The goal of this proposal is to elucidate the mechanisms of cortical structural plasticity by combining innovative in vivo imaging technology with classical visual manipulations. This integrative approach holds the potential to revolutionize our understanding of adaptive circuit modification, a fundamental aspect of brain function. Characterizing the dynamic potential of cortical neurons will provide a baseline for future testing of molecules with therapeutic potential for promoting plasticity in the cerebral cortex. Such molecules may be used to compensate for insults or deterioration at multiple levels of the visual pathway. To investigate the mechanisms underlying structural plasticity in the mammalian brain we utilized a multi- photon microscope system for chronic in vivo imaging of neuronal morphology in the intact rodent cerebral cortex. Using this system we have imaged and reconstructed the dendritic trees of neurons in visual cortex of thy1-GFP transgenic mice. These mice express GFP in a random subset of neurons sparsely distributed within the superficial cortical layers that are optically accessible through surgically implanted cranial windows. We will chronically image neurons in the superficial layers of the neocortex in control thy1-GFP mice, or thy1-GFP mice before, during, and after visual perturbations, to address the following aims:
Specific aim 1 : To clarify cell type-specific rules that delimit structural plasticity in the adult cortex, we will conduct a survey of structural dynamics in a cross section of neurons that reflects the diversity of neocortical cell types within the superficial layers of visual cortex. A comparative analysis of visual, somatosensory, and pre-frontal cortex will allow us to address whether interneuron remodeling is a general phenomenon.
Specific aim 2 : To investigate the role of visual experience in structural dynamics of layer 2/3 cortical neurons, we will manipulate visual input using experimental protocols that produce ocular dominance (OD) plasticity in the adult rodent cortex: prolonged monocular lid suture, monocular lid suture preceded by a previous monocular deprivation (MD), or monocular lid suture preceded by dark adaptation. For comparison, we will also apply two additional manipulations, binocular deprivation (BD) and monocular blockade by intraocular TTX injection. By comparing dendritic arbor changes in the cortex of untreated adult thy1-GFP mice with those in mice after a long MD, after a brief MD primed by a previous deprivation or by dark adaptation, after BD, or intraocular TTX injection, we can test the hypothesis that only the forms of activity that produce OD shifts will also enhance structural plasticity in the imaged neurons. Principle component analysis and cluster analysis will be used to quantitatively classify and analyze the morphological and cellular characteristics of imaged neurons. Cluster analysis should provide insight as to whether there are interneuron cell types that are more structurally plastic than others, and whether subsets of interneurons exhibit structural plasticity correlated with OD plasticity.
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