Clustered c-Fos Activation in Rat Hippocampus at the Acquisition Stage of Appetitive Instrumental Learning


To address the issue of how hippocampal neurons are involved into learning progress, we studied c-Fos expression in rat hippocampal subfields at different stages of appetitive instrumental learning. To model the first stage of learning, we pre-trained animals to approach the lever to obtain the food, and then made this behavior ineffective by not reinforcing it during the last session (“mismatch” group). Another group just acquired lever-pressing behavior at that day (“acquisition” group). Animals of the third group performed this well-trained behavior (“performance” group). The number of Fos-positive neurons in all hippocampal regions of the “mismatch” group animals was higher than in the ones of the home cage control group animals. The number of Fos-positive neurons was increased in CA1 and CA3 areas, but not in the dentate gyrus of both the “acquisition” and “performance” group animals as compared with the control group. We also found segmented c-Fos expression, which was more evident in “acquisition” group animals. Thus, our results suggest that during the first (mismatch) stage of learning hippocampal neurons are activated in an equally distributed manner. The following clustered pattern of activated CA1 neurons during the acquisition stage may reflect specialization of these neurons in respect to the specific lever-pressing behavior.

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Svarnik, O. , Alexandrov, Y. and Anokhin, K. (2015) Clustered c-Fos Activation in Rat Hippocampus at the Acquisition Stage of Appetitive Instrumental Learning. Journal of Behavioral and Brain Science, 5, 69-80. doi: 10.4236/jbbs.2015.53006.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Buitrago, M.M., Ringer, T., Schulz, J.B., Dichgans, J. and Luft, A.R. (2004) Characterization of Motor Skill and Instrumental Learning Time Scales in a Skilled Reaching Task in Rat. Behavioural Brain Research, 155, 249-256.
[2] Karni, A., Meyer, G., Rey-Hipolito, C., Jezzard, P., Adams, M.M., Turner, R. and Ungerleider, L.G. (1998) The Acquisition of Skilled Motor Performance: Fast and Slow Experience-Driven Changes in Primary Motor Cortex. Proceedings of the National Academy of Sciences of the United States of America, 95, 861-868.
[3] Zielinski, K. (1993) Intertrial Responses in Defensive Instrumental Learning. Acta Neurobiologiae Experimentalis (Wars), 53, 215-229.
[4] Shvyrkov, V.B. (1986) Behavioral Specialization of Neurons and the System-Selection Hypothesis of Learning. In: Klix, F. and Hagendorf, H., Eds., Human Memory and Cognitive Capabilities: Mechanisms and Performances, Elsevier Science Publishers, Amsterdam, 599-611.
[5] Thompson, L.T. and Best, P.J. (1990) Long-Term Stability of the Place-Field Activity of Single Units Recorded from the Dorsal Hippocampus of Freely Behaving Rats. Brain Research, 509, 299-308.
[6] Gorkin, A.G. and Shevchenko, D.G. (1991) The Stability of Units Behavioral Specialization. Neuroscience and Behavioral Physiology, 21, 222-229.
[7] Alexandrov, Yu.I., Grechenko, T.N., Gavrilov, V.V., Gorkin, A.G., Shevchenko, D.G., Grinchenko, Yu.V., et al. (2000) Formation and Realization of Individual Experience: A Psychophysiological Approach. In: Miller, R., Ivanitsky, A.M. and Balaban, P.M., Eds., Conceptual Advances in Russian Neuroscience: Complex Brain Functions, Harwood Academic Publishers, Amsterdam, 181-200.
[8] Brosch, M., Selezneva, E. and Scheich, H. (2005) Nonauditory Events of a Behavioral Procedure Activate Auditory cortex of Highly Trained Monkeys. The Journal of Neuroscience, 25, 6797-6806.
[9] Mruczek, R.E. and Sheinberg, D.L. (2007) Activity of Inferior Temporal Cortical Neurons Predicts Recognition Choice Behavior and Recognition Time during Visual Search. The Journal of Neuroscience, 27, 2825-2836.
[10] Matsumora, T., Koida, K. and Komatsu, H. (2008) Relationship between Color Discrimination and Neural Responses in the Inferior Temporal Cortex of the Monkey. The Journal of Neuroscience, 100, 3361-3374.
