Team Gradinaru

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Circuitry and Brain-Body Interactions | 2021

Gut-to-Brain Circuit Contributions to Parkinson-Like Phenotypes in Disease Models

Study Rationale: Although clinicians have long reported that Parkinson’s disease (PD) does not affect the brain alone, the field has only recently started to investigate gut dysfunction in experimental models of PD. Consequently, the anatomical and functional basis of gut-to-brain circuitry dysfunction in PD—such as network activity and dopamine signaling—remain poorly understood. Team Gradinaru will characterize circuit mechanisms underlying gut-to-brain disease spread and progression in the earliest appearance of Parkinson’s symptoms.

Hypothesis: Team Gradinaru’s hypothesis is that environmental and genetic factors impact the connections between neurons in the enteric nervous system (ENS), which regulates the gastrointestinal tract. This disruption may increase susceptibility to PD triggers—including aggregation of alpha-synuclein, which is toxic to cells and can trigger PD symptoms and gut inflammation. This inflammation could, in turn, augment the toxic form of alpha-synuclein that circulates to the brain and causes dysfunctions in neural circuits and motor deficits.

Study Design: Team Gradinaru will determine PD-relevant gut and brain anatomic and physiologic profiles in rodents, primates, and human cells by clarifying the anatomic pathways underlying gut-to-brain propagation of aggregated alpha-synuclein in mice, and by constructing anatomic and functional maps of macaque ENS and central nervous system PD-relevant circuits at single-cell resolution. The team also will test whether disruption of ENS circuitry mitigates gut-brain disease outcome and evaluate whether spiny mice (a rodent model that can repair damaged tissue) show protection from PD-related gut-brain degeneration.

Impact on Diagnosis: Using powerful new technologies across multiple PD-relevant model systems, this project could uncover novel circuit mechanisms that mediate symptoms, and embolden new therapeutic options to slow, halt, or perhaps reverse peripheral symptoms of PD.

Leadership
Viviana Gradinaru, BS, PhD
Coordinating Lead PI

Viviana Gradinaru, BS, PhD

California Institute of Technology
Andrew Fox, PhD
Co-Investigator

Andrew Fox, PhD

University of California at Davis
Sarkis Mazmanian, PhD
Co-Investigator

Sarkis Mazmanian, PhD

California Institute of Technology
Ashley Seifert, MSc, PhD
Co-Investigator

Ashley Seifert, MSc, PhD

University of Kentucky
David Van Valen, MD, PhD
Co-Investigator

David Van Valen, MD, PhD

California Institute of Technology
Catherine Oikonomou, PhD
Project Manager

Catherine Oikonomou, PhD

California Institute of Technology

Project Outcomes

This project will use powerful sensor, actuator, and gene delivery technologies across multiple model systems to characterize the anatomical and functional bases of gut-brain circuitry dysfunction in PD, enabling new therapeutic options to slow, halt, or perhaps even reverse peripheral symptoms of PD. View Team Outcomes.

Team Outputs

Click the following icons to learn more about the team’s outputs

Overall Contributions

Here is an overview of how this team’s article findings have contributed to the PD field as of November 2023. There are two different categorizations of these contributions – one by impact to the PD community and a second by scientific theme.

Impact

Theme

Featured Output

Below is an example of a research output from the team that contributes to the ASAP mission of accelerating discoveries for PD.

Adeno-associated viral vectors for functional intravenous gene transfer throughout the non-human primate brain 

Team Gradinaru has generated a novel adeno-associated virus (AAV) variant, AAV.CAP-Mac, that enables systemic, brain-wide gene delivery in infants of two Old World primate species, rhesus macaque and green monkey. The vector robustly transduces human neurons in vitro and Old World primate neurons in vivo, targeting all lobes of the cortex, the cerebellum, and multiple subcortical regions relevant to neurodegenerative disease. This tool can be used in anatomical and functional mapping of the macaque CNS, and opens up possibilities for non-invasive delivery of therapeutics in disease models.

Team Accolades

Members of the team have been recognized for their contributions.

Other Team Activities

  • Working Groups: Microbiome – Sarkis Mazmanian (Co-Chair)
  • Interest Groups: Anatomical Tracing of Circuit Connectivity – Viviana Gradinaru (Chair)

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