RUI: Adult neurogenesis: Contributions from the innate immune system

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This project examines the role that the immune system plays in the production of new cells (neurons) in the adult brain. Adult crayfish are used for this research because the cell populations that produce new neurons are much easier to study and manipulate than in other animals commonly used for this type of research. Unlike neural stem cells in other animals such as mice, the population of cells that directly produces new neurons in adult brains do not self-renew; rather, this population appears to be replenished by cells coming from some other source in the body. Previous data indicate that the immune system provides these precursor cells to the adult crayfish brain. The goal of this proposal is to build on this previous research to definitively identify how the immune system contributes to the generation of adult-born neurons. The experiments are designed to test three hypotheses. The first aim examines the hypothesis that circulating blood/immune cells (hemocytes) interact with specific physical locations in the crayfish brain (neurogenic niches), that cause these cells to remain and produce descendants that differentiate into neurons. The second aim examines the hypothesis that hemocytes are chemically attracted to the neurogenic niches by specific molecules. The third aim examines the hypothesis that the nervous system regulates the production of the neural precursors by the immune system via the release of a chemical (serotonin) that biochemically modulates the fate of immune system cells. By clearly identifying these cellular and molecular influences, these studies will contribute to fundamental knowledge about how stem cells enable the production of new neurons in adult brains. This work also contributes to society through training undergraduates in stem cell research, and educating the general public about the value of non-mammalian biological research and the potential for life-long plasticity in the nervous system.In this project, GFP-positive (GFP+) hemocytes originating in transgenic crayfish will be adoptively transferred to recipient non-transgenic animals, and their target organs and differentiated properties will be determined. In addition, GFP+ cells extracted from different regions of the immune system in transgenic crayfish will be used in adoptive transfers to define the tissue origins of cells that are competent to produce adult-born neurons. These studies will also identify local guidance cues that attract hemocytes to the neurogenic niche using in vitro cell migration assays, as well as in situ nucleic acid hybridization and immunocytochemistry to locate candidate molecules that have been identified by transcriptome analyses. Finally, the coordinated regulation of the innate immune system and adult neurogenesis by a 5-HT-activated cytokine (astakine 1; AST1) pathway will be tested. Differential expression and localization of AST1 in niche, brain and immune tissues will be assessed after altering 5-HT levels. By testing the hypothesis that cells originating in the innate immune system produce adult-born neurons, these studies challenge the canonical view that the ectodermal origins of embryonic neural tissues are the sole source of neurons in the adult brain.