LTP takes route in the hippocampus.

Based on behavioral and lesion data and on the discovery of location-specific place cells in the hippocampus, O'Keefe and Nadel proposed that the hippocampus was the neural substrate of a cognitive map, used not only for navigation but as “an objective spatial framework within which the items and events of an organism's experience are located and interrelated” (O'Keefe and Nadel 1978xO'Keefe, J. and Nadel, L. See all ReferencesO'Keefe and Nadel 1978, p. 1). Place cells are hippocampal principal cells whose firing rate increases when the animal is at a particular location—the “place field”—in its environment (O'Keefe and Dostrovsky 1971xO'Keefe, J. and Dostrovsky, J. Brain Res. 1971; 34: 171–175CrossRef | PubMed | Scopus (1897)See all ReferencesO'Keefe and Dostrovsky 1971). The functional properties of these cells have long been a source of fascination for cognitive scientists, as they would appear to provide an important inroad into how learning and memory is encoded. Most research on place cells has focused either on the determinants of their spatial tuning (Redish 1999xRedish, A.D. See all ReferencesRedish 1999) or on the extent to which they encode nonspatial information (Cohen and Eichenbaum 1993xCohen, N.J. and Eichenbaum, H. See all ReferencesCohen and Eichenbaum 1993). Although a number of theoretical models have been proposed to explain how place cells might control navigation, little experimental data exist to test these models. In this issue of NeuronMehta et al. 2000xMehta, M.R., Quirk, M.C., and Wilson, M.A. Neuron. 2000; 25: 707–715Abstract | Full Text | Full Text PDF | PubMedSee all ReferencesMehta et al. 2000 present data that confirm the predictions of a certain subset of these models. While these results do not by themselves prove the validity of the models, they demonstrate a powerful approach to testing the predictions of models based on population analyses of neuronal ensemble data.Mehta et al. recorded ensembles of place cells as rats made stereotyped linear trajectories. An earlier paper reported that, on average, place fields on such linear tracks became larger with experience and shifted backward, opposite to the direction of motion of the rat (Mehta et al. 1997xMehta, M.R., Barnes, C.A., and McNaughton, B.L. Proc. Natl. Acad. Sci. USA. 1997; 94: 8918–8921CrossRef | PubMed | Scopus (274)See all ReferencesMehta et al. 1997). In the current paper, the authors build on this earlier study, which examined the average behavior of populations of neurons, to track what happens on a cell-by-cell basis, and they show that the shapes of individual place fields became skewed over the first five to six laps on each day of recording. The direction of the skew was found to be opposite to the stereotyped path of the rat and thus could potentially explain both the place field expansion and the backward shift demonstrated earlier.How might experience cause such changes in place fields? The authors reasoned that one potential explanation might involve long-term potentiation (LTP) at these hippocampal synapses. To explore this possibility, the authors modeled changes in place field shape using a network that incorporates temporally asymmetric LTP between CA3 and CA1. Since LTP is induced between two neurons if the presynaptic neuron is active before the postsynaptic neuron, but not vice versa (Levy and Steward 1983xLevy, W.B. and Steward, O. Neuroscience. 1983; 8: 791–797CrossRef | PubMed | Scopus (379)See all ReferencesLevy and Steward 1983), synapses between a given place cell and its afferent place cells that fire slightly earlier should be enhanced selectively over synapses between that cell and its afferent cells that fire later. Thus, before experience, both CA3 and CA1 encode the current location of the rat in the model (i.e., the red place cells fire strongly when the rat is centered in the red “place field”) (see panel A in figure). After repetitions of the green–red–yellow–blue trajectory, however, the temporal asymmetry of LTP induction causes an asymmetric strengthening of connections between the CA3 and CA1 place cells. After experience, when the rat is at the same location as before, the newly strengthened connections between the red CA3 cell and the yellow and blue cells in CA1 cause the latter cells to also fire moderately. As a result, the CA1 place fields shift backwards, and the population activity in CA1 now encodes a location slightly ahead of the rat, corresponding to the rat's previously experienced trajectories (see panel B in figure).Figure 101Changes to Place Fields with ExperienceThe size of the circles representing active place cells is proportional to the firing rate, and the line thickness is proportional to synaptic strength. The water maze model is reproduced with permission from Blum and Abbott 1996xBlum, K.I. and Abbott, L.F. Neural Comput. 