October 20

Molecular routes of memory enhancement

Most students are no strangers to cognitive enhancers such as caffeine or Adderall. However, these and other cognitive enhancers tend to have non-specific effects on the nervous system (e.g., jitteriness), or are specifically formulated for a disease or disorder1. Drugs or treatments that specifically target some aspect of a cognitive behavior are lacking, and require a fine-grained understanding of the cellular and molecular mechanisms that underlie that behavior. Cristina Alberini, a professor at NYU, is studying how specific genes, proteins, and pathways that mediate the formation and retrieval of long-term memories. She and her colleagues discovered that administering a protein to rats soon after training strengthened their memories even three weeks after the initial training2. This could represent a new target for memory enhancing therapies by direct analogy: could a similar protein be administered to humans to produce similar effects? (And would this work as a treatment for memory loss in dementia or Alzheimer’s?) Moreover, those with an interest in molecular signaling pathways may find the proposed mechanism intriguing for its implications for long-term potentiation across synapses. More generally, their evidence also coheres with theories of distributed memory traces across the brain.

Read on for a brief introduction to Dr. Alberini’s research, and learn more by attending her talk on October 22nd at 4pm in the CNCB conference room as part of the UCSD Neuroscience Graduate Program Seminar Series.

The researchers specifically find that this protein has effects on memory consolidation, which is a critical period after memory formation that stabilizes a memory and moves it to long-term storage.In a 2011 report to Nature, Alberini and her colleagues provide evidence that insulin-like growth factor II (IGF-2) is required during memory consolidation after training rats in an inhibitory avoidance paradigm (example here). In addition, bilaterally injecting IGF-2 into the hippocampus immediately after training enhances the strength of long-term memories (see A and B below).

nature09667-f3.2

(A) Latency to enter the dark/shock chamber is increased with hippocampal IGF-2 administration, both at 24 hours after training and 7 days after training. (B) 3 weeks later, memory of the foot shock experience persists in rats injected with IGF-2, as compared to vehicle-injected controls. (C) This effect generalizes to an auditory fear conditioning task–see text for details. (D) Injecting IGF-2 into the amygdala does not enhance learning, unlike injection in the hippocampus. Graphics from Figure 3 of Chen et al. 2011.

Specific mechanisms for IGF-2 memory enhancement

In addition, they find that the memory enhancing effects of IGF-2 depend on GSK3ß (glycogen synthase kinase 3 ß). Together these proteins increase the expression of GluR1 AMPA receptor subunits in the synapse. This finding is contrary to their original hypothesis that IGF-2, as a downstream target of C/EBPß (CCAAT enhancer binding protein), would affect memory enhancement by altering cell-wide mechanisms of transcription. Based on their evidence, they instead theorize that IGF-2 mainly enhances memory consolidation by acting at the synaptic level. This is confirmed when they inject IGF-2 into hippocampal slices and induce long-term potentiation (LTP) with weak high-frequency stimulation. As one might expect, IGF-2 not only enhances memory but also strengthens LTP.

The amygdala vs. the hippocampus

Alberini and her colleagues also show that injecting IGF-2 into the amygdala has no effect on memory (see D in the figure above). Although the amygdala is involved in the fear response and is critical to the inhibitory avoidance paradigm, it is not involved in the specific mechanism of consolidation enhancement that they investigate in this paper. This adds to previous evidence that the amygdala and hippocampus play different roles in memory formation, consolidation, and retrieval.4

Vy Vo is a first-year Ph.D. student currently rotating in the Reynolds lab at the Salk Institute. She is interested in perception, cognition, and information coding in the brain.

References

1 Graff, J., Tsai, L. 2011. Cognitive enhancement: A molecular memory booster. Nature 469, 474-475.

2 Chen D.Y., Stern S.A., Garcia-Osta A., Saunier-Rebori B., Pollonini G., Bambah-Mukku D., Blitzer R.D. & Alberini C.M. (2011). A critical role for IGF-II in memory consolidation and enhancement, Nature, 469 (7331) 491-497. DOI:

3 “Memory Consolidation”, Wikipedia: http://en.wikipedia.org/wiki/Memory_consolidation.

4 Milner, B., Squire, L.R., Kandel, E.R. 1998. Cognitive neuroscience and the study of memory. Neuron 20, 445-468. As cited in Chen et al. 2011.

Featured image from John C. Fiala & Josef Spacek, online here.

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