate structures required for compensation during aversive memory processing following prolonged inhibition or damage to the hippocampus (Goshen et al 2011;Zelikowsky et al 2013).…”

Fear Memory

“…The recent finding by Michael Fanselow's group that in animals in which the hippocampus is removed surgically, microcircuits in PL and in IL take over its functions in CFC acquisition and extinction (680), makes things even more complex. Accounts of purported mechanisms for these behavioral processes were not prepared to include vicarious roles for the vmPFC (58,98,116,121,229,310,421,598).…”

“…Admitting that different brain areas may participate concurrently in a given task is not a break of canonical wisdom; it may simply be accepting what a considerable array of evidence suggests (93,273,380,680). …”

Neural Structures Mediating Expression and Extinction of Platform-Mediated Avoidance

“…The lack of effect on freezing contrasts with our previous fear-conditioning studies, in which PL inactivation reduced both freezing and suppression of bar pressing to a conditioned tone (Sierra-Mercado et al, 2011). Platform-mediated avoidance requires many more days of training than fear conditioning (10 d vs 1 d), which may recruit additional regions into the freezing circuit (Poulos et al, 2010;Zelikowsky et al, 2013). Unit recording data will be needed to further understand the role of PL in avoidance.…”