The calcium signal in this area was specific for the retrieval of a long-term memory from a learned avoidance behavioral program, because it was not present immediately after fish were trained to criterion. This response was accompanied by the emergence of neurons in the area becoming sharply tuned to the cue onset and presumably entrained by learning. Finally, when the behavioral rule was changed, a distinct

ensemble of neurons was recruited for memory retrieval. Together, these results provide a functional characterization of cortical mnemonic activity necessary for the retrieval and rapid OSI-906 mouse modification of a learned associative behavioral program in the vertebrate brain. The activity we observed was delayed in appearance check details because it did not appear even when fish had effectively retrieved the task at 30 min after training. These results support

the interpretation that the bilateral activity we observed is specific to associative retrieval from long-term memory of the learned avoidance program. Long-term memory is believed to be stored in cortical sites in mammalian brain. According to the comparative pallial organization of teleosts with that of mammals, the activated areas within Dc may correspond to mammalian cortex (Mueller and Wullimann, 2009). In support of this idea, these regions express ephA4a and are rich in glutamatergic neurons ( Figures S4E–S4J). In mammals, long-lasting associative memories are known to be gradually established within the cortex through time-dependent coordinated hippocampal-cortical interactions on the order of heptaminol months (Maviel et al., 2004; Frankland et al., 2004). However, it has been demonstrated that a memory-specific subset of cortical neurons may be engaged shortly after learning for the later establishment of a long-lasting remote memory (Yasuda

and Mayford, 2006; Lesburguères et al., 2011; Tse et al., 2011). This process depends on both AMPA- and N-methyl-D-aspartate (NMDA) receptors and thus presumably accompanies an activity-dependent intracellular Ca2+ increase ( Lesburguères et al., 2011; Tse et al., 2011). Moreover, NMDA receptor-based Ca2+ activities are thought to initiate the memory formation by activating Ca2+/calmodulin-dependent protein kinase (CaMKII), a key activator of long-term potentiation (LTP) at synapses ( Mayford, 2007; Yasuda and Mayford, 2006). Therefore, the calcium signals specific to the retrieval of a behavioral program observed in our experiments could reflect an ongoing consolidation process. We detected a learning-dependent change in the firing pattern of zebrafish neurons from cue inhibited to highly cue tuned. These results suggest that learning-entrained neurons become tuned to the cue by the modification of a local inhibitory circuit.