Synaptic plasticity and Repair
We study the regulation of synaptic connectivity in the adult neocortex, a brain region affected in numerous developmental and degenerative diseases as well as acute injuries, which are incurable to date. Specifically, we are trying to understand basic principles of synaptic development and plasticity by visualizing and manipulating both rodent and, more recently, human cortical circuits directly in the living brain. We believe this knowledge is ultimately important to understand "what goes wrong" in a range of neurocognitive disorders, including acute injury and neurodegeneration, as well as to enhance the brain regenerative potential. The team uses a multidisciplinary approach, combining advanced molecular genetic and behavioral studies, transplantation of human iPSC-derived neurons (in collaboration with Dr. Rick Livesey in Cambridge), with a variety of neuroimaging techniques such as correlative in vivo 2-photon-electron microscopy, calcium and super-resolution imaging, pharmaco/opto-genetics and MR/PET imaging (in collaboration with Dr. Oliver Howes). For more information visit our personal web page www.DePaolaLab.com.
(A) Cranial window overlying the somatosensory cortex. (B) Vasculature. (C) Same area as in B imaged with 2-photon microscopy. (D) Synaptic loss on lesioned cortical layer 6 axons. (E) Synaptic stability on lesioned cortical layer 2/3 axons. Arrows indicate synapses that are stable (white), gained (green) or lost (red). Scale bar in D, E: 10 μm. Ref. Holtmaat et al. Nature Protocols 2009 and Canty et al. Journal of Neuroscience 2013.
Below a 3D rendering of a regenerating axon (light blue) making a new connection on a dendrite (grey) in the adult brain (from Canty et al. Nature Communication 2013)
et al., 2015, Removing synaptic brakes on learning, Nature Neuroscience, Vol:18, ISSN:1097-6256, Pages:1062-1064
et al., 2013, In vivo single branch axotomy induces GAP-43-dependent sprouting and synaptic remodeling in cerebellar cortex, Proceedings of the National Academy of Sciences of the United States of America, Vol:110, ISSN:0027-8424, Pages:10824-10829
et al., 2013, In-vivo single neuron axotomy triggers axon regeneration to restore synaptic density in specific cortical circuits, Nature Communications, Vol:4, ISSN:2041-1723
et al., 2013, Synaptic elimination and protection after minimal injury depend on cell type and their prelesion structural dynamics in the adult cerebral cortex., Journal of Neuroscience, Vol:33, ISSN:0270-6474, Pages:10374-10383
et al., 2013, Increased axonal bouton dynamics in the aging mouse cortex, Proceedings of the National Academy of Sciences of the United States of America, Vol:110, ISSN:0027-8424, Pages:E1514-E1523
et al., 2011, Axonal Reconstructions Going Live, Neuroinformatics, Vol:9, ISSN:1539-2791, Pages:129-131
et al., 2006, Cell type-specific structural plasticity of axonal branches and boutons in the adult neocortex, Neuron, Vol:49, ISSN:0896-6273, Pages:861-875
et al., 2002, ETS gene Pea3 controls the central position and terminal arborization of specific motor neuron pools, Neuron, Vol:35, ISSN:0896-6273, Pages:877-892
et al., 2003, AMPA receptors regulate dynamic equilibrium of presynaptic terminals in mature hippocampal networks, Nature Neuroscience, Vol:6, ISSN:1097-6256, Pages:491-500
et al., 2009, Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window, Nature Protocols, Vol:4, ISSN:1754-2189, Pages:1128-1144
et al., 2005, Diverse modes of axon elaboration in the developing neocortex, PLOS Biology, Vol:3, ISSN:1544-9173, Pages:1473-1487