Abstract
BackgroundAssociative conditioning is a ubiquitous form of learning throughout the animal kingdom and fear conditioning is one of the most widely researched models for studying its neurobiological basis. Fear conditioning is also considered a model system for understanding phobias and anxiety disorders. A fundamental issue in fear conditioning regards the existence and location of neurons in the brain that receive convergent information about the conditioned stimulus (CS) and unconditioned stimulus (US) during the acquisition of conditioned fear memory. Convergent activation of neurons is generally viewed as a key event for fear learning, yet there has been almost no direct evidence of this critical event in the mammalian brain.Methodology/Principal FindingsHere, we used Arc cellular compartmental analysis of temporal gene transcription by fluorescence in situ hybridization (catFISH) to identify neurons activated during single trial contextual fear conditioning in rats. To conform to temporal requirements of catFISH analysis we used a novel delayed contextual fear conditioning protocol which yields significant single- trial fear conditioning with temporal parameters amenable to catFISH analysis. Analysis yielded clear evidence that a population of BLA neurons receives convergent CS and US information at the time of the learning, that this only occurs when the CS-US arrangement is supportive of the learning, and that this process requires N-methyl-D-aspartate receptor activation. In contrast, CS-US convergence was not observed in dorsal hippocampus.Conclusions/SignificanceBased on the pattern of Arc activation seen in conditioning and control groups, we propose that a key requirement for CS-US convergence onto BLA neurons is the potentiation of US responding by prior exposure to a novel CS. Our results also support the view that contextual fear memories are encoded in the amygdala and that the role of dorsal hippocampus is to process and transmit contextual CS information.
Highlights
Neurobiological models of basic associative conditioning propose that neurons critical to learning receive convergent information from pathways responsive to the conditioned stimulus (CS) and unconditioned stimulus (US), and that activity-dependent changes in these neurons encode the formation of the associative memory trace [1,2,3]
In mammalian fear conditioning, where an initially innocuous CS becomes capable of evoking conditioned fear responses (CRs) after contingent pairing with an aversive US [4,5], long-lasting synaptic plasticity and learning-induced changes in cellular and molecular activity have been demonstrated in the BLA, a brain region implicated in the encoding of fear memory [6,7,8,9,10,11]
Animals can acquire long-term fear associations when a novel context is paired with shock 26 minutes later (DS group), but not when a familiar context is paired with shock (LI group)
Summary
Neurobiological models of basic associative conditioning propose that neurons critical to learning receive convergent information from pathways responsive to the CS and US, and that activity-dependent changes in these neurons encode the formation of the associative memory trace [1,2,3]. In mammalian fear conditioning, where an initially innocuous CS becomes capable of evoking conditioned fear responses (CRs) after contingent pairing with an aversive US [4,5], long-lasting synaptic plasticity and learning-induced changes in cellular and molecular activity have been demonstrated in the BLA (basal and lateral nuclei of the amygdala), a brain region implicated in the encoding of fear memory [6,7,8,9,10,11]. CatFISH analysis of sections from both the BLA (the putative site of fear conditioning) [6,7,8,9,10,11] and dorsal hippocampus (implicated in processing context-spatial information) [20,21,22,23], allowed us to determine whether neurons in these regions are dually activated by the CS and US during acquisition of conditioned fear
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