We used fluorescent in-situ hybridization and confocal microscopy to monitor the subcellular distribution of the immediate-early gene Arc. Arc RNA appeared in discrete intranuclear foci within minutes of neuronal activation and subsequently disappeared from the nucleus and accumulated in the cytoplasm by 30 minutes. The time course of nuclear versus cytoplasmic Arc RNA accumulation was distinct, and could therefore be used to infer the activity history of individual neurons at two times. Following sequential exposure of rats to two different environments or to the same environment twice, the proportion of CA1 neurons with cytoplasmic, nuclear or overlapping Arc expression profiles matched predictions derived from ensemble neurophysiological recordings of hippocampal neuronal ensembles. Arc gene induction is thus specifically linked to neural encoding processes.
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Morgan, J. I., Cohen, D. R., Hempstead, J. L. & Curran, T. Mapping patterns of c-fos expression in the central nervous system after seizure. Science 237, 192–197 (1987).
Kubie, J. L. & Ranck, J. B. J. in Neurobiology of the Hippocampus (ed. Seifert, W.) 433–447 (Academic, New York, 1983).
Gothard, K. M., Skaggs, W. E., Moore, K. M. & McNaughton, B. L. Binding of hippocampal CA1 neural activity to multiple reference frames in a landmark-based navigation task. J. Neurosci. 16, 823–835 (1996).
Wilson, M. A. & McNaughton, B. L. Dynamics of the hippocampal ensemble code for space. Science 261, 1055–1058 (1993).
Lyford, G. L. et al. Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites. Neuron 14, 433–445 (1995).
Link, W. et al. Somatodendritic expression of an immediate-early gene is regulated by synaptic activity. Proc. Natl. Acad. Sci. USA 92, 5734–5738 (1995).
Thompson, L. T. & Best, P. J. Long-term stability of the place-field activity of single units recorded from the dorsal hippocampus of freely moving rats. Brain Res. 509, 299–308 (1990).
Lanahan, A. A. & Worley, P. F. Immediate-early genes and synaptic function. Neurobiol. Learn. Mem. 70, 37–43 (1998).
Cole, A. J., Saffen, D. W., Baraban, J. M. & Worley, P. F. Rapid increase of an immediate early gene messenger RNA in hippocampal neurons by synaptic NMDA receptor activation. Nature 340, 474–476 (1989).
Wallace, C., Lyford, G. L., Worley, P. F. & Steward, O. Differential intracellular sorting of immediate-early gene mRNAs depends on signals in the mRNA sequence. J. Neurosci. 18, 26–35 (1998).
Jung, M. W. & McNaughton, B. L. Spatial selectivity of unit activity in the hippocampal granular layer. Hippocampus 3, 165–182 (1993).
Cirelli, C., Pompeiano, M. & Tononi, G. In vivo antisense approaches to the role of immediate early gene expression in the brain. Regul. Pept. 59, 151–162 (1995).
Steward, O., Wallace, C. S., Lyford, G. L. & Worley, P. F. Synaptic activation causes the mRNA for the immediate early gene Arc to localize selectively near activated postsynaptic sites on neuronal dendrites. Neuron 21, 741–751 (1998).
Skaggs, W. E. & McNaughton, B. L. Spatial firing properties of hippocampal CA1 populations in an environment containing two visually identical regions. J. Neurosci. 18, 8455–8466 (1998).
Knierim, J. J., Kudrimoti, H. S. & McNaughton, B. L. Interactions between idiothetic cues and external landmarks in the control of place cells and head direction cells. J. Neurophysiol. 80, 425–446 (1998).
O'Keefe, J. & Burgess, N. Geometric determinants of the place fields of hippocampal neurons. Nature 381, 425–428 (1996).
Tanila, H., Shapiro, M. L. & Eichenbaum, H. Discordance of spatial representation in ensembles of hippocampal place cells. Hippocampus 7, 613–623 (1997).
Wood, E. R., Dudchenko, P. A. & Eichenbaum, H. The global record of memory in hippocampal neuronal activity. Nature 397, 613–616 (1999).
Femino, A. M., Fay, F. S., Fogarty, K. & Singer, R. H. Visualization of single RNA transcripts in situ. Science 280, 585–590 (1998).
Trembleau, A. & Bloom, F. E. Subcellular localization of tyrosine hydroxylase (TH) gene transcripts: New insights into the pattern of TH gene expression in the locus coeruleus under pharmacological stimulation. Biol. Cell 90, 39–51 (1998).
Hess, U. S., Lynch, G. & Gall, C. M. Changes in c-fos mRNA expression in rat brain during odor discrimination learning: Differential involvement of hippocampal subfields CA1 and CA3. J. Neurosci. 15, 4786–4795 (1995).
Grimm, R. & Tischmeyer, W. Complex patterns of immediate-early gene induction in rat brain following brightness discrimination training and pseudotraining. Behav. Brain Res. 84, 109–116 (1997).
Wan, H., Aggleton, J. P. & Brown, M. W. Different contributions of the hippocampus and perirhinal cortex to recognition memory. J. Neurosci. 19, 1142–1148 (1999).
Kentros, C. et al. Abolition of long-term stability of new hippocampal place cell maps by NMDA receptor blockade. Science 280, 2121–2126 (1998).
Cole, A., Abu-Shakra, S., Saffen, D., Baraban, J. & Worley, P. Rapid rise in transcription factor messenger RNAs in rat brain after electroshock induced seizures. J. Neurochem. 55, 1920–1927 (1990).
Christy, B. A., Lau, L. F. & Nathans, D. A gene activated in mouse 3T3 cells by serum growth factors encodes a protein with "zinc finger" sequences. Proc. Natl. Acad. Sci. USA 85, 7857–7861 (1988).
West, M. J. New stereological methods for counting neurons. Neurobiol. Aging 14, 275–285 (1993).
Paxinos, G. & Watson, C. The Rat Brain in Stereotaxic Coordinates (Academic, San Diego, 1986).
We thank G. Stevenson, F. Houston and M. Papapavlou for technical assistance. This work was supported by the National Institute on Aging and the National Institute of Mental Health.
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Guzowski, J., McNaughton, B., Barnes, C. et al. Environment-specific expression of the immediate-early gene Arc in hippocampal neuronal ensembles. Nat Neurosci 2, 1120–1124 (1999). https://doi.org/10.1038/16046
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