Striatal cholinergic interneurons (SCIs) and basal forebrain cholinergic projection neurons (BFCNs), which together encompass all forebrain cholinergic neurons, are required for neuromodulation throughout the forebrain. However, both the specification and diversity of these neurons are poorly understood. The precursors for all forebrain cholinergic neurons are born in the same region of the embryonic brain, and it is not known how these cholinergic precursors ultimately develop into diverse populations of interneurons and projection neurons. Although there is phenotypic diversity within SCIs and BFCNs, the developmental origins of this diversity has not been characterized, nor are there molecular markers to define the subclasses of cholinergic neurons that embody this diversity. This project aims to address these questions. There are two primary goals of this project: 1) to link the properties of mature forebrain cholinergic neurons with properties of their precursor cells, and to use this information to understand how they give rise to distinct classes of forebrain cholinergic neurons; and 2) to characterize the transcriptional cascades that give rise to the diversity of forebrain cholinergic neurons, particularly those that distinguish cholinergic interneurons and projection neurons. These goals will be accomplished through a combination of genetic fate mapping, transcriptional profiling, and assessment of candidate transcription factors in vitro and in vivo. At the conclusion of this study, a framework for classifying forebrain cholinergic neurons beyond their anatomical location and morphology will have been developed, and this classification scheme will be linked to their development. Furthermore, key genes in the transcriptional cascades during development that distinguish cholinergic interneurons and projection neurons will be identified. This will both improve our understanding of what is required for the normal development of the forebrain cholinergic system and provide us with genetic tools to specifically study and manipulate discrete populations of cells within this system.
Dysfunction and degeneration of cholinergic neurons in the forebrain have been linked to both developmental disorders (including autism and Down Syndrome) and neurodegenerative diseases (including Alzheimer?s and Parkinson?s). An improved understanding of the principles underlying the development of these neurons is crucial to address their roles in developmental diseases and to accurately and efficiently generate stem-cell derived forebrain cholinergic neurons for study and potential therapeutics. In addition, molecularly defining subclasses of neurons within the forebrain cholinergic system will allow for precise targeting of functionally relevant subpopulations, which will be invaluable when studying these populations and developing more precisely targeted interventions for disease. !
| Mayer, Christian; Hafemeister, Christoph; Bandler, Rachel C et al. (2018) Developmental diversification of cortical inhibitory interneurons. Nature 555:457-462 |
