The human brain forms about 100 trillion synapses during development. These synapses determine how neural circuits process information and perform computations, and when dysregulated, likely form the basis of many neurological and psychiatric diseases. Both autonomous genetic programs and spontaneous activity are thought to contribute to synaptogenesis. However, the precise role of spontaneous activity and the mechanisms underlying its generation are not well understood. Recent work has established that spontaneous activity accompanies the development of synapses in the Drosophila visual system. The fly brain was previously thought to develop synapses solely via preprogrammed genetic protocols, and this observation is the first evidence to suggest that spontaneous activity may also contribute to synaptogenesis in this system. Preliminary studies have characterized the natural history of this activity, its mechanisms of propagation, and its patterns at the level of individual cell types. Remarkably, cells that are synaptic partners in the adult show correlated activity patterns. These data suggest that spontaneous activity is a fundamental phenomenon of circuit assembly. The extensive genetic toolbox and mapped connectome in the fly visual system allow for molecular and cellular dissection of the relationship between spontaneous activity and synapse formation. The proposed research plan will use two- photon calcium imaging and genetic advantages in Drosophila to elucidate the role of spontaneous activity in synaptogenesis. Further studies will identify molecular and cellular mechanisms underlying the generation and propagation of spontaneous activity. These results will indicate how spontaneous activity influences synapse formation in the developing brain and will provide important insights into the mechanisms of this activity in the assembly of neural circuits.

Public Health Relevance

The dysregulation of neuronal circuit assembly is implicated in neurodevelopmental diseases including autism and schizophrenia. However, many mechanisms underlying circuit formation remain poorly understood, making these disorders difficult to treat. In this proposal, I investigate the role of spontaneous network activity in circuit assembly to provide insight into fundamental mechanisms underlying brain development.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30EY029952-02
Application #
9873821
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Agarwal, Neeraj
Project Start
2019-04-01
Project End
2023-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Biochemistry
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095