Development and Neurobiology Research Faculty
Development of the neurons in the inner ear
The long-term goal of the research in the Coate laboratory will be to define the signaling mechanisms underlying neural development within sensory systems and how synaptic connections can be reestablished in cases of damage or disease. In the field of developmental neuroscience, we are now at an exciting time where we can take multi-faceted approaches to understanding (with excellent temporal and spatial resolution) the mechanisms by which precise cell types coordinate appropriate axon guidance decisions and synapse formation. In our research, we aim to understand the mechanisms by which spiral ganglion neurons (SGNs) make functional connections with mechanosensory hair cells in the mouse cochlea. We are currently addressing how secreted Semaphorins, which activate Neuropilin/Plexin co-receptors, control SGN axon guidance decisions in the cochlear sensory epithelium. We are also investigating how the transcription factor Pou3f4 controls the expression of axon guidance factors in the developing cochlea (such as ephrins and Eph receptors) and how those factors control cochlear innervation. The cochlea provides an excellent model for discovering how circuits assemble within a complex organ system, as it is composed of an array of cell types and structures precisely arranged to detect a range of sound frequencies.
Encoding of Memory
My research program focuses on trying to understand how memories are encoded in the brain and how they are forgotten. This research is significant because it has been suggested that deficits in active forgetting are part of the pathophysiology of human brain disorders like ASD, PTSD or schizophrenia. To develop my research, I use the relatively simple and well-studied Drosophila brain, a biological model that offers tremendous advantages in the study of neuroscience. I am particularly interested in understanding how scaffold proteins regulate memory forgetting. Synaptic scaffolding molecules, which by virtue of their ability to simultaneously bind several proteins play crucial roles in the orchestration of structural and functional building blocks of the synaptic connections.
Plasticity and Stability
The long-term goal of my lab is to unravel the molecular and cellular mechanisms underlying the intricate balance between plasticity and stability of neural circuits in both early embryonic development and adulthood, with a special focus on inhibitory neurons. We use the albino Xenopus laevis (tadpole) as our animal model. The central nervous system of the tadpole is amenable to a wide variety of manipulations from molecular to circuit level. It provides a unique in vivo vertebrate system to study the basic laws governing the organization and formation of nascent neural circuits, where plasticity and stability are both pivotal for the survival of the animal. We use a number of techniques in the lab, including time-lapse in vivo imaging of neuronal structure and function and using bio-orthogonal non-canonical amino acid (BONCAT) to tag activity-induced newly synthesized proteins, as well as behavioral evaluation of visual functions. Current projects include investigating how excitatory and inhibitory synaptic inputs are coordinated in response to experience changes and examining functional roles of the degradation of newly-synthesized protein in maintaining neuronal homeostasis.
Neural regeneration and neuron-glia interaction
The goal of my research is to understand how glial cells regulate neuronal function in the mammalian central nervous system (CNS). We focus on oligodendrocytes, a type of glia, whose cellular processes engage with and enwrap CNS axons, and form the lipid-rich myelin membranes required for rapid, saltatory axonal conduction. Oligodendrocyte loss or dysfunction has profound impact on brain development, homoeostasis, and aging, and has been implicated in many neurological disorders including certain leukodystrophies, multiple sclerosis (MS), cerebral palsy, Alzheimer’s disease, schizophrenia, and autism.
We are currently investigating the mechanisms by which oligodendrocytes interact and communicate with axons, and how their interactions might promote axonal integrity and survival. We are also investigating the mechanism of CNS regeneration, with a focus on how oligodendrocytes regenerate from endogenous neural progenitor cells to replace myelin during homeostatic turnover or after demyelination. We use primary oligodendrocyte/neuron co-cultures, transgenic mice, and models of experimental CNS injury and demyelination, combined with molecular biology and imaging tools to address these questions.
Neurodegeneration and neuroinflammation
The Maguire-Zeiss laboratory studies the role of the brain’s innate immune system in neurodegenerative disorders (Parkinson’s disease, HIV-associated neurocognitive disorder). We investigate the signaling responses of glial cells (microglia and astrocytes) to misfolded or pathogen-associated proteins and the subsequent effect on neuronal function. The lab uses a variety of models to address inflammation and neuronal-glial crosstalk, such as cell lines and primary cells derived from animal models, treatment of cells in vitro and in vivo with recombinant and cell-derived proteins, rAAV overexpression of proteins, and transgenic mouse models. We combine these models with biochemical, molecular, and imaging approaches in an effort to identify novel mechanisms of disease. Our hope is that this primary focus on understanding signaling pathways in brain cells will reveal new therapeutic targets for neurodegenerative disorders.
Neural induction in Xenopus laevis
The goal of the Silva lab is to understand the transcriptional regulation of a class of genes involved in the formation of the early vertebrate body plan. Patterning events such as the establishment of neural tissues require a series of signal transduction events that lead to the transcription of a set of genes. Few of the details of transcriptional regulation in vertebrate development have been deciphered. However, the ability to generate transgenic frogs has revolutionized the field, allowing rapid analysis of promoter function in a large number of embryos. This technique, along with embryology, traditional biochemical and molecular assays, and expression screens now enable us to define the factors required for regulation of genes involved in early vertebrate development.