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Early consolidation of instrumental learning requires protein synthesis in the nucleus accumbens

Nature Neuroscience volume 5, pages 1327–1331 (2002)Cite this article

Abstract

It is widely held that long-term memories are established by consolidation of newly acquired information into stable neural representations, a process that requires protein synthesis and synaptic plasticity. Plasticity within the nucleus accumbens (NAc), a major component of the ventral striatum, is thought to mediate instrumental learning processes and many aspects of drug addiction. Here we show that the inhibition of protein synthesis within the NAc disrupts consolidation of an appetitive instrumental learning task (lever-pressing for food) in rats. Post-trial infusions of anisomycin immediately after the first several training sessions prevented consolidation, whereas infusions delayed by 2 or 4 hours had no effect. However, if the rats were allowed to learn the task, the behavior was not sensitive to disruption by intra-accumbens anisomycin. Control infusions into the medial NAc shell or the dorsolateral striatum did not impair learning; in fact, an enhancement was observed in the latter case. These results show that de novo protein synthesis within the NAc is necessary for the consolidation, but not reconsolidation, of appetitive instrumental memories.

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Figure 1: Representative injection sites for all experiments.
Figure 2: Memory consolidation requires protein synthesis in the NAc core, but not the medial shell, during early stages of appetitive instrumental learning.
Figure 3: Delayed infusion of the protein synthesis inhibitor anisomycin into the NAc core does not impair consolidation of memory for the instrumental learning task.
Figure 4: Effect of ANI in the NAc core after learning has been established.

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References

  1. Thorndike, E. Animal Intelligence (Macmillan, New York, 1911).

    Google Scholar 

  2. Skinner, B.F. Science and Human Behavior (Macmillan, New York, 1953).

    Google Scholar 

  3. Rescorla, R.A. Associative relations in instrumental learning: the eighteenth Bartlett memorial lecture. Q. J. Exp. Psychol. B 43, 1–23 (1991).

    Google Scholar 

  4. Dickinson, A. & Balleine, B. Motivational control of goal-directed action. Anim. Learn. Behav. 22, 1–18 (1994).

    Article  Google Scholar 

  5. Abel, T. & Lattal, K.M. Molecular mechanisms of memory acquisition, consolidation and retrieval. Curr. Opin. Neurobiol. 11, 180–187 (2001).

    Article  CAS  Google Scholar 

  6. Mishkin, M. & Petri, H.L. in Neuropsychology of Memory (eds. Butters, N. & Squire, L. R.) 287–296 (Guilford, New York, 1984).

    Google Scholar 

  7. Nader, K., Schafe, G.E. & LeDoux, J.E. The labile nature of consolidation theory. Nat. Rev. Neurosci. 1, 216–219 (2000).

    Article  CAS  Google Scholar 

  8. Dudai, Y. Consolidation: fragility on the road to the engram. Neuron 17, 367–370 (1996).

    Article  CAS  Google Scholar 

  9. McGaugh, J.L. Memory—a century of consolidation. Science 287, 248–251 (2000).

    Article  CAS  Google Scholar 

  10. Flexner, L.B., Flexner, J.B. & Stellar, E. Memory and cerebral protein synthesis in mice as affected by graded amoutns of puromycin. Exp. Neurol. 13, 264–272 (1965).

    Article  CAS  Google Scholar 

  11. Davis, H.P. & Squire, L.R. Protein synthesis and memory: a review. Psychol. Bull. 96, 518–559 (1984).

    Article  CAS  Google Scholar 

  12. Agranoff, B.W. Memory and protein synthesis. Sci. Am. 216, 115–122 (1967).

    Article  CAS  Google Scholar 

  13. Flood, J.F., Rosenzweig, M.R., Bennett, E.L. & Orme, A.E. The influence of duration of protein synthesis inhibition on memory. Physiol. Behav. 10, 555–562 (1973).

