Fundamental to furthering our understanding of the brain is the ability to longitudinally track changes in gene expression over time in different contexts (e.g. development or learning)(Aim1)andtodevelopmethodstotargetandmanipulatespecificneuronalcell typesregardlessofspecies(Aim2).Thisproposalisaimedatachievingthesegoalsin both genetically amenable and non-amenable species. While we anticipate that the methodologies we will develop will be broadly useful in a multitude of contexts, we will leverage our experience and knowledge of the specification and development of interneurons as a means to validate our approaches. Forebrain interneurons are a particularly robust context to develop these methods because the circuits interneurons contribute to during development are both dynamic and transient. This makes them a particularlyattractivetargetforexploringlongitudinalgeneexpression(Aim1).Thiswill be achieved using a modification of the DamID method, which we have redesigned to makeinducibleatparticulardevelopmentaltimepoints.Moreover,thediversitywithinthis population is considerable, making them an ideal target for exploring methods to efficientlytargetsubpopulationswithouttheneedfortransgenictools(Aim2).Inthisaim we will leverage transcriptome data sets, including data produced in Aim1. Utilizing a computational program identify enhancer elements for mediating directed gene expressioninrAAVs.Virusesproducedinthisaimwillbevalidatedforuseinmiceand lessgeneticallyamenablespecies,includingnon-humanprimates.
Interneuron dysfunction has been linked to several major neurological diseases such as epilepsy, schizophrenia and autism, with emerging evidence indicating that defects of specific interneuron subgroups duringdevelopmentmayplayaroleintheetiologiesofthesediseases.Onepotentialtherapeuticavenueisto developnovelstrategiestomodulatethefunctionofspecificinterneuronsubgroups.Theexperimentsoutlined in this proposal will utilize innovative strategies to characterize genes expressed by specific interneuron subgroups, and harness this knowledge to develop a series of viruses for manipulating activity in distinct interneuronpopulations.
| Quattrocolo, Giulia; Fishell, Gord; Petros, Timothy J (2017) Heterotopic Transplantations Reveal Environmental Influences on Interneuron Diversity and Maturation. Cell Rep 21:721-731 |
| McKenzie, Melissa; Fishell, Gord (2016) Human brains teach us a surprising lesson. Science 354:38-39 |
