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"Focusing on connections and signaling mechanisms to dissect cortical plasticity." Michael P. Stryker My thoughts about the science of learning start from the point of view that the engram, the result of learning, must consist of some reasonably specific set of changes in neural connections corresponding to the thing learned. In the area of my own research, the development and plasticity of the central visual system, we have learned something about how to study problems in which neural activity operates to alter connections. I believe that some of these approaches should also be pursued in order to understand learning. Many of my thoughts on the role of neural activity in the development and plasticity of the mammalian central nervous system are outlined in a recent review [1] Major achievement #1: Map and connection formation in the developing visual system consists of both wiring and rewiring and may be an appropriate model for studying mechanisms that also underlie learning. Learning something novel presumably involves formation of some new connections (“wiring”), and the differentiation of learning presumably involves an adjustment of those connection (“rewiring”). It is spontaneous neural activity rather than experience operates in association with intercellular chemical gradient signals to organize the initial functional and anatomical retinotopic maps. Interfering with either the chemical signal or the structured pattern of neural activity produces a somewhat messy but basically normal map of azimuth in primary visual cortex (V1). Interfering with both completely prevents map formation [2]. The normally orderly connections between brain areas form with similar rules, although in the case we have studied the activity signal overcomes the chemical signal when they are in conflict [3]. Major achievement #2: The experience-dependent rewiring of the visual cortex during a critical period in juvenile binocular mammals is perhaps the most dramatic form of activity-dependent plasticity in a circuit that is already fully formed and functional, and in those respects resembles learning. Monocular visual deprivation produces a series of changes in responses to the two eyes as well as a substantial rewiring of cortical circuitry. We have discovered that the characteristic changes in response take place in 3 temporally distinct phases mediated by at least 3 distinct signaling mechanisms: an initial calciumand NMDA-receptor-dependent loss of response to the deprived eye; a subsequent homeostatic synaptic scaling mediated in part by tumor necrosis factor alpha signaling that increases response to the open eye [4] and finally a recovery of response and restoration of connections mediated by BDNF-TrkB signaling when normal vision is restored during the critical period [5]. Two-photon microscopy in vivo of genetically labeled neurons and presynaptic and postsynaptic proteins reveals quantitatively as well as qualitatively which changes are due to rewiring and which due to changes in the efficacy of existing synapses. In the study of learning, it seems possible that different experiences that give rise to different patterns of activity may analagously engage distinct mechanisms to regulate the same set of connections. The biggest challenge for understanding the rewiring underlying most forms of learning is the identification of the neurons whose change in response accounts for the change in behavior. The connections made and received by these neurons could then be examined, and the signaling mechanisms responsible for these changes elucidated. One approach to this problem relies on the hope of increased expression of particular, to date mostly immediate-early, genes by cells responsible for learning [6]. Genetically encoded calcium indicators observed in two-photon microscopy in vivo also have the potential to identify responses in large numbers of neurons in surface structures like the neocortex, and to allow identification with neurons to be studied anatomically. The challenge will be to demonstrate causality of neural changes observed in learning in behavioral experiments. Links to all our papers on these topics at http://brain.cin.ucsf.edu/~idl/reprints-by-topic.htm [1] Espinosa, J.S. and Stryker, M.P. (2012) Development and plasticity of the primary visual cortex. Neuron 75: 230-249. [2] Cang*, J.C., Niell*, C.M., Liu, X., Pfeiffenberger, C., Feldheim, D.A. and Stryker, M.P., (2008) Selective disruption of one Cartesian axis of cortical maps and receptive fields by deficiency in ephrin-As and structured activity. Neuron 57: 511-523. [3] Triplett, J.W., Owens, M.T., Yamada, J., Lemke, G., Cang, J., Stryker, M.P. and Feldheim, D.A. (2009) Retinal input instructs alignment of visual topographic maps. Cell 139: 175-185. [4] Kaneko, M., Stellwagen, D., Malenka, R.C., and Stryker, M.P. (2008). Tumor necrosis factor-alpha mediates one component of competitive, experience-dependent plasticity in developing visual cortex. Neuron 58: 673-680. [5] Kaneko, M., Hanover, J.L. England, P.M.. and Stryker, M.P. (2008) TrkB kinase is required for recovery, but not loss, of cortical responses following monocular deprivation. Nature Neuroscience 11: 497-504. [6] Silva, A.J. et al. (2009). Molecular and cellular approaches to memory allocation in neural circuits. Science 326: 391-395.