    Article  CAS  Google Scholar 

  14. Nader, K., Schafe, G.E. & Le Doux, J.E. Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406, 722–726 (2000).

    Article  CAS  Google Scholar 

  15. Berman, D.E. & Dudai, Y. Memory extinction, learning anew, and learning the new: dissociations in the molecular machinery of learning in cortex. Science 291, 2417–2419 (2001).

    Article  CAS  Google Scholar 

  16. Mogenson, G.J., Jones, D.L. & Yim, C.Y. From motivation to action: functional interface between the limbic system and the motor system. Prog. Neurobiol. 14, 69–97 (1980).

    Article  CAS  Google Scholar 

  17. Smith-Roe, S.L. & Kelley, A.E. Coincident activation of NMDA and dopamine D1 receptors within the nucleus accumbens core is required for appetitive instrumental learning. J. Neurosci. 20, 7737–7742 (2000).

    Article  CAS  Google Scholar 

  18. Kelley, A.E., Smith-Roe, S.L. & Holahan, M.R. Response-reinforcement learning is dependent on N-methyl-D-aspartate receptor activation in the nucleus accumbens core. Proc. Natl. Acad. Sci. USA 94, 12174–12179 (1997).

    Article  CAS  Google Scholar 

  19. Zahm, D.S. An integrative neuroanatomical perspective on some subcortical substrates of adaptive responding with emphasis on the nucleus accumbens. Neurosci. Biobehav. Rev. 24, 85–105 (2000).

    Article  CAS  Google Scholar 

  20. Kelley, A.E., Domesick, V.B. & Nauta, W.J.H. The amygdalostriatal projection in the rat: an anatomical study by anterograde and retrograde tracing methods. Neuroscience 7, 615–630 (1982).

    Article  CAS  Google Scholar 

  21. Marshall, J.F., Berrios, N. & Sawyer, S. Neostriatal dopamine and sensory inattention. J. Comp. Physiol. Psychol. 94, 833–846 (1980).

    Article  CAS  Google Scholar 

  22. Kandel, E.R. The molecular biology of memory storage: a dialogue between genes and synapses. Science 294, 1030–1038 (2001).

    Article  CAS  Google Scholar 

  23. Vianna, M.R., Szapiro, G., McGaugh, J.L., Medina, J.H. & Izquierdo, I. Retrieval of memory for fear-motivated training initiates extinction requiring protein synthesis in the rat hippocampus. Proc. Natl. Acad. Sci. USA 98, 12251–12254 (2001).

    Article  CAS  Google Scholar 

  24. Lattal, K.M. & Abel, T. Different requirements for protein synthesis in acquisition and extinction of spatial preferences and context-evoked fear. J. Neurosci. 21, 5773–5780 (2001).

    Article  CAS  Google Scholar 

  25. Gurden, H., Takita, M. & Jay, T.M. Essential role of D1 but not D2 receptors in the NMDA receptor-dependent long-term potentiation at hippocampal-prefrontal cortex synapses in vivo. J. Neurosci. 20, RC106 (2000).

    Article  CAS  Google Scholar 

  26. Wang, J. & O'Donnell, P. D(1) dopamine receptors potentiate nmda-mediated excitability increase in layer V prefrontal cortical pyramidal neurons. Cereb. Cortex 11, 452–462 (2001).

    Article  CAS  Google Scholar 

  27. Baldwin, A.E., Holahan, M.R., Sadeghian, K. & Kelley, A.E. N-methy-D-aspartate receptor-dependent plasticity within a distributed corticostriatal network mediates appetitive instrumental learning. Behav. Neurosci. 114, 1–15 (2000).

    Article  Google Scholar 

  28. Meiri, N. & Rosenblum, K. Lateral ventricle injection of the protein synthesis inhibitor anisomycin impairs long-term memory in a spatial memory task. Brain Res. 789, 48–55 (1998).

