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PSYC 3832 NEURAL BASIS OF LEARNING Week 9 Chapter 11 TIAN YU, PhD Department of Psychology College of Liberal Arts and Sciences A Labile STM Trace Evolves into a Stable LTM Shortly after an experience, memory retrieval is supported by an active short-term trace. As this trace decays, a more stable, long-term memory trace is generated that can support memory retrieval for a much longer period of time. The Generic Research Paradigm This figure illustrates the generic research design for determining the contribution of a particular molecule(s) to memory storage. A drug or gene is evaluated by assessing its effect on memory at two retention intervals—a short interval (1 to 2 hours) designed to assess short-term memory (STM) and a longer interval, usually about 24 hours, designed to assess long-term memory (LTM). The Research Paradigm: Hypothetical Outcomes (A) The drug targeted at Mx impaired performance at the 24-hour retention interval but had no effect at the 1-hour retention interval. This result is consistent with the hypothesis that Mx is important for the consolidation of the long-term memory trace and is not critical for the short-term memory trace. (B) The treatment impaired performance at both the 1-hour and 24-hour retention intervals. This result is consistent with the hypothesis that Mx contributes to both short-term and long-term memory but is also consistent with other interpretations. Transcription and Enduring Memories: CREB A behavioral experience such as inhibitory avoidance training initiates a genomic signaling cascade that results in new plasticity products (mRNA and protein) needed to consolidate the memory for the experience. (Photo courtesy of James McGaugh.) Transcription and Enduring Memories: CREB Deletion Rusiko Bourtchouladze Mice genetically engineered to repress CREB display fear when tested 3 hours after training but not when tested 24 hours after training. These results are consistent with the hypothesis that long-term memory but not short-term memory requires plasticity products transcribed by CREB. (After Bourtchouladze et al., 1994.) Transcription and Enduring Memories: CREB Overexpression This graph illustrates the results of a long-term memory test when the inter-trial interval (ITI)—the time separating light– shock conditioning trials—was either 10 seconds or 8 minutes. Note that long-term memory was poor when the ITI was 10 seconds compared to when the ITI was 8 minutes. (B) This graph shows that injecting a virus that expresses CREB into the lateral amygdala (LA) prior to the conditioning trials can eliminate the impaired long-term memory normally found when the ITI is only 10 seconds. Translation and Enduring Memories: The De Novo Protein Synthesis Hypothesis (A) Anisomycin injected immediately after training disrupts retention performance at the 6- and 24-hour retention intervals but not at the 1-hour interval. (B) The effect of anisomycin depends on the interval between training and the injection. It interfered with memory formation only when it was given immediately (0 hour) after training. This result indicates that the consolidation process was about 3 hours. (After Bourtchouladze et al., 1998.) The De Novo Protein Synthesis Hypothesis: Methodological Issues In addition to blocking protein synthesis, anisomycin has other effects on neurons. The drug is toxic and can kill neurons. It also causes an excessive release of neurotransmitters in the region of the injection and induces genomic signaling cascades in the neuron that result in an overproduction of mRNAs. These additional effects make it difficult to accept the conclusion that the reason anisomycin disrupts memory consolidation is that it inhibits protein synthesis. The De Novo Protein Synthesis Hypothesis: Methodological Issues Anisomycin directly injected into the brain can prevent the consolidation of the memory trace. However, these infusions also have major side effects. Strong conclusion from the use of general protein synthesis inhibitors: if the memory is not impaired then it does not depend on new protein, only on post-translation processes. Protein Degradation Also Contributes to Memory Consolidation Protein Degradation Also Contributes to Memory Consolidation Protein degradation is important for long-term fear memories. (A) Fear conditioning (FC) induces polyubiquitination in the amygdala. This process is prevented by the NMDA antagonist ifrenprodil. (B) The proteasome inhibitor βlactone (βlac) impairs both cued and contextual fear conditioning. These results indicate that protein degradation is critical for consolidating long-term fear memories. (After Jarome et al., 2011.) Memory Consolidation Processes Operate in at least Three Waves