Commonalities and Differences in the Substrates Underlying Consolidation of First- and Second-Order Conditioned Fear

• Published in: The Journal of neuroscience 2018-02, Vol.38 (8), p.1926-1941
• Main Authors: Lay, Belinda P P, Westbrook, R Frederick, Glanzman, David L, Holmes, Nathan M
• Format: Article
• Language: English
• Subjects: Amygdala; Animals; Anxiety; Basolateral Nuclear Complex - physiology; Conditioning; Conditioning, Classical; Consolidation; Cues; Deoxyribonucleic acid; DNA; DNA methylation; DNA Methylation - physiology; Fear; Fear - physiology; Fear conditioning; Hazards; Information processing; Learning; Male; Memory; Memory Consolidation - physiology; Pharmacology; Protein biosynthesis; Protein synthesis; Proteins; Rats; Rats, Sprague-Dawley; Substrates; Transcription, Genetic - physiology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.2966-17.2018

Consolidation of newly formed fear memories requires a series of molecular events within the basolateral complex of the amygdala (BLA). Once consolidated, new information can be assimilated into these established associative networks to form higher-order associations. Much is known about the molecular events involved in consolidating newly acquired fear memories but little is known about the events that consolidate a secondary fear memory. Here, we show that, within the male rat BLA, DNA methylation and gene transcription are crucial for consolidating both the primary and secondary fear memories. We also show that consolidation of the primary, but not the secondary, fear memory requires protein synthesis in the BLA. These findings show that consolidation of a fear memory and its updating to incorporate new information recruit distinct processes in the BLA, and suggest that DNA methylation in the BLA is fundamental to consolidation of both types of conditioned fear. Our data provide clear evidence that a different set of mechanisms mediate consolidation of learning about cues that signal learned sources of danger (i.e., second-order conditioned fear) compared with those involved in consolidation of learning about cues that signal innate sources of danger (i.e., first-order conditioned fear). These findings carry important implications because second-order learning could underlie aberrant fear-related behaviors (e.g., in anxiety disorders) as a consequence of neutral secondary cues being integrated into associative fear networks established through first-order pairings, and thereby becoming potent conditioned reinforcers and predictors of fear. Therefore, our data suggest that targeting such second-order conditioned triggers of fear may require pharmacological intervention different to that typically used for first-order conditioned cues.