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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH111529-03
Application #
9539406
Study Section
Special Emphasis Panel (ZMH1)
Program Officer
Freund, Michelle
Project Start
2017-08-01
Project End
2019-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Broad Institute, Inc.
Department
Type
DUNS #
623544785
City
Cambridge
State
MA
Country
United States
Zip Code
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