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Controlling forelimb actions through basal ganglia to brainstem signaling

Project description

Signalling controlling forelimb movement

Behavior is orchestrated within distributed circuits and constructed by piecing together different movements. The brainstem contains specialized neuronal populations dedicated to the control of specific actions, including skilled forelimb movements and locomotion. It receives inputs from the substantia nigra reticulata (SNR), a major output of the basal ganglia. However, it remains poorly understood how the brainstem processes these inputs to start actions. Thus, the SNR-brainstem system is ideal for understanding the mechanisms underlying behavior initiation and control. The EU-funded StartAct project will investigate the impact of SNR signaling on the activity of specific brainstem neurons when a mouse initiates forelimb movements. It will elucidate the architecture of SNR to brainstem connections and how it supports the forelimb movement, opening new horizons in the treatment of diseases characterized by impairment in self-initiated actions.

Objective

Behavior arises through the combination of movements within distributed circuits. Most work in the past focused on high motor centers and executive circuits in the spinal cord, but how these systems are linked in order to function is poorly understood.
The substantia nigra reticulata (SNR), a basal ganglia output, sends projections to the brainstem. Yet how the brainstem processes these inputs to control actions remains unknown. The Arber lab discovered that the parvocellular reticular formation (PCRt) of the mouse brainstem harbors neurons controlling forelimb behaviors including reaching. PCRt neurons receive inhibitory inputs from the SNR. Thus, the SNR-PCRt circuit is an excellent stepping stone for understanding the mechanisms behind self-initiated actions.
I propose to investigate the impact of the SNR signaling on the activity of PCRt neurons when a mouse self-initiates forelimb reaching. I will characterize the anatomy and nature of SNR to PCRt connections to understand whether and how this architecture supports forelimb movement. I will combine a behavioral task designed to isolate the neuronal events around the triggering of a self-initiated action with loss- and gain of function perturbations to unravel the building blocks of self-initiated actions. Finally, I will use the task while monitoring the activity of specific SNR and PCRt neurons to understand how the different actors physically implement the operations for self-initiated actions.
Together, my experiments will disclose the fine-scale machinery for initiating and controlling an action. This level of understanding is key for designing new therapies to help people impaired in self- initiating actions such in Parkinson’s disease. The fellowship will provide me with the unique opportunity to expand my expertise and establish the foundations of my future career as an independent group leader.

Coordinator

FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH FONDATION
Net EU contribution
€ 203 149,44
Address
MAULBEERSTRASSE 66
4058 Basel
Switzerland

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Region
Schweiz/Suisse/Svizzera Nordwestschweiz Basel-Stadt
Activity type
Research Organisations
Links
Total cost
€ 203 149,44