Skip to main content
NCBI home page
Cellular and Molecular Neurobiology logoLink to Cellular and Molecular Neurobiology
. 2004 Feb;24(1):25–36. doi: 10.1023/B:CEMN.0000012722.45805.c8

Molecular Signals into the Insular Cortex and Amygdala During Aversive Gustatory Memory Formation

Federico Bermúdez-Rattoni 1, Leticia Ramírez-Lugo 1, Ranier Gutiérrez 1, María Isabel Miranda 1
PMCID: PMC11529945  PMID: 15049508

Abstract

In this paper, we will provide evidence of the putative molecular signals and biochemical events that mediate the formation of long-lasting gustatory memory trace. When an animal drinks a novel taste (the conditioned stimulus; CS) and it is later associated with malaise (unconditioned stimulus; US), the animal will reject it in the next presentation, developing a long-lasting taste aversion, i.e., the taste cue becomes an aversive signal, and this is referred to as conditioning taste aversion. Different evidence indicates that the novel stimulus (taste) induces a rapid and strong cortical acetylcholine activity that decreases when the stimulus becomes familiar after several presentations. Cholinergic activation via muscarinic receptors initiates a series of intracellular events leading to plastic changes that could be related to short- and/or long-term memory gustatory trace. Such plastic changes facilitate the incoming US signals carried out by, in part, the glutamate release induced by the US. Altogether, these events could produce the cellular changes related to the switch from safe to aversive taste memory trace. A proposed working model to explain the biochemical sequence of signals during taste memory formation will be discussed.

Keywords: conditioned taste aversion, learning, short-term memory, long-term memory, glutamate, acetylcholine, consolidation

