Neuronal identity is established during development through a complex set of events that combine both genetic and activity dependent mechanisms. Interneurons within the forebrain provide a particularly attractive context to explore the process by which cell identity is achieved, as populations derived from focal sources disperse across a variety of pallial and subpallial circuits. In this proposal, we develop and combine multi-disciplinary methods that allow a precise assignment of lineage boundaries within groups of interneurons to determine the significance of clonality for cell migration and the integration of sibling cells into a wide swath of diverse circuits. Moreover, by combining a fine grain lineal analysis with RNA-Seq methodologies, coupled with physiological measures, this proposal will provide unprecedented insight into how developmental events and changes in gene expression manifest the establishment of both complex and diversity excitatory (Cortical, Hippocampal and lateral Amygdala) and inhibitory (Striatal and medial Amydala) circuits. This will be achieved through the execution of three independent but interrelated aims.
Aim 1 will provide a comprehensive determination of interneuronal lineage and subtypes.
Aim2 will complement this by providing a ?ground truth? understanding of how gene expression evolves in sister interneurons derived from a common clone. Finally aim 3 will provide insight as to how activity regulates gene expression in establishing the connectivity and intrinsic physiology of different interneuron subtypes. The successful execution of these aims will fundamentally allow use to understand the interplay between pre-existing intrinsic programs against extrinsic signals in the development of forebrain interneuron diversity.

Public Health Relevance

Our aim by the completion of the funding for this proposal is to establish how interneuron progenitors within the forebrain develop to maturity regarding their lineage relationships relative to their emergent molecular and physiological properties.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH071679-16
Application #
9932491
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Panchision, David M
Project Start
2017-07-01
Project End
2021-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
16
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Biology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Mayer, Christian; Hafemeister, Christoph; Bandler, Rachel C et al. (2018) Developmental diversification of cortical inhibitory interneurons. Nature 555:457-462
Priya, Rashi; Paredes, Mercedes Francisca; Karayannis, Theofanis et al. (2018) Activity Regulates Cell Death within Cortical Interneurons through a Calcineurin-Dependent Mechanism. Cell Rep 22:1695-1709
Wilson, Daniel E; Smith, Gordon B; Jacob, Amanda L et al. (2017) GABAergic Neurons in Ferret Visual Cortex Participate in Functionally Specific Networks. Neuron 93:1058-1065.e4
Quattrocolo, Giulia; Fishell, Gord; Petros, Timothy J (2017) Heterotopic Transplantations Reveal Environmental Influences on Interneuron Diversity and Maturation. Cell Rep 21:721-731
Tuncdemir, Sebnem N; Wamsley, Brie; Stam, Floor J et al. (2016) Early Somatostatin Interneuron Connectivity Mediates the Maturation of Deep Layer Cortical Circuits. Neuron 89:521-35
McKenzie, Melissa; Fishell, Gord (2016) Human brains teach us a surprising lesson. Science 354:38-39
Mayer, Christian; Bandler, Rachel C; Fishell, Gord (2016) Lineage Is a Poor Predictor of Interneuron Positioning within the Forebrain. Neuron 92:45-51
Dimidschstein, Jordane; Chen, Qian; Tremblay, Robin et al. (2016) A viral strategy for targeting and manipulating interneurons across vertebrate species. Nat Neurosci 19:1743-1749
Miyoshi, Goichi; Young, Allison; Petros, Timothy et al. (2015) Prox1 Regulates the Subtype-Specific Development of Caudal Ganglionic Eminence-Derived GABAergic Cortical Interneurons. J Neurosci 35:12869-89
Mayer, Christian; Jaglin, Xavier H; Cobbs, Lucy V et al. (2015) Clonally Related Forebrain Interneurons Disperse Broadly across Both Functional Areas and Structural Boundaries. Neuron 87:989-98

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