barrel cortex; 2-photon microscopy; long-term potentiation; experience-dependent plasticity; synaptic plasticity; dendritic spines
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Cortical map plasticity and learning are thought to rely on structural and activity-dependent forms of plasticity. Hebbian-like plasticity, in which neurons that fire together wire together, is thought to be a key process. For example, long-term potentiation (LTP) of synapses may serve to strengthen pre-established synapses and stabilize newly formed synapses between neurons that are co-activated. The relationship between coincident neuronal activity, cortical plasticity and structural network changes in vivo remains unclear, and is the subject of the current proposal.We hypothesize that (exogenously) forced coincident activity of neurons in the mouse somatosensory cortex in vivo will evoke structural synaptic changes and consequently drive alterations in their receptive fields. In our research proposal we aim at finding causal relationships between synaptic structure dynamics and receptive field plasticity in the barrel cortex.We will follow a targeted approach in which we employ three recently developed cortical activity-dependent plasticity paradigms. In the first approach we will use a rhythmic whisker stimulation protocol (a purely sensory stimulus) to elicit LTP in layer 2/3 (L2/3) pyramidal cells. In the second approach we will utilize the light-gated channel channelrhodopsin-2 (ChR2) to non-invasively elicit LTP, by combining whisker-evoked synaptic input with photostimulation-mediated activation of various cortical neuronal networks. In the third approach we will investigate the structural consequences of a photostimulation-based learning task. In all approaches, we will perform 2-photon laser scanning microscopy of fluorescent proteins (XFPs) that mark synaptic morphology (cytosolic XFPs, PSD-95-XFP, Synaptophysin-XFP) and/or genetically encoded Ca2+ sensors (GCaMPs) to monitor over days to weeks synaptic structural dynamics and the size and strength of receptive fields respectively. Since plasticity will be specifically induced in a small subset of neurons and be confined to anatomically well-defined networks we will be able to compare the plasticity between those neurons that were activated and those that were not within the same cortical structure. This will allow us to make strong predictions about the causality between the various forms of plasticity. Our proposal will further our understanding of the links between structural and functional aspects of activity-dependent plasticity. This may help to advance the design of strategies towards the treatment of traumatic brain injuries or neurodegenerative and psychiatric diseases that are characterized by synaptopathies.