Sensitivity of cortical cells to precisely timed paired pulse stimulation in culture

Recurring firing patterns with high temporal precision involving two or more neurons have been observed in many neural systems, including cortex. Precisely timed spike trains, especially if synchronized between several neurons, carry much more information than can be transmitted through a simple rate code (Rieke et al. 1997). The question remains whether animals actually exploit this source of information: Do neurons respond specifically to correlated inputs (Alonso et al. 1996; Roy and Alloway 2001)? After all, it is hardly surprising that correlations in firing patterns occur in cells that have partially overlapping receptive fields; if no downstream neuron responds specifically to correlations, they are mere epiphenomena. Despite years of theoretical argumentation and observational experiments, the question whether millisecond scale timing is used broadly 1 in cortical coding remains unresolved, with increasing polarization between camps. Proponents have argued that precisely timed activity does occur in many cortical areas including visual cortex (Brecht et al. 1998) and pre-motor cortex (Prut et al. 1998), and why wouldn’t these correlations be used? Correlations between firing patterns in pairs of cells in LGN can be used by experimenters to reconstruct more information about visual stimuli than can be obtained from reading the two spike trains independently (Dan et al. 1998). Thus, LGN encodes stimulus information in correlations between pairs of firing cells, and Alonso et al. (1996) have demonstrated a correlation between the level of synchrony in LGN neurons and the activity of their targets in V1. Moreover, cells were found in motor cortex that increased their synchrony without changing their firing rate while the animal performed certain behaviors (Riehle et al. 1997), and in pre-motor cortex recurring sequences of three or more precisely timed spikes were observed, some of which were linked to particular overt behaviors (Prut et al. 1998). Similar patterns have been reported in hippocampus (Ńadasdy et al. 1999; Ń adasdy 2000). All these examples indicate that there might be a link between the degree of synchronization between sets of neurons and the impact on their target cells. Opponents have pointed out that in none of these cases is there direct proof that the precise timing itself is responsible for the response: For example in the case of synchrony in motor cortex, it remains possible that this synchrony is a side effect of increased firing in a non-observed cell that is directly responsible for the behavior (Shadlen and Movshon 1999). Furthermore, models have been used to argue that relatively small networks of neurons can decode a pure rate code within one inter-spike interval (Shadlen and Newsome 1998), weakening the strength of the informationtheoretical argument. However, there exists a large literature of modelling studies that indicate that synchrony in synaptic inputs matters to neurons. Both detailed single cell models (Mel 1993; Azouz and Gray 2000) and large scale network models (Lumer et al. 1997) have been used to argue that spike output depends on precise timing of inputs. Electrophysiology on single cells has provided further