Neurodegeneration has proven notoriously difficult to study and there is currently no proven or acceptable method to prevent or slow down the course of disease in humans. A very successful intervention for Parkinson's disorder (PD) is neuromodulation via deep brain stimulation (DBS). DBS successfully restores motor function but what DBS does to the course of the disease is very poorly understood. Intriguingly, a few rodent model studies and clinical observations suggest that DBS could be neuroprotective, but because current practice is to implant the electrodes late in the progression of the disease, neuroprotective effects of electrical stimulation have been challenging to document. It is therefore vital that we are not missing on a crucial opportunity for neurological patients and research the causal links, mechanisms, and timelines associated with neuroprotection via neuromodulation. I propose an interdisciplinary approach for which I am uniquely trained that uses optogenetics, electrophysiology, biochemistry, and collaborative device engineering to study the interplay between neuronal health and brain circuit activity in intact behaving rodents. Specifically, I propose to study the factors influencing the function and health of dopaminergic neurons in the brain and their role in animal behavior. Our findings could allow us to positively interfere with cells such as the dopaminergic neurons in the substantia nigra pars compacta (SNc) that degenerate and die in PD. Below I list 3 specific challenges that I will tackle using innovative, interdisciplinary, approaches. 1. Are all SNc dopaminergic neurons equally impactful on behavior or are there hotspots where cells, due to their heterogeneous electrical and neurochemical characteristics and connectivity, can maximally interfere with behavior when degenerated? 2. Once dopaminergic degeneration starts, can neurodegeneration be halted or slowed down by altering the activity of defined brain circuits? I will test this intriguing hypotheis by performing chronic optogenetic control of inputs to the SNc and measure changes in the degeneration rate. 3. Is growth factor signaling directly contributing to dopaminergic neuroprotection and what are the timelines needed for neuroprotection? Previous experiments applied growth factors liberally in a non-specific fashion and/or with poor temporal resolution. I will develop optogenetic methods to achieve cell-type specific control of growth factor signaling so I can directly probe the protective role of growth factors in defined cell types, and especially cells prone to degeneration. These tools could also be applied to research beyond the nervous system since growth factor signaling is involved in key cellular phenomena such gene transcription that can impact the cell survival, differentiation, and function. Together these innovative projects will contribute to my long-term goals of building cellular resilience via neuromodulation and have a paradigm-shifting impact in neurodegeneration research.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
NIH Director’s New Innovator Awards (DP2)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MOSS-C (56)R)
Program Officer
Sieber, Beth-Anne
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
California Institute of Technology
Schools of Arts and Sciences
United States
Zip Code
Robinson, J Elliott; Gradinaru, Viviana (2018) Dopaminergic dysfunction in neurodevelopmental disorders: recent advances and synergistic technologies to aid basic research. Curr Opin Neurobiol 48:17-29
Patriarchi, Tommaso; Cho, Jounhong Ryan; Merten, Katharina et al. (2018) Ultrafast neuronal imaging of dopamine dynamics with designed genetically encoded sensors. Science 360:
Chan, Ken Y; Jang, Min J; Yoo, Bryan B et al. (2017) Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems. Nat Neurosci 20:1172-1179
Nath, Ravi D; Bedbrook, Claire N; Abrams, Michael J et al. (2017) The Jellyfish Cassiopea Exhibits a Sleep-like State. Curr Biol 27:2984-2990.e3
Greenbaum, Alon; Jang, Min J; Challis, Collin et al. (2017) Q&A: How can advances in tissue clearing and optogenetics contribute to our understanding of normal and diseased biology? BMC Biol 15:87
Deverman, Benjamin E; Pravdo, Piers L; Simpson, Bryan P et al. (2016) Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain. Nat Biotechnol 34:204-9
Treweek, Jennifer Brooke; Gradinaru, Viviana (2016) Extracting structural and functional features of widely distributed biological circuits with single cell resolution via tissue clearing and delivery vectors. Curr Opin Biotechnol 40:193-207
Xiao, Cheng; Cho, Jounhong Ryan; Zhou, Chunyi et al. (2016) Cholinergic Mesopontine Signals Govern Locomotion and Reward through Dissociable Midbrain Pathways. Neuron 90:333-47
Bedbrook, Claire N; Kato, Mihoko; Ravindra Kumar, Sripriya et al. (2015) Genetically Encoded Spy Peptide Fusion System to Detect Plasma Membrane-Localized Proteins In Vivo. Chem Biol 22:1108-21
Treweek, Jennifer B; Chan, Ken Y; Flytzanis, Nicholas C et al. (2015) Whole-body tissue stabilization and selective extractions via tissue-hydrogel hybrids for high-resolution intact circuit mapping and phenotyping. Nat Protoc 10:1860-1896

Showing the most recent 10 out of 13 publications