New neurons are added to both the adult olfactory bulb and the olfactory sensory neuron (OSN) population throughout life. This continuous neurogenesis allows for adaptive structural responses to sensory experience, olfactory learning, and even injury that continuously shape functional circuitry to fit the behavioral needs of the animal. Production of new bulb interneurons occurs in excess of the numbers that will ultimately integrate, and those that fail are eliminated by apoptosis, a situation reminiscent of developmental neuron death. Activity plays a role in selecting new cells for survival, and impacts the sensory neuron population as well, making it likely that these effects are coordinated to structurally modify responsive olfactory circuits. The underlying cellular mechanisms are not known, but neurotrophic factors are attractive candidate molecules. They exhibit activity-dependent expression, and during development, play essential roles in sculpting neuronal circuitry by regulating neuronal apoptosis and stabilizing connections. In other adult systems that add neurons, notably the song nuclei of male birds, members of the NGF family of neurotrophins regulate seasonal neuronal survival and are obtained from local sources, and by anterograde transport from innervating populations. We hypothesize that similar mechanisms work in the primary olfactory pathway to modulate survival of new neurons in adults. Evidence for this comes from transgenic mice expressing the LacZ reporter under control of neurotrophin promoters;the transgene products are expressed in subpopulations of OSNs, and in their axon projections to the olfactory bulb. Results from studies localizing the native peptides or mRNAs have been inconclusive. To test the hypothesis that OSNs express neurotrophins, and transport the peptides to the adult olfactory bulb, we will 1) use laser capture micro-dissection and quantitative PCR to measure levels of neurotrophin mRNAs in OSNs, and 2) infect OSNs in vivo with adenovirus vectors we have designed to introduce genes encoding neurotrophin- green fluorescent protein (GFP) fusion proteins. Expression of the GFP-tagged peptides will make it possible to monitor neurotrophin trafficking in these cells. These studies will provide insights into mechanisms underlying the plasticity of adult neural circuits that undergo neuronal replacement.
Adult neurogenesis provides the olfactory system with a continuous supply of new neurons throughout life, a process that is regulated by sensory experience. Communication between odor-stimulated sensory neurons and their target neurons coordinates adaptive changes in these populations. Potential signaling molecules involved in this communication include trophic factors. In this proposal, adenovirus vectors will be used to transfer genes encoding trophic factor-GFP fusion peptides into sensory neurons to determine if these peptides are anterogradely supplied to target neurons in vivo.
| Isgor, C; Pare, C; McDole, B et al. (2015) Expansion of the dentate mossy fiber-CA3 projection in the brain-derived neurotrophic factor-enriched mouse hippocampus. Neuroscience 288:10-23 |
| Liu, Huan; Lu, Michael; Guthrie, Kathleen M (2013) Anterograde trafficking of neurotrophin-3 in the adult olfactory system in vivo. Exp Neurol 241:125-37 |
| Liu, Huan; Guthrie, Kathleen M (2011) Neuronal replacement in the injured olfactory bulb. Exp Neurol 228:270-82 |
