Periodic Reporting for period 1 - StartAct (Controlling forelimb actions through basal ganglia to brainstem signaling)
Okres sprawozdawczy: 2021-09-01 do 2023-08-31
Behavior arises from the combination of different movements and is controlled by neuronal circuits distributed throughout the nervous system. Most work in the past focused on high motor centers and executive circuits in the spinal cord, but how these systems are linked to function is poorly understood. The Substantia Nigra Reticulata (SNR), a basal ganglia output involved in action initiation and control, sends projections to many different structures, including the brainstem. However, how the brainstem processes these inputs to control actions remains unknown.
The brainstem contains specialized neuronal populations that control specific actions, including skilled forelimb movements and locomotion. Here, we proposed to investigate the impact of SNR signaling on the activity of specific brainstem neurons when a mouse initiates forelimb movements. Understanding the role of SNR input should disclose the fine-scale machinery for initiating and controlling actions. This level of understanding is critical for designing new therapies to help people impaired in self-initiating actions, as in Parkinson’s disease.
This project aims to understand the mechanisms by which the basal ganglia output circuits influence brainstem centers in the initiation, execution, and modulation of specific forms of movement. To this end, we planned to characterize and exploit the functional specialization of both the brainstem and the basal ganglia by focusing on the input to the circuit controlling forelimb-reaching movements in the Lateral Rostral Medulla (LatRM).
We found that the SNR sends direct GABAergic input to the LatRM region, where it contacts a variety of neuronal subpopulations. Furthermore, we found that these LatRM neurons also receive direct GABAergic input from a region contiguous to the SNR, yet belonging to a different brain-wide circuit. From these results, we conclude that the SNR-to-LatRM circuit can be exploited to gain a mechanistic understanding of the role of basal ganglia in action initiation and control. However, a higher-than-anticipated molecular and functional specificity level is required to restrict the investigative focus to the specific role of the basal ganglia in a single behavioral module. Finally, preliminary high-density recordings from the SNR-to-LatRM neurons in behaving mice began to unravel the dynamic profile of these neurons under physiological conditions. Such dynamics highlighted a possible role of these neurons in shaping the timing of behavior.
The brainstem contains specialized neuronal populations that control specific actions, including skilled forelimb movements and locomotion. Here, we proposed to investigate the impact of SNR signaling on the activity of specific brainstem neurons when a mouse initiates forelimb movements. Understanding the role of SNR input should disclose the fine-scale machinery for initiating and controlling actions. This level of