1996; 8: 85–93CrossRef | PubMedSee all ReferencesBlum and Abbott 1996.View Large Image | View Hi-Res Image | Download PowerPoint SlideIn support of the idea that changes in receptive field properties may involve NMDA-dependent LTP, preliminary reports by Mehta and McNaughton (1997, Soc. Neurosci., abstract) and Ekstrom et al. (1999, Soc. Neurosci., abstract) claim that NMDA receptor blockers eliminate or reduce the place field expansion and backward shift. In addition, while only a correlation, it is interesting to note that the effects of place field expansion have been found to be reduced in aged rats, which generally have deficiencies in LTP and in spatial learning (Shen et al. 1997xShen, J., Barnes, C.A., McNaughton, B.L., Skaggs, W.E., and Weaver, K.L. J. Neurosci. 1997; 17: 6769–6782PubMedSee all ReferencesShen et al. 1997). If these associations between LTP and the effects reported by Mehta et al. hold true, then it adds another important clue into the functions of LTP in the hippocampus. Kentros et al. 1998xKentros, C., Hargreaves, E., Hawkins, R.D., Kandel, E.R., Shapiro, M., and Muller, R.U. Science. 1998; 280: 2121–2126CrossRef | PubMed | Scopus (272)See all ReferencesKentros et al. 1998 recently showed that blocking LTP does not affect place field expression per se, but blocks the maintenance of a stable representation of a novel environment over subsequent exposures to that environment. The present results suggest an additional role for LTP, but it remains to be determined where in the brain these effects really occur and it will be necessary to experimentally tie these results to LTP in different subfields of the hippocampus. For example, it could be that LTP in CA3 is responsible for one effect, whereas LTP in CA1 or dentate gyrus may be responsible for another (or even that the effects are due to LTP-dependent changes upstream from the hippocampus).These results also have relevance to recent computational models of place cells, including models of route learning, sequence learning, and theta phase precession (for references, see Mehta et al. 2000xMehta, M.R., Quirk, M.C., and Wilson, M.A. Neuron. 2000; 25: 707–715Abstract | Full Text | Full Text PDF | PubMedSee all ReferencesMehta et al. 2000). For instanceBlum and Abbott 1996xBlum, K.I. and Abbott, L.F. Neural Comput. 1996; 8: 85–93CrossRef | PubMedSee all ReferencesBlum and Abbott 1996 incorporated temporally asymmetric LTP in a goal finding/navigation model in which the rat learns the Morris water maze task. As the model rat learned the task, shifts in the locations of place fields generated a map of potential routes toward the goal. In the figure, panel A (right) shows the state of their model at the beginning of training, when there is little information encoded in the map. At the end of training (see panel B [right]), the map now encodes the directions at each location that incrementally lead to the hidden platform. The observations made by Mehta et al. in the current paper suggest that such a representation may be encoded in the hippocampus. However, it is not yet known how such a representation would be read out and translated into the motor commands necessary for the rat to follow the route(s) laid out in this map, and there is as yet no evidence that the effect seen by Mehta et al. is actually related to goal finding. A potential means of addressing these issues would be to record multielectrode data on a navigational task similar to the Morris water maze. One predicts that place fields would be symmetric as the rat initially learns the task, but after training place fields would be skewed in a direction away from the general direction toward the learned goal location.Mehta et al. also suggest that these results may have broad relevance to cortical receptive fields in general. Indeed, these results may offer insight into how stereotyped or repeated behaviors or perceptual experiences, such as in reading, skill learning, or enduring thousands of trials in a psychophysics experiment, are encoded and ultimately translated into the increased motor or perceptual performance associated with such tasks (Abbott and Blum 1996xAbbott, L.F. and Blum, K.I. Cereb. Cortex. 1996; 6: 406–416CrossRef | PubMed | Scopus (165)See all ReferencesAbbott and Blum 1996). It might therefore be interesting to look for effects similar to those demonstrated by Mehta et al. in visual or motor cortex. The discovery of such general effects could elucidate a key mechanism by which neuronal populations learn sequences of neural firing patterns that underlie a multitude of perceptual and skill-learning processes.