[11] MacDonald, C.J., Lepage, K.Q., Eden, U.T. and Eichenbaum, H. (2011) Hippocampal “Time Cells” Bridge the Gap in Memory for Discontiguous Events. Neuron, 71, 737-749.
[12] Alexandrov, Y.I. (2008) How We Fragment the World: The View from Inside versus the View from Outside. Social Science Information, 47, 419-457.
[13] Suzuki, W.A. (2008) Associative Learning Signals in the Brain. Progress in Brain Research, 169, 305-320.
[14] Cahusac, P.M., Rolls, E.T., Miyashita, Y. and Niki, H. (1993) Modification of the Responses of Hippocampal Neurons in the Monkey during the Learning of a Conditional Spatial Response Task. Hippocampus, 3, 29-42.
[15] Ahissar, E., Vaadia, E., Ahissar, M., Bergman, H., Arieli, A. and Abeles, M. (1992) Dependence of Cortical Plasticity on Correlated Activity of Single Neurons and on Behavioral Context. Science, 257, 1412-1415.
[16] Ponomarenko, A.A., Li, J.S., Korotkova, T.M., Huston, J.P. and Haas, H.L. (2008) Frequency of Network Synchronization in the Hippocampus Marks Learning. European Journal of Neuroscience, 27, 3035-3042.
[17] Anokhin, К.V. and Rose, S.P. (1991) Learning-Induced Increase of Immediate Early Gene Messenger RNA in the Chick Forebrain. European Journal of Neuroscience, 3, 162-167.
[18] Lanahan, A. and Worley, P. (1998) Immediate-Early Genes and Synaptic Function. Neurobiology of Learning and Memory, 70, 37-43.
[19] Svarnik, O.E., Alexandrov, Y.I., Gavrilov, V.V., Grinchenko, Y.V. and Anokhin, K.V. (2005) Fos Expression and Task-Related Neuronal Activity in Rat Cerebral Cortex after Instrumental Learning. Neuroscience, 136, 33-42.
[20] Suge, R., Kato, H. and McCabe, B.J. (2010) Rapid Induction of the Immediate Early Gene c-fos in a Chick Forebrain System Involved in Memory. Experimental Brain Research, 200, 183-188.
[21] Miyashita, T., Kubik, S., Haghighi, N., Steward, O. and Guzowski, J.F. (2009) Rapid Activation of Plasticity-Associated Gene Transcription in Hippocampal Neurons Provides a Mechanism for Encoding of One-Trial Experience. Journal of Neuroscience, 29, 898-906.
[22] Guzowski, J.F. (2002) Insights into Immediate-Early Gene Function in Hippocampal Memory Consolidation Using Antisense Oligonucleotide and Fluorescent Imaging Approaches. Hippocampus, 12, 86-104.
[23] Alexandrov, Y.I., Grinchenko, Y.V., Shevchenko, D.G., Averkin, R.G., Matz, V.N., Laukka, S., et al. (2013) The Effect of Ethanol on the Neuronal Subserving of Behavior in the Hippocampus. Journal of Behavioral and Brain Science, 3, 107-130.
[24] Pickering, C., Avesson, L., Lindblom, J., Liljequist, S. and Schioth, H.B. (2007) To Press or Not to Press? Differential Receptor Expression and Response to Novelty in Rats Learning an Operant Response for Reward. Neurobiology of Learning and Memory, 87, 181-191.
[25] Corbit, L.H. and Balleine, B.W. (2000) The Role of the Hippocampus in Instrumental Conditioning. Journal of Neuroscience, 20, 4233-4239.
[26] Cheung, T.H. and Cardinal, R.N. (2005) Hippocampal Lesions Facilitate Instrumental Learning with Delayed Reinforcement but Induce Impulsive Choice in Rats. BMC Neuroscience, 6, 36.
[27] Hess, U.S., Lynch, G. and Gall, C.M. (1995) Changes in c-Fos mRNA Expression in Rat Brain during Odor Discrimination Learning: Differential Involvement of Hippocampal Subfields CA1 and CA3. Journal of Neuroscience, 15, 4786-4795.
[28] Hess, U.S., Lynch, G. and Gall, C.M. (1995) Regional Patterns of c-Fos mRNA Expression in Rat Hippocampus Following Exploration of a Novel Environment versus Performance of a Well-Learned Discrimination. Journal of Neuroscience, 15, 7796-7809.
