Thus, for a circuit consisting of N neurons, there may be of order N2 nonlinear synaptic interactions. This modeling challenge has traditionally been tackled by two highly disparate approaches. Conceptual models use strong simplifying assumptions on the forms of synaptic connectivity and neuronal responses to provide tractability in modeling complex neural circuits (Figure 1). Although such studies provide qualitative insight, the chosen assumptions limit the set of possible mechanisms explored and make close comparison

to experiment difficult. Alternatively, to make close contact with experiment, other studies have used brute-force explorations Screening Library chemical structure of the large parameter space defined by multiple intrinsic

and synaptic variables (Goldman et al., 2001, Prinz, 2007 and Prinz et al., 2004). These studies have successfully demonstrated how circuit function can be highly sensitive to changes in certain combinations of parameters but insensitive to changes in others. However, the combinatoric explosion of parameter combinations has limited such studies to exploration of approximately ten or fewer parameters at a time, a minute fraction of the total parameter space needed to fully describe a circuit. Here we describe a modeling framework in which a wide range of experimental data from cellular, network, and behavioral investigations are directly incorporated into a single coherent model, while predictions for difficult-to-measure quantities, such as synaptic connection strengths and synaptic PF-01367338 clinical trial nonlinearities, are generated by directly fitting the model Ergoloid to these data. This approach is applied to data from a well-characterized circuit exhibiting persistent neural activity, the oculomotor neural integrator of the eye movement system (Robinson, 1989). This circuit receives transient inputs that encode the desired velocity of the eyes, and stores the running total of these inputs (the desired eye position) as a pattern of persistent neuronal firing across a population of cells. Such maintenance of a running total represents the defining feature of temporal integrators or

accumulators, which are widely found in neural systems (Gold and Shadlen, 2007, Goldman et al., 2009 and Major and Tank, 2004). Previous studies of the goldfish oculomotor integrator have gathered data at each of the levels of analysis typical of studies of memory systems: intrinsic cellular properties (Aksay et al., 2001), anatomy (Aksay et al., 2000), behavior (Aksay et al., 2000), and functional circuit interactions (Aksay et al., 2003 and Aksay et al., 2007). Thus, this system provides an ideal setting in which to illustrate how data at each of these levels can be coherently combined to gain a fuller understanding of memory-guided behavior. The results described below comprise the following principal findings.