Prefrontal microcircuit underlies contextual learning after hippocampal loss.

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.

Cholinergic blockade frees fear extinction from its contextual dependency.

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 after 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 (Scop) blocks contextual fear conditioning. Importantly, this effect was replicated with a noninvasive technique in which a low dose of Scop was administered systemically. We aimed to transfer the effects of this noninvasive approach to block the contextualization of fear extinction. METHODS: Rats were tone fear conditioned and extinguished under various systemic doses of Scop or the saline vehicle. They were subsequently tested (off drug) for tone fear in a context that was the same (control subjects) or shifted (renewal group) with respect to the extinction context. RESULTS: The lowest dose of Scop 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 Scop severely disrupted extinction learning. CONCLUSIONS: We discovered that disrupting contextual processing during extinction with the cholinergic antagonist Scop blocked subsequent fear renewal. Low doses of Scop might be a clinically promising adjunct to exposure therapy by making extinction more relapse-resistant.