Research Assistant Professor of Biomedical Engineering; Primary faculty - UNC Neuroscience Center and Carolina Institute for Developmental Disabilities
UNC Chapel Hill 111 Mason Farm Rd 4340C MBRB Chapel Hill, NC 27599-7575 (919) 843-8156
Postdoc, California Institute of Technology Ph.D. Biomedical Engineering, University of California, Irvine B.S. Civil Engineering, B.S. Engineering and Public Policy, Washington University in St. Louis
Research and Publications:
Research Area: Biomedical Microdevices
Research Interests: Micro-Scale Devices, Microfluidics, Synapse Formation, Synaptic Plasticity, Protein Synthesis, neuron-based micro-devices, synaptic plasticity, neuron-based assay development, injury-induced synaptic remodeling
Research: Our lab exploits micro-scale technology and microfluidics as experimental tools to spatially and temporally probe synapses of the CNS. We are also focused on basic science research, using these tools to understand the role of local translation during synapse development and how synapse function is altered following injury and in neurodevelopmental disorders. We are interested in developing therapeutic strategies that have clinical relevance to promote proper synapse re-formation and circuit development.
1. Cellular determinants of synaptic remodeling after axotomy in pyramidal neurons
Brain injury and stroke induce significant synaptic reorganization, even in remote uninjured cortical regions. This enhanced plasticity makes the brain particularly receptive to therapeutic interventions following injury. While this plasticity is a guiding principle in clinical rehabilitation, very little is known about its cellular basis. Long projection pyramidal neurons which have somatodendritic domains housed in cortex, extend axons into numerous distant areas of the CNS, including the spinal cord and apposing cortical hemisphere. Following distal axon injury, enhanced excitability occurs in cortical layers containing pyramidal somatodendritic regions due to loss of local GABAergic inhibition which unmask preexisting excitatory connections. While enhanced excitability contributes to neural plasticity, there are also negative aspects of hyper-excitability such as excitotoxicity and increase risk of seizures. Because of the importance of pyramidal neurons in injury and disease, are interested in determining the progression of events that occur intrinsically within pyramidal neurons following distal axonal injury to affect retrograde synaptic remodeling and alter excitability. We use a microfluidic approach to specifically identify long projecting pyramidal neurons using retrograde labeling and subject them to axonal injury at an unprecedented distance away from their somatodendritic compartments. This has allowed us, for the first time, to examine how synapses onto these directly injured neurons are altered over time and to examine the trans-synaptic changes that influence excitability of their uninjured synaptic inputs (Nagendran et al., BioRxiv, 2016). Future studies will focus on determining the signaling cascade and in vivo therapeutic potential of key signaling molecules in collaboration with Prof. Randolph Nudo at the University of Kansas Medical Center.
2. Microfluidic tools for studying neurons
Neurons are highly specialized, polarized cells with a cell body, an axon that transmits signals, and dendrites that receive signals. Traditional neuron-cell culture approaches result in random outgrowth of processes which prevent the study of neurons in their unique polarized morphology. Neurons extend processes over long distances and can experience multiple local environments; thus, their study demands an approach able to examine soma, axon and dendrite domains separately. One of my major contributions to science has been the development of the first microfluidic device to compartmentalize neurons which has opened the door for multiple novel investigations that were not previously possible. The resulting paper in Nature Methods has been cited over 500 times. While in Erin Schuman’s lab as a postdoc, I developed another novel microfluidic device to visualize and manipulate synapses (Taylor et al., Neuron, 2010). In my own laboratory, I designed and fabricated a microfluidic device to expose axons to extremely stable soluble gradients for axon guidance studies (Taylor et al., Lab Chip, 2015). This latter device uses only passive forces (no pumps), making it easily accessible to biologists. Our collaborator at UNC, Prof. Stephanie Gupton (Cell Biology and Physiology) has now adopted this method for her axon guidance studies (Menon et al., Dev Cell, 2015). In collaboration with Michael Dickey at NC State (Chemical Engineering), we used eutectic gallium indium (a.k.a., liquid metal) to pattern electrodes within a single microfluidic device allowing us to target and align electrodes with subcellular resolution (Hallfors et al., Lab Chip, 2013). These techniques are straightforward and eliminate the need for manual alignment. We have numerous collaboration underway focusing on making easy-to-use devices that will enable novel investigations in neurobiology.
3. Axonal mRNA translation during synaptogenesis and synaptic plasticity
During development pyramidal neurons extend long axons to form appropriate connections in remote regions of the CNS. These distal axons have considerable autonomy to form and modify functional synapses in response to local cues from target cells. During synapse maturation changes occur locally at presynaptic terminals, including an enlargement of the synaptic vesicle pool and a reduced rate of synaptic vesicle release. The mechanism by which synaptic vesicles accumulate and release rate is modified at distal presynaptic terminals with autonomy from the rest of the neuron is of fundamental importance to brain development, learning and memory.
The identification of polyribosomes within dendrites has directed attention for local mRNA translation toward the postsynaptic compartment. Little is known about axonal translation in the CNS, mainly because of the difficulty in visualizing and manipulating presynaptic terminals in isolation without the overwhelming signal from the larger-diameter postsynaptic compartment. Using microfluidic tools, I initiated and led a project to characterize the uninjured and regenerating axonal transcriptome of mature cortical neurons (Taylor et al., J Neurosci, 2009). I subsequently identified ribosomal RNA and mRNA within presynaptic terminals which may regulate presynaptic vesicle release (Taylor et al., J Neurosci, 2013). More recently we have examined the transcriptome localized to distal projections of human neurons differentiated for stem cells (Bigler et al, BioRxiv, 2016). These works have contributed to our understanding of the autonomy of synapse development and may lead to fundamental insights into how neurodevelopmental disorders involving dysregulation of mRNA targeting and local translation, such as fragile X syndrome, may lead to abnormal circuit development. Our current work continues to focus on the role that axonal translation plays in synapse development and plasticity.