Infralimbic cortex controls fear memory generalization and susceptibility to extinction during consolidation

Abstract

Lesioning or inactivating the infralimbic (IL) subregion of the medial prefrontal cortex before acquisition produces more generalized and extinction-resistant fear memories. However, whether and how it modulates memory specificity and extinction susceptibility while consolidation takes place is still unknown. The present study aims to investigate these questions using muscimol-induced temporary inactivation and anisomycin-induced protein synthesis inhibition in the rat IL following contextual fear conditioning. Results indicate that the IL activity immediately after acquisition, but not six hours later, controls memory generalization over a week, regardless of its strength. Such IL function depends on the context-shock pairing since muscimol induced no changes in animals exposed to immediate shocks or the conditioning context only. Animals in which the IL was inactivated during consolidation extinguished similarly to controls within the session but were unable to recall the extinction memory the following day. Noteworthy, these post-acquisition IL inactivation-induced effects were not associated with changes in anxiety, as assessed in the elevated plus-maze test. Anisomycin results indicate that the IL protein synthesis during consolidation contributes more to producing extinction-sensitive fear memories than memory specificity. Collectively, present results provide evidence for the IL's role in controlling generalization and susceptibility to extinction during fear memory consolidation.

The Three Musketeers in the Medial Prefrontal Cortex: Subregion-specific Structural and Functional Plasticity Underlying Fear Memory Stages

“…Inactivation of IL with muscimol and lidocaine before extinction learning was sufficient to impair the consolidation of extinction learning [55,56]. Finally, treatment with the protein synthesis inhibitor anisomycin before extinction training affected the reconsolidation of extinction training and susceptibility to extinction training [56,57].…”

The Medial Prefrontal Cortex and Fear Memory: Dynamics, Connectivity, and Engrams

“…Two neuronal subpopulations encoding either fear or safety after extinction were identified, both projecting to the mPFC but part of distinct neuronal circuits: BLA fear neurons received input mainly from the ventral HPC and extinction neurons from the mPFC. Subsequent studies confirmed that fear and extinction neurons project to the PL or the IL, respectively [71][72][73].…”

“…This theory would explain how new schemas can be integrated faster into an existing framework that was previously learned [88]. It is supported by studies highlighting the role of the HPC at late times post-encoding [49,63], of the mPFC at early times [9,10,[53][54][55][56]71], as well as by reports of distributed engram cells throughout the brain [31,39,[89][90][91][92][93].…”

“…Several findings have in the meantime challenged this standard model. On the one side, cortical areas were shown to be involved in early phases of memory formation as well [9,10,[53][54][55][56]71], and on the other side, the HPC was also found to be necessary for the recall of remote memories, and not only recent ones, by means of pharmacological [63] as well as optogenetic inhibition [49]. Precisely, an acute optogenetic inhibition of CA1 during remote recall impaired memory, but a prolonged inhibition that started before the recall itself did not impair memory and resulted in increased cFos expression in ACC, which suggested the recruitment of alternative cortical circuits when the HPC is inhibited for an extended period of time [49].…”

Direct Thalamic Inputs to Hippocampal CA1 Transmit a Signal That Suppresses Ongoing Contextual Fear Memory Retrieval

“…The input driving the NR-CA1 pathway is most likely from the mPFC, encompassing both the prelimbic (PL) and infralimbic (IL) regions. While PL is needed for fear acquisition and retrieval, IL is necessary for the opposing task of fear suppression and preventing overgeneralization [56][57][58][59] . The likely opposing influences of IL and PL on NR during CFMR illustrates the importance of understanding NR output pathways.…”