Neurogenesis of olfactory sensory neurons is an ongoing process that starts early in development, continues in adults, and requires that newly generated axons successfully navigate through the lamina propria, cross the cribriform plate and enter the central nervous system. At the same time axonal debris from the neurons that die needs to be removed. The goal of this proposal is by studying the regenerative capacity of the olfactory epithelium to understand what are the interactions between olfactory sensory neuron axonal debris, olfactory ensheathing glia, and microglia during regeneration. Despite the interest in the regeneration process of these neurons for its potential therapeutic use, the most fundamental features of injury-related axon growth remain unknown. The same can be said about the olfactory ensheathing glia that allows this axonal outgrowth. An important event to allow the growing of new axons is the removal of the old ones after the cell body of the olfactory sensory neuron died. This is done without any signs of infiltration of microglia in the olfactory nerve layer of the olfactory bulb. We will begin addressing these questions by using a chemical ablation approach together with our recently developed genetic fate mapping strategy. With this transgenic mouse, axons can be tracked with extraordinary precision. Injury to the olfactory epithelium will be done by a single injection of methimazole. Methimazole is a drug commonly used to treat hyperthyroidism in humans with side effects that include temporal loss of the sense of smell. In mice, methimazole induces loss of the olfactory epithelium leaving only stem cells that regenerate the lost neurons. First, we will compare the ability of ensheathing glial cells versus mononuclear phagocytes to engulf degenerating axons. Because our preliminary data shows no increase in the infiltration of mononuclear phagocytes, but changes in their morphology were observed, in the second part of this proposal we will analyze the differentiation of these phagocytes. Finally, we will look into the signaling molecules that differentiate mononuclear phagocytes without producing an inflammatory response. The results obtained with this proposal will prove to be critical in understanding the regeneration process and will be of general interest to understand how a response to an injury in the central nervous system can proceed with a minimal inflammatory response.
Loss of the sense of smell is an early indicator of several major neurological diseases in humans including Alzheimer?s disease, Parkinson?s disease, and schizophrenia. Olfactory sensory neurons are constantly dying and being generated in the nasal cavity, and they extend an axon that navigates into the central nervous system while the remains of the dead cells need to be removed. This project proposes understanding the interaction between dying olfactory sensory neuron axons, olfactory ensheathing glia cells, and microglia to understand how this process occurs without major inflammatory responses.
