A requirement for memory retrieval during and after long-term extinction learning

Abstract

Current learning theories are based on the idea that learning is driven by the difference between expectations and experience (the delta rule). In extinction, one learns that certain expectations no longer apply. Here, we test the potential validity of the delta rule by manipulating memory retrieval (and thus expectations) during extinction learning. Adrenergic signaling is critical for the timelimited retrieval (but not acquisition or consolidation) of contextual fear. Using genetic and pharmacologic approaches to manipulate adrenergic signaling, we find that long-term extinction requires memory retrieval but not conditioned responding. Identical manipulations of the adrenergic system that do not affect memory retrieval do not alter extinction. The results provide substantial support for the delta rule of learning theory. In addition, the timing over which extinction is sensitive to adrenergic manipulation suggests a model whereby memory retrieval occurs during, and several hours after, extinction learning to consolidate long-term extinction memory.M odern learning theories are based on the detection of a mismatch between expectations and experience (the delta rule) (1-5), with expectations depending on the retrieval of past experiences. When an organism is naïve, there are no relevant memories (expectations) to retrieve, and learning may occur because of the large difference (delta) between experience and the lack of any expectations. In extinction, however, one learns that a previously acquired association, outcome, or concept no longer applies, at least under some circumstances (6-9). According to learning theories based on the delta rule, the process of extinction begins when an expected event fails to occur. Thus, it is postulated that memory for the expected event must be retrieved during extinction learning. On the other hand, extinction learning could proceed in the absence of retrieval, similar to what may occur for naïve learning; however, this situation would be contrary to learning theories based on the delta rule. Thus, examining the requirement for memory retrieval in extinction learning provides an opportunity to test a fundamental tenet of modern learning theories. This hypothesis has been difficult to examine because it has not been clear how to specifically block memory retrieval under conditions that elicit extinction.Pavlovian conditioning is a learning paradigm in which neutral stimuli become associated with a salient event (unconditioned stimulus, US) (10). Neutral stimuli become conditioned stimuli (CSs) that predict the US and elicit a conditioned response (CR). This simple form of associative learning has been widely used to study learning and memory in humans and animals (11). A paradigm for rapid Pavlovian learning, fear conditioning results in robust associative memory after a single experience. In one training session, rodents can learn to associate CSs such as the apparatus (context) and a cue (e.g., tone) with shock. Extinction of fear occurs when there is sufficient exposure to a...

Mechanisms of fear extinction

“…Ouyang and Thomas 270 focused on the contribution of norepinephrine to fear extinction to the extent that it is required for fear memory retrieval. A previous report from their laboratory indicated that adrenergic signaling within the dorsal hippocampus 2 h-4 days after acquisition, but not at other times, is required for retrieval of context fear memory but not tone fear memory.…”

“…A previous report from their laboratory indicated that adrenergic signaling within the dorsal hippocampus 2 h-4 days after acquisition, but not at other times, is required for retrieval of context fear memory but not tone fear memory. 271 As error-correction accounts of extinction rely on retrieval of the current predictive value of the CS with respect to the US in order to drive learning, Ouyang and Thomas 270 hypothesized that extinction should be impaired by pharmacologic or genetic impairment of adrenergic signaling when such signaling is required for fear memory retrieval, but not otherwise. Consistent with this, when context extinction training occurred 1 day after acquisition, extinction (tested later) was impaired in mutant mice lacking both copies of the dopamine b-hydroxylase gene (DbhÀ/À), which codes for the enzyme that converts dopamine to norepinephrine in norepinephrine neurons, and in phenotypically normal heterozygous mutants (Dbh þ /À) administered the adrenergic antagonists propranolol or CGP 20712A before extinction training.…”

“…Interestingly, the lack of impairment of DbhÀ/À mice in tone fear extinction or context fear extinction 5 days after acquisition (see above) indicates that both the first and second windows of adrenergic involvement are time-limited. Ouyang and Thomas 270 proposed that the second window corresponds to a second wave of memory retrieval that occurs in the hours following the completion of extinction training.…”

Inhibition of β-Adrenergic Receptors Induces a Persistent Deficit in Retrieval of a Cocaine-Associated Memory Providing Protection against Reinstatement

“…Furthermore, it is well accepted that norepinephrine facilitates, rather than impedes, memory formation through b-receptor activation (McGaugh, 2000). Finally, research has demonstrated that propranolol impairs extinction learning (for review see Mueller and Cahill, 2010) in both aversive (Do-Monte et al, 2010;Merlo and Izquierdo, 1967;Mueller et al, 2008;Ouyang and Thomas, 2005) and appetitive paradigms (LaLumiere et al, 2010).…”

Pharmacological Discrimination of Extinction and Reconsolidation of Contextual Fear Memory by a Potentiator of AMPA Receptors

“…The reexposure reactivates the fear memory, which induces reconsolidation of the memory first, and then extinction of the fear response (Myers and Davis, 2002;Ouyang and Thomas, 2005;Suzuki et al, 2004). Reconsolidation is a process that results in a persistent or greater fear response once consolidated memory is destabilized and reconstructed into a more stable state by short exposure to a CS (Sara, 2000;Nader et al, 2000).…”