REFERENCES

  1. Acquas, E., Wilson, C., and Fibiger, H. C. (1996). Conditioned and unconditioned stimuli increase frontal cortical and hippocampal acetylcholine release: Effects of novelty, habituation, and fear. J. Neurosci.16:3089-3096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bakin, J. S., and Weinberger, N. M. (1996). Induction of a physiological memory in the cerebral cortex by stimulation of the nucleus basalis. Proc. Natl. Acad. Sci. U.S.A.93:11219-11224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Berman, D. E., Hazvi, S., Neduva, V., and Dudai, Y. (2000). The role of identified neurotransmitter systems in the response of insular cortex to unfamiliar taste: Activation of ERK1-2 and formation of a memory trace. J. Neurosci.20:7017-7023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Berman, D. E., Hazvi, S., Rosenblum, K., Seger, R., and Dudai, Y. (1998). Specific and differential activation of mitogen-activated protein kinase cascades by unfamiliar taste in the insular cortex of the behaving rat. J. Neurosci.18:10037-10044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bermúdez-Rattoni, F., Christopher, E. O., Martha, L. E., and Hernández-Echeagaray, E. (1995). The role of the insular cortex in the acquisition and long lasing memory for aversively motivated behavior. In McGaugh, J. L., Rattoni, F. B., and Prado-Alcalá, R. (eds.), Plasticity in the Central Nervous System. Learning and Memory, Mahwah, NJ, pp. 67-79
  6. Bermúdez-Rattoni, F., and Escobar, M. L. (2000). Neurobiology of learning. In Pawlik, K., and Rosenzweig, M. (eds.), The International Handbook of Psycology, London, pp. 136-150
  7. Bermúdez-Rattoni, F., and Yamamoto, T. (1998). Neuroanatomy of CTA: Lesions studies. In Bures, J., Bermúdez-Rattoni, F., and Yamamoto, T. (eds.), Conditioned Taste Aversion. Memory of a Special Kind, Oxford University Press, New York, pp. 28-46 [Google Scholar]
  8. Bielavska, E., Miksik, I., and Krivanek, J. (2000). Glutamate in the parabrachial nucleus of rats during conditioned taste aversion. Brain Res.887:413-417. [DOI] [PubMed] [Google Scholar]
  9. Bures, J. (1998). Ethology, phychological psychology, and neurobiology. In Bures, J., Bermúdez-Rattoni, F., and Yamamoto, T., (eds.), Conditioned taste aversion: Memory of a special kind, Oxford University Press, New York, pp. 1-13 [Google Scholar]
  10. Buresova, O., and Bures, J. (1973). Cortical and subcortical components of conditioned saccharin aversion in rats. Acta Neurobiol. Exp. (Warsz) 33:689-698. [PubMed] [Google Scholar]
  11. Castro, A., and Borrel, J. (1995). Functional recovery of forelimb response capacity after forelimb primary motor cortex damage in the rat is due to the reorganization of adjacent areas of cortex. Neuroscience68:793-805. [DOI] [PubMed] [Google Scholar]
  12. Chin, J., Miranda, M. I., LaLumiere, R. T., Bermúdez-Rattoni, F., and McGaugh, J. L. (2002). Infusions of a Noradrenergic Antagonist Into the Basolateral Amygdala Before Induction of Malaise Impair Memory for Conditioned Taste Aversion. Program No. 397.13, Abstract Viewer/itinerary Planner, Society for Neuroscience, Washington, DC.
  13. Cuello, A. C., Garofalo, L., and Maysinger, D. (1990). Evidence for nerve growth factorganglioside interaction in forebrain cholinergic neurons. Acta Neurobiol. Exp. (Warsz)50:451-460. [PubMed] [Google Scholar]
  14. Davis, S., Butcher, S. P., and Morris, R. G. (1992). The NMDA receptor antagonist D-2-amino-5-phosphonopentanoate (D-AP5) impairs spatial learning and LTP in vivo at intracerebral concentrations comparable to those that block LTP in vitro. J. Neurosci.12:21-34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Decker, M. W., and McGaugh, J. L. (1991). The role of interactions between the cholinergic system and other neuromodulatory systems in learning and memory. Synapse7:151-168. [DOI] [PubMed] [Google Scholar]
  16. Domjan, M. (1976). Determinants of the enhancement of flavored-water intake by prior exposure. J. Exp. Psychol. Anim. Behav. Process2:17-27. [DOI] [PubMed] [Google Scholar]
  17. English, J. D., and Sweatt, J. D. A. (1997). Requirement for mitogen-activated protein kinase cascade in hippocampal long term potentiation. Lett. Nat.417:19103-19106. [DOI] [PubMed] [Google Scholar]