[29] Gall, C.M., Hess, U.S. and Lynch, G. (1998) Mapping Brain Networks Engaged by, and Changed by, Learning. Neurobiology of Learning and Memory, 70, 14-36.
[30] Hampson, R.E., Simeral, J.D. and Deadwyler, S.A. (1999) Distribution of Spatial and Nonspatial Information in Dorsal Hippocampus. Nature, 402, 610-614.
[31] Kelly, M.P. and Deadwyler, S.A. (2003) Experience-Dependent Regulation of the Immediate-Early Gene Arc Differs across Brain Regions. Journal of Neuroscience, 23, 6443-6451.
[32] Paxinos, G. and Watson, C. (1997) The Rat Brain in Stereotaxic Coordinates. Academic Press, New York.
[33] Lee, M.Y., Chiang, C.C., Chiu, H.Y., Chan, M.H. and Chen, H.H. (2014) N-Acetylcysteine Modulates Hallucinogenic 5-HT2A Receptor Agonist-Mediated Responses: Behavioral, Molecular, and Electrophysiological Studies. Neuropharmacology, 81, 215-223.
[34] Lkhagvasuren, B., Oka, T., Nakamura, Y., Hayashi, H., Sudo, N. and Nakamura, K. (2014) Distribution of Fos-Immunoreactive Cells in Rat Forebrain and Midbrain Following Social Defeat Stress and Diazepam Treatment. Neuroscience, 272, 34-57.
[35] Takahashi, T., Zhu, Y., Hata, T., Shimizu-Okabe, C., Suzuki, K. and Nakahara, D. (2009) Intracranial Self-Stimulation Enhances Neurogenesis in Hippocampus of Adult Mice and Rats. Neuroscience, 158, 402-411.
[36] Wanner, S.P., Yoshida, K., Kulchitsky, V.A., Ivanov, A.I., Kanosue, K. and Romanovsky, A.A. (2013) Lipopolysaccharide-Induced Neuronal Activation in the Paraventricular and Dorsomedial Hypothalamus Depends on Ambient Temperature. PLoS ONE, 8, e75733.
[37] Fanous, S., Guez-Barber, D.H., Goldart, E.M., Schrama, R., Theberge, F.R., Shaham, Y., et al. (2013) Unique Gene Alterations Are Induced in FACS-Purified Fos-Positive Neurons Activated during Cue-Induced Relapse to Heroin Seeking. Journal of Neurochemistry, 124, 100-108.
[38] Mayhew, T.M. and Gundersen, H.J. (1996) “If You Assume, You Can Make an Ass Out of U and Me”: A Decade of the Disector for Stereological Counting of Particles in 3D Space. Journal of Anatomy, 188, 1-15.
[39] Jinno, S. and Kosaka, T. (2006) Cellular Architecture of the Mouse Hippocampus: A Quantitative Aspect of Chemically Defined GABAergic Neurons with Stereology. Neuroscience Research, 56, 229-245.
[40] Bechtholt-Gompf, A.J., Walther, H.V., Adams, M.A., Carlezon Jr., W.A., Ongür, D. and Cohen, B.M. (2010) Blockade of Astrocytic Glutamate Uptake in Rats Induces Signs of Anhedonia and Impaired Spatial Memory. Neuropsychopharmacology, 35, 2049-2059.
[41] Suzuki, A., Josselyn, S.A., Frankland, P.W., Masushige, S., Silva, A.J. and Kida, S. (2004) Memory Reconsolidation and Extinction Have Distinct Temporal and Biochemical Signatures. Journal of Neuroscience, 24, 4787-4795.
[42] Stollhoff, N., Menzel, R. and Eisenhardt, D. (2008) One Retrieval Trial Induces Reconsolidation in an Appetitive Learning Paradigm in Honeybees (Apis mellifera). Neurobiology of Learning and Memory, 89, 419-425.
[43] Mickley, G.A., Hoxha, Z., Bacik, S., Kenmuir, C.L., Wellman, J.A., Biada, J.M., et al. (2007) Spontaneous Recovery of a Conditioned Taste Aversion Differentially Alters Extinction-Induced Changes in c-Fos Protein Expression in Rat Amygdala and Neocortex. Brain Research, 1152, 139-157.
[44] Strekalova, T., Zorner, B., Zacher, C., Sadovska, G., Herdegen, T. and Gass, P. (2003) Memory Retrieval after Contextual Fear Conditioning Induces c-Fos and JunB Expression in CA1 Hippocampus. Genes, Brain and Behavior, 2, 3-10.
