, 1967). If one neuron has a synaptic connection with another, the connection can be demonstrated by an increase in the firing probability of the postsynaptic cell, several milliseconds after the presynaptic cell fires. Because

Enzalutamide in vitro correlation is not causation, however, only under special circumstances can an actual synaptic connection be inferred rigorously. One example is in a strong feedforward pathway, such as the retina to the thalamus (Cleland et al., 1971; Mastronarde, 1987; Usrey et al., 1998) or the thalamus to the cortex (Tanaka, 1983; Reid and Alonso, 1995; Reid, 2001). Cross-correlation analysis was highly effective in deciphering the functional logic of thalamocortical connections in the visual system (Figures 1B and 1C; Reid and Alonso, 1995; Alonso et al., 2001; Reid et al., 2001), as well as in the somatosensory (Bruno and Simons, 2002; Swadlow, 1995; Swadlow and Gusev, 2002; see Alonso and Swadlow, 2005) and auditory systems (Miller et al., 2001). Due to the difficulty of recording from more than a handful of neurons at a time (Alonso et al., 2001), this approach was still a long way from Hubel and Wiesel’s dream of recording from “all the afferents projecting upon that cell” (Hubel and

Wiesel, 1962); the number of thalamic afferents to a simple cell is at least 30 (Alonso et al., check details 2001), and the number of cortico-cortical afferents is in the thousands. Further, it is important to emphasize that both the model itself and the supporting data did not exclude a role for intracortical connections in determining the response properties of simple cells (see Priebe and Ferster, 2012 in this issue of Neuron). It is therefore unfortunate that cross-correlation analysis cannot reliably detect weak connections within the cortex (except in the special case of strong feedforward connections, see Alonso and Martinez, 1998). Instead, studies of the functional logic of intracortical circuitry had to wait too for 21st

century approaches that combine optical physiology with network analysis ( Figures 1E and 1F; Bock et al., 2011; Ko et al., 2011). These new approaches hold the promise to achieve complete functional and structural imaging of cortical circuits, so that functional relationships in the network can be examined in principle for any pair of neurons. Before reviewing new methods for examining synaptic connections, it is useful to consider two complementary ways of thinking about connectivity. First, the wiring diagram can be thought of as the substrate of a local computation. In this view, the information delivered by afferent inputs is routed and recombined to yield a different representation of this information—the output—that is relayed to other local circuits. Alternatively, the network can be thought of as storing information (Chklovskii et al., 2004), such as in an associative memory.