Complexity of neural systems often makes impracticable explicit measurements of all interactions between their constituents. Inverse statistical physics approaches, which infer effective couplings between neurons from their spiking activity, have been so far hindered by their computational complexity. Here, we present 2 complementary, computationally efficient inverse algorithms based on the Ising and ''leaky integrate-and-fire'' models. We apply those algorithms to reanalyze multielectrode recordings in the salamander retina in darkness and under random visual stimulus. We find strong positive couplings between nearby ganglion cells common to both stimuli, whereas long-range couplings appear under random stimulus only. The uncertainty on the inferred couplings due to limitations in the recordings (duration, small area covered on the retina) is discussed. Our methods will allow realtime evaluation of couplings for large assemblies of neurons.inference and inverse problems ͉ multielectrode recordings ͉ neural couplings A vertebrate retina is a structured, complex network of interacting neurons that process visual input stimuli at the photoreceptors into an output pattern of action potentials of the retinal ganglion cells (1-2). It is now a well-established fact that retinal cells process information in a collective fashion: The firing of one ganglion cell is correlated with the firing pattern of other cells (3-4). Multielectrode recordings have made accessible hours-long, simultaneous spiking activity of tens of retinal ganglion cells and thus have become a powerful tool to investigate the information processing performed by a vertebrate retina (5-7). The analysis of pairwise correlations in the activity has revealed different patterns of synchrony between 2 cells that have been related to different retina circuits (7).Analyzing the concerted activity of all of the recorded cells is, however, a very challenging task. Recently Schneidman et al. (8) and Shlens et al. (9) pointed out that correlations in the firing activity of cell populations can be reconstructed from the average firing rates, f i , and 2-cell correlations, c ij , alone. The theoretical model, which has been used to generate the frequencies of all possible 2 N spiking configurations for a system of N neurons, is the well-known Ising model. It is characterized by a reduced set of ϷN 2 parameters: N ''fields,'' h i , experienced by individual cells, and N(N Ϫ 1)/2 ''couplings,'' J ij , between pairs of cells. Computing the parameters h i and J ij from the firing patterns can be viewed as an example of the inverse statistical physics method.The existence of a low-dimensional parameterization of the retinal activity (8-11) is an interesting and encouraging result. Naively, one may be tempted to assign to the inferred parameters a simple interpretation: The fields could represent the external stimuli, and the couplings could reflect the physiological interactions between the cells. However, because most of the neural circuitry (all cells in intermediat...