Abstract
Animals can learn causal relationships between pairs of stimuli separated in time and this ability depends on the hippocampus. Such learning is believed to emerge from alterations in network connectivity, but large-scale connectivity is difficult to measure directly, especially during learning. Here, we show that area CA1 cells converge to time-locked firing sequences that bridge the two stimuli paired during training, and this phenomenon is coupled to a reorganization of network correlations. Using two-photon calcium imaging of mouse hippocampal neurons we find that co-time-tuned neurons exhibit enhanced spontaneous activity correlations that increase just prior to learning. While time-tuned cells are not spatially organized, spontaneously correlated cells do fall into distinct spatial clusters that change as a result of learning. We propose that the spatial re-organization of correlation clusters reflects global network connectivity changes that are responsible for the emergence of the sequentially-timed activity of cell-groups underlying the learned behavior. DOI: http://dx.doi.org/10.7554/eLife.01982.001.
Highlights
The mechanisms of memory formation have been the subject of considerable study (Morris et al, 1988; Kandel, 2001)
Head-restrained mice were trained on a trace eyeblink conditioning task (Tseng et al, 2004), where they learned to associate a neutral tone stimulus (Conditioned Stimulus–conditioned stimulus (CS)) with an aversive puff of air to the eye (Unconditioned Stimulus–unconditioned stimulus (US)) within a single session (‘Materials and methods-Behavioral training’)
We found that naïve mice responded to tone presentation with small, but distinct and measurable eyelid movements early in training, even on trials prior to the introduction of the puff stimulus (Figure 1C)
Summary
The mechanisms of memory formation have been the subject of considerable study (Morris et al, 1988; Kandel, 2001). Much evidence points to Hebbian plasticity as the neural mechanism for the association of two co-occurring stimuli (Bliss and Collingridge, 1993; Morris, 2003) This mechanism alone is not sufficient to account for learning under conditions where the two stimuli are separated in time by more than 100 ms (Levy and Steward, 1983), as has been commonly observed (Solomon et al, 1986; Baeg et al, 2003). Lesion studies have shown that the hippocampus is required for learning the trace conditioning task, but not a related delay conditioning task, where the CS and US overlap in time (Büchel et al, 1999; Tseng et al, 2004) These observations indicate a role for the hippocampus during the association of temporally discontiguous events (Wallenstein et al, 1998), during the ‘trace’ period separating stimulus pairs
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