[45] Reijmers, L.G., Perkins, B.L., Matsuo, N. and Mayford, M. (2007) Localization of a Stable Neural Correlate of Associative Memory. Science, 317, 1230-1233.
[46] Hobin, J.A., Goosens, K.A. and Maren, S. (2003) Context-Dependent Neuronal Activity in the Lateral Amygdala Represents Fear Memories after Extinction. Journal of Neuroscience, 23, 8410-8416.
[47] McKenzie, S. and Eichenbaum, H. (2011) Consolidation and Reconsolidation: Two Lives of Memories? Neuron, 71, 224-233.
[48] Tse, D., Takeuchi, T., Kakeyama, M., Kajii, Y., Okuno, H., Tohyama, C., et al. (2011) Schema-Dependent Gene Activation and Memory Encoding in Neocortex. Science, 333, 891-895.
[49] Kaczmarek, L. and Kaminska, B. (1989) Molecular Biology of Cell Activation. Experimental Cell Research, 183, 24-35.
[50] Clayton, D.F. (2000) The Genomic Action Potential. Neurobiology of Learning and Memory, 74, 185-216.
[51] Edelman, G.M. (1989) Neural Darwinism: The Theory of Neuronal Group Selection. Oxford University Press, Oxford.
[52] McGaugh, J.L. (2000) Memory—A Century of Consolidation. Science, 287, 248-251.
[53] Dudai, Y. (2012) The Restless Engram: Consolidations Never End. Annual Review of Neuroscience, 35, 227-247.
[54] Stickgold, R. and Walker, M.P. (2005) Memory Consolidation and Reconsolidation: What Is the Role of Sleep? Trends in Neurosciences, 28, 408-415.
[55] Best, J., Diniz Behn, C., Poe, G.R. and Booth, V. (2007) Neuronal Models for Sleep-Wake Regulation and Synaptic Reorganization in the Sleeping Hippocampus. Journal of Biological Rhythms, 22, 220-232.
[56] Jackson, C., McCabe, B.J., Nicol, A.U., Grout, A.S., Brown, M.W. and Horn, G. (2008) Dynamics of a Memory Trace: Effects of Sleep on Consolidation. Current Biology, 18, 393-400.
[57] Gorkin, A.G. and Shevchenko, D.G. (1996) Distinctions in the Neuronal Activity of the Rabbit Limbic Cortex under Different Training Strategies. Neuroscience and Behavioral Physiology, 26, 103-112.
[58] Alexandrov, Yu.I., Grinchenko, Y.V., Shevchenko, D.G., Averkin, R.G., Matz, V.N., Laukka, S., et al. (2001) A Subset of Cingulate Cortical Neurones Is Specifically Activated during Alcohol-Acquisition Behaviour. Acta Physiologica Scandinavica, 171, 87-97.
[59] Silberberg, G., Gupta, A. and Markram, H. (2002) Stereotypy in Neocortical Microcircuits. Trends in Neurosciences, 25, 227-230.
[60] Wang, Y., Gupta, A., Toledo-Rodriguez, M., Wu, C.Z. and Markram, H. (2002) Anatomical, Physiological, Molecular and Circuit Properties of Nest Basket Cells in the Developing Somatosensory Cortex. Cerebral Cortex, 12, 395-410.
[61] Peters, A. and Yilmaz, E. (1993) Neuronal Organization in Area 17 of Cat Visual Cortex. Cerebral Cortex, 3, 49-68.
[62] Nakashiba, T., Cushman, J.D., Pelkey, K.A., Renaudineau, S., Buhl, D.L., McHugh, T.J., et al. (2012) Young Dentate Granule Cells Mediate Pattern Separation, whereas Old Granule Cells Facilitate Pattern Completion. Cell, 149, 188-201.
[63] Zangenehpour, S. and Chaudhuri, A. (2002) Differential Induction and Decay Curves of c-fos and zif268 Revealed through Dual Activity Maps. Molecular Brain Research, 109, 221-225.
[64] Acquaviva, C., Bossis, G., Ferrara, P., Brockly, F., Jariel-Encontre, I. and Piechaczyk, M. (2002) Multiple Degradation Pathways for Fos Family Proteins. Annals of the New York Academy of Sciences, 973, 426-434.

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