  18. Escobar, M. L., Alcocer, I., and Bermúdez-Rattoni (2002). In vivo effects of intracortical administration of NMDA and metabotropic glutamate receptors antagonists on neocortical long-term potentiation and conditioned taste aversion. Behav. Brain Res.129:101-106. [DOI] [PubMed] [Google Scholar]
  19. Escobar, M. L., Alcocer, I., and Chao, V. (1998a). The NMDA receptor antagonist CPP impairs conditioned taste aversion and insular cortex long-term potentiation in vivo. Brain Res.812:246-251. [DOI] [PubMed] [Google Scholar]
  20. Escobar, M. L., and Bermúdez-Rattoni, F. (2000). Long-term potentiation in the insular cortex enhances conditioned taste aversion retention. Brain Res.852:208-212. [DOI] [PubMed] [Google Scholar]
  21. Escobar, M. L., Chao, V., and Bermúdez-Rattoni, F. (1998b). In vivo long-term potentiation in the insular cortex: NMDA receptor dependence. Brain Res.779:314-319. [DOI] [PubMed] [Google Scholar]
  22. Fanselow, M. S., Kim, J. J., Yipp, J., and De, O. (1994). Differential effects of the N-methyl-D-aspartate antagonist DL-2-amino-5-phosphonovalerate on acquisition of fear of auditory and contextual cues. Behav. Neurosci.108:235-240. [DOI] [PubMed] [Google Scholar]
  23. Farr, S. A., Flood, J. F., and Morley, J. E. (2000). The effect of cholinergic, GABAergic, serotonergic, and glutamatergic receptor modulation on posttrial memory processing in the hippocampus. Neurobiol. Learn. Mem.73:150-167. [DOI] [PubMed] [Google Scholar]
  24. Felder, C. C. (1995). Muscarinic acetylcholine receptors: Signal transduction through multiple effectors. FASEB J.9:619-625. [PubMed] [Google Scholar]
  25. Ferreira, G., Gutierrez, R., De La Cruz, V., and Bermúdez-Rattoni, F. (2002). Differential involvement of cortical muscarinic and NMDA receptors in short-and long-term taste aversion memory. Eur. J. Neurosci.16:1139-1145. [DOI] [PubMed] [Google Scholar]
  26. Fibiger, H. C., Damsma, G., and Day, J. C. (1991). Behavioral pharmacology and biochemistry of central cholinergic neurotransmission. Adv. Exp. Med. Biol.295:399-414. [DOI] [PubMed] [Google Scholar]
  27. Gallo, M., Roldan, G., and Bures, J. (1992). Differential involvement of gustatory insular cortex and amygdala in the acquisition and retrieval of conditioned taste aversion in rats. Behav. Brain Res.52:91-97. [DOI] [PubMed] [Google Scholar]
  28. Giovannini, M. G., Rakovska, A., Benton, R. S., Pazzagli, M., Bianchi, L., and Pepeu, G. (2001). Effects of novelty and habituation on acetylcholine, GABA, and glutamate release from the frontal cortex and hippocampus of freely moving rats. Neuroscience106:43-53. [DOI] [PubMed] [Google Scholar]
  29. Gutierrez, H., Gutierrez, R., Ramirez-Trejo, L., Silva-Gandarias, R., Ormsby, C. E., Miranda, M. I., and Bermúdez-Rattoni, F. (1999a). Redundant basal forebrain modulation in taste aversion memory formation. J. Neurosci.19:7661-7669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Gutierrez, H., Hernandez-Echeagaray, E., Ramirez-Amaya, V., and Bermúdez-Rattoni, F. (1999b). Blockade of N-methyl-D-aspartate receptors in the insular cortex disrupts taste aversion and spatial memory formation. Neuroscience89:751-758. [DOI] [PubMed] [Google Scholar]
  31. Gutierrez, H., Miranda, M. I., and Bermúdez-Rattoni, F. (1997). Learning impairment and cholinergic deafferentation after cortical nerve growth factor deprivation. J. Neurosci.17:3796-3803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Gutierrez, R., Tellez, L., and Bermúdez-Rattoni, F. (2001). Attenuation of Taste Neophobia Depends on Activation of Muscarinic Receptors in the Insular Cortex, Program No. 854.6. Abstract. Viewer/itinerary Planner, Society for Neuroscience, Washington, DC
  33. Houpt, T. A., and Berlin, R. (1999). Rapid, labile, and protein synthesis-independent short-term memory in conditioned taste aversion. Learn. Mem.6:37-46. [PMC free article] [PubMed] [Google Scholar]
  34. Inglis, F. M., Day, J. C., and Fibiger, H. C. (1994). Enhanced acetylcholine release in hippocampus and cortex during the anticipation and consumption of a palatable meal. Neuroscience62:1049-1056. [DOI] [PubMed] [Google Scholar]