    Article  CAS  Google Scholar 

  29. Bracha, V. et al. Microinjections of anisomycin into the intermediate cerebellum during learning affect the acquisition of classically conditioned responses in the rabbit. Brain Res. 788, 169–178 (1998).

    Article  CAS  Google Scholar 

  30. Springer, A.D. & Agranoff, B.W. Puromycin-induced retention deficit in goldfish as a function of attained training performance level. Behav. Biol. 17, 547–554 (1976).

    Article  CAS  Google Scholar 

  31. Scharf, M.T. et al. Protein synthesis is required for the enhancement of long-term potentiation and long-term memory by spaced training. J. Neurophysiol. 87, 2770–2777 (2002).

    Article  CAS  Google Scholar 

  32. Fairley, P.C. & Marshall, J.F. Dopamine in the lateral caudate-putamen of the rat is essential for somatosensory orientation. Behav. Neurosci. 100, 652–663 (1986).

    Article  CAS  Google Scholar 

  33. Carli, M., Evenden, J.L. & Robbins, T.W. Depletion of unilateral striatal dopamine impairs initiation of contralateral actions and not sensory attention. Nature 313, 679–682 (1985).

    Article  CAS  Google Scholar 

  34. Crofts, H.S. et al. Differential effects of 6-OHDA lesions of the frontal cortex and caudate nucleus on the ability to acquire an attentional set. Cereb. Cortex 11, 1015–1026 (2001).

    Article  CAS  Google Scholar 

  35. Haber, S.N., Fudge, J.L. & McFarland, N.R. Striatonigrostriatal pathways in primates form an ascending spiral from the shell to the dorsolateral striatum. J. Neurosci. 20, 2369–2382 (2000).

    Article  CAS  Google Scholar 

  36. Parkinson, J.A., Cardinal, R.N. & Everitt, B.J. Limbic cortical-ventral striatal systems underlying appetitive conditioning. Prog. Brain Res. 126, 263–285 (2000).

    Article  CAS  Google Scholar 

  37. Corbit, L.H., Muir, J.L. & Balleine, B.W. The role of the nucleus accumbens in instrumental conditioning: evidence of a functional dissociation between accumbens core and shell. J. Neurosci. 21, 3251–3260 (2001).

    Article  CAS  Google Scholar 

  38. Hyman, S.E. & Malenka, R.C. Addiction and the brain: the neurobiology of compulsion and its persistence. Nat. Rev. Neurosci. 2, 695–703 (2001).

    Article  CAS  Google Scholar 

  39. Rosenblum, K., Meiri, N. & Dudai, Y. Taste memory: the role of protein synthesis in gustatory cortex. Behav. Neural Biol. 59, 49–56 (1993).

    Article  CAS  Google Scholar 

  40. Paxinos, G. & Watson, C.W. The Rat Brain in Stereotaxic Coordinates (Academic, San Diego, 1998).

    Google Scholar 

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Acknowledgements

This work was supported by grant DA04788 from the National Institute on Drug Abuse. P.J.H. is supported by grant GM07507 from the National Institute of General Medical Sciences.

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Authors and Affiliations

  1. Neuroscience Training Program, University of Wisconsin-Madison, 7226 Medical Sciences Center, 1300 University Avenue, Madison, 53706, Wisconsin, USA

    Pepe J. Hernandez

  2. Department of Psychiatry, University of Wisconsin-Madison Medical School, 6001 Research Park Blvd., Madison, 53719, Wisconsin, USA

    Pepe J. Hernandez, Kenneth Sadeghian & Ann E. Kelley

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  1. Pepe J. Hernandez
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Correspondence to Pepe J. Hernandez.

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Hernandez, P., Sadeghian, K. & Kelley, A. Early consolidation of instrumental learning requires protein synthesis in the nucleus accumbens. Nat Neurosci 5, 1327–1331 (2002). https://doi.org/10.1038/nn973

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