Abstract
Extinction of a conditioned association is typically viewed as the establishment of new learning rather than the erasure of the original memory. However, recent research in the nudibranch, Hermissenda crassicornis (H.c.) demonstrated that extinction training (using repeated light-alone presentations) given 15 min, but not 23 h, after memory acquisition reversed both the cellular correlates of learning (enhanced Type B cell excitability) and the behavioral changes (reduced phototaxis) produced by associative conditioning (pairings of light, CS, and rotation, US). Here, we investigated the putative molecular signaling pathways that underlie this extinction in H.c. by using a novel in vitro protocol combined with pharmacological manipulations. After intact H.c. received either light-rotation pairings (Paired), random presentations of light and rotation (Random), or no stimulation (Untrained), B cells from isolated CNSs were recorded from during exposure to extinction training consisting of two series of 15 consecutive light-steps (LSs). When in vitro extinction was administered shortly (2 h, but not 24 h) after paired training, B cells from Paired animals showed progressive and robust declines in spike frequency by the 30th LS, while control cells (Random and Untrained) did not. We found that several molecules implicated in H.c. conditioned inhibitory (CI) learning, protein phosphatase 1 (PP1) and arachidonic acid (AA)/12-lipoxygenase (12-LOX) metabolites, also contributed to the spike frequency decreases produced by in vitro extinction. Protein phosphatase 2B (PP2B) also appeared to play a role. Calyculin A (PP1 inhibitor), cyclosporin A (PP2B inhibitor), and baicalein (a 12-LOX inhibitor) all blocked the spike frequency declines in Paired B cells produced by 30 LSs. Conversely, injection of catalytically-active PP1 (caPP1) or PP2B (caPP2B) into Untrained B cells partially mimicked the spike frequency declines observed in Paired cells, as did bath-applied AA, and occluded additional LS-produced reductions in spiking in Paired cells.
Highlights
After an association has been formed between a conditioned stimulus (CS) and an unconditioned stimulus (US), repeated presentations of the CS without the US result in the reduction of the conditioned response (CR), a process known as extinction (Pavlov, 1927)
Because these methods produce many of the same learning-produced alterations in B cell excitability and phototactic behavior elicited by paired training in vivo, the current procedure consisting of LSs presented to isolated CNSs was used to act as a substitute for whole-animal extinction training (e.g., Richards et al, 1984)
Our results indicated that both phosphatase- and lipidsignaling pathways appeared to be involved in the reductions in B cell excitability produced by in vitro extinction
Summary
After an association has been formed between a conditioned stimulus (CS) and an unconditioned stimulus (US), repeated presentations of the CS without the US result in the reduction of the conditioned response (CR), a process known as extinction (Pavlov, 1927). The fact that the original associative memory can reappear after extinction training has led to a pervasive view that extinction involves the formation of new fragile, contextdependent learning that counteracts or inhibits the original learning (Rescorla and Cunningham, 1978; Robbins, 1990; Bouton, 1994). Recent research has indicated that, under certain conditions, extinction can “erase” the original associative memory, without reappearance of the original CR (Monfils et al, 2009; Schiller et al, 2010). Apparent erasure has been observed on the cellular level, where extinction training abolished the behavioral effects of associative fear conditioning and reversed conditioning-produced insertion of AMPA GluR1 receptors in mouse (Clem and Huganir, 2010) and rat (Mao et al, 2006) amygdala neurons. In Mao et al (2006), extinction-produced cellular erasure effects were only observed when extinction was given shortly (1 h, but not 24 h) after the end of learning acquisition, suggesting that erasure might be sensitive to specific acquisitionextinction intervals
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