  35. Izquierdo, I. (1994). Pharmacological evidence for a role of long-term potentiation in memory. FASEB J.8:1139-1145. [PubMed] [Google Scholar]
  36. Izquierdo, I., Medina, J. H., Vianna, M. R., Izquierdo, L. A., and Barros, D. M. (1999). Separate mechanisms for short-and long-term memory. Behav. Brain Res.103:1-11. [DOI] [PubMed] [Google Scholar]
  37. Izquierdo, L. A., Barros, D. M., Ardenghi, P. G., Pereira, P., Rodrigues, C., Choi, H., Medina, J. H., and Izquierdo, I. (2000). Different hippocampal molecular requirements for short-and long-term retrieval of one-trial avoidance learning. Behav. Brain Res.111:93-98. [DOI] [PubMed] [Google Scholar]
  38. Jones, M. W., French, P. J., Bliss, T. V., and Rosenblum, K. (1999). Molecular mechanisms of long-term potentiation in the insular cortex in vivo. J. Neurosci.19:RC36. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Kiefer, S. W. (1985). Neural mediation of conditioned food aversions. Ann. N.Y. Acad. Sci.443:100-109. [DOI] [PubMed] [Google Scholar]
  40. Kim, M., and McGaugh, J. L. (1992). Effects of intra-amygdala injections of NMDA receptor antagonists on acquisition and retention of inhibitory avoidance. Brain Res.585:35-48. [DOI] [PubMed] [Google Scholar]
  41. McGaugh, J. L., Cahill, L., Parent, B. M., Mesches, M. H., Coleman-Mesches, K., and Salinas, A. J. (1995). Involvement of the amygdala in the regulation of memory storage. In McGaugh, J. L., Bermúdez-Rattoni, F., and Prado-Alcalá, R. (eds.), Plasticity in the Central Nervous System. Learning and Memory, Erlbaum, Mahwah, NJ, pp 17-39. [Google Scholar]
  42. McGaugh, J. L. (2000). Memory—A century of consolidation. Science287:248-251. [DOI] [PubMed] [Google Scholar]
  43. Miranda, M. I., and Bermúdez-Rattoni, F. (1999). Reversible inactivation of the nucleus basalis magnocellularis induces disruption of cortical acetylcholine release and acquisition, but not retrieval, of aversive memories. Proc. Natl. Acad. Sci. U.S.A96:6478-6482. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Miranda, M. I., Bermúdez-Rattoni, F., and McGaugh, J. L. (2002a). Effects of Insular Cortex Infusions of Oxotremorine and 8-Br-cAMP on Inhibitory Avoidance Consolidation and Taste Aversion Learning, Program No. 82.3. Abstract Viewer/itinerary Planner, Society for Neuroscience, Washington, DC [Google Scholar]
  45. Miranda, M. I., Ferreira, G., Ramírez-Lugo, L., and Bermúdez-Rattoni, F. (2002b). Glutamatergic activity in the amygdala signals visceral input during taste memory formation. Proc. Natl. Acad. Sci. U.S.A.99:11417-11422. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Miranda, M. I., Ramírez-Lugo, L., and Bermúdez-Rattoni, F. (2000). Cortical cholinergic activity is related to the novelty of the stimulus. Brain Res.882:230-235. [DOI] [PubMed] [Google Scholar]
  47. Mitchell, D. (1976). Experiments on neophobia in wild and laboratory rats: A reevaluation. J. Comp. Physiol. Psychol.90:190-197. [DOI] [PubMed] [Google Scholar]
  48. Miyashita, T., and Williams, C. L. (2002). Glutamatergic transmission in the nucleus of the solitary tract modulates memory through influences on amygdala noradrenergic systems. Behav. Neurosci.116:13-21. [DOI] [PubMed] [Google Scholar]
  49. Morris, R. G. (1989). Synaptic plasticity and learning: Selective impairment of learning rats and blockade of long-term potentiation in vivo by the N-methyl-D-aspartate receptor antagonist AP5. J. Neurosci.9:3040-3057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Naor, C., and Dudai, Y. (1996). Transient impairment of cholinergic function in the rat insular cortex disrupts the encoding of taste in conditioned taste aversion. Behav. Brain Res.79:61-67. [DOI] [PubMed] [Google Scholar]
  51. Navarro, M., Spray, K. J., Cubero, I., Thiele, T. E., and Bernstein, I. L. (2000). cFos induction during conditioned taste aversion expression varies with aversion strength. Brain Res.887:450-453. [DOI] [PubMed] [Google Scholar]
  52. O'Dell, T. J., Kandel, E. R., and Grant, S. G., (1991). Long-term potentiation in the hippocampus is blocked by tyrosine kinase inhibitors. Nature353:558-560. [DOI] [PubMed] [Google Scholar]
  53. Orban, P. C., Chapman, P. F., and Brambilla, R. (1999). Is the Ras-MAPK signalling pathway necessary for long-term memory formation? Trends Neurosci.22:38-44. [DOI] [PubMed] [Google Scholar]
  54. Orsetti, M., Casamenti, F., and Pepeu, G. (1996). Enhanced acetylcholine release in the hippocampus and cortex during acquisition of an operant behavior. Brain Res.724:89-96. [DOI] [PubMed] [Google Scholar]
  55. Radcliffe, K. A., and Dani, J. A. (1998). Nicotinic stimulation produces multiple forms of increased glutamatergic synaptic transmission. J. Neurosci.18:7075-7083. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Ramírez-Lugo, L., Miranda, M. I., Escobar, M. L., Espinosa, E., and Bermúdez-Rattoni, F. (2003). The role of chortical cholinergic pre-post-synaptic receptors in taste aversion memory. Neurobiol Learn Mem. 79:184-193. [DOI] [PubMed] [Google Scholar]
  57. Rasmusson, D., and Szerb, J. C. (1976). Acetylcholine release from visual and sensorimotor cortices of conditioned rabbits: The effects of sensory cuing and patterns of responding. Brain Res.104:243-259. [DOI] [PubMed] [Google Scholar]
  58. Roldan, G., and Bures, J. (1994). Tetrodotoxin blockade of amygdala overlapping with poisoning impairs acquisition of conditioned taste aversion in rats. Behav. Brain Res.65:213-219. [DOI] [PubMed] [Google Scholar]
  59. Rosenblum, K., Berman, D. E., Hazvi, S., and Dudai, Y. (1996). Carbachol mimics effects of sensory input on tyrosine phosphorylation in cortex. Neuroreport7:1401-1404. [DOI] [PubMed] [Google Scholar]
  60. Rosenblum, K., Berman, D. E., Hazvi, S., Lamprecht, R., and Dudai, Y. (1997). NMDA receptor and the tyrosine phosphorylation of its 2B subunit in taste learning in the rat insular cortex. J. Neurosci.17:5129-5135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Rosenblum, K., Futter, M., Jones, M., Hulme, E. C., and Bliss, T. V. (2000). ERKI/II regulation by the muscarinic acetylcholine receptors in neurons. J. Neurosci.20:977-985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Rosenblum, K., Meiri, N., and Dudai, Y. (1993). Taste memory: The role of protein synthesis in gustatory cortex. Behav. Neural. Biol.59:49-56. [DOI] [PubMed] [Google Scholar]
  63. Rostas, J. A., Brent, V. A., Voss, K., Errington, M. L., Bliss, T. V., and Gurd, J. W. (1996, Sept.). Enhanced tyrosine phosphorylation of the 2B subunit of the N-methyl-D-aspartate receptor in long-term potentiation. Proc. Natl. Acad. Sci. U.S.A.93:10452-104526. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Sarter, M. F., and Bruno, J. P. (1994). Cognitive functions of cortical ACh: Lessons from studies on trans-synaptic modulation of activated efflux. Trends Neurosci.17:217-221. [DOI] [PubMed] [Google Scholar]
  65. Shimoshige, Y., Maeda, T., Kaneko, S., Akaike, A., and Satoh, M. (1997). Involvement of M2 receptor in an enhancement of long-term potentiation by carbachol in Schaffer collateral-CA1 synapses of hippocampal slices. Neurosci. Res.27(2):175-180. [DOI] [PubMed] [Google Scholar]
  66. Weinberger, N. M., and Bakin, J. S. (1198). Learning-induced physiological memory in adult primary auditory cortex: Receptive fields plasticity, model, and mechanisms. Audiol. Neurootol.3:145-167. [DOI] [PubMed] [Google Scholar]
  67. Williams, S., and Johnston, D. (1988). Muscarinic depression of long-term potentiation in CA3 hippocampal neurons. Science242:84-87. [DOI] [PubMed] [Google Scholar]
  68. Woolf, N. J. (1996). The critical role of cholinergic basal forebrain neurons in morphological change and memory encoding: A hypothesis. Neurobiol. Learn. Mem.66:258-266. [DOI] [PubMed] [Google Scholar]
  69. Woolf, N. J. (1998) A structural basis for memory storage in mammals. Prog. Neurobiol.55:59-77. [DOI] [PubMed] [Google Scholar]
  70. Yamamoto, T., Matsuo, R., Kiyomitsu, Y., and Kitamura, R. (1989). Taste responses of cortical neurons in freely ingesting rats. J. Neurophysiol.61:1244-1258. [DOI] [PubMed] [Google Scholar]
  71. Yamamoto, T., Shimura, T., Sako, N., Yasoshima, Y., and Sakai, N. (1994). Neural substrates for conditioned taste aversion in the rat. Behav. Brain Res.65:123-137. [DOI] [PubMed] [Google Scholar]

Articles from Cellular and Molecular Neurobiology are provided here courtesy of Springer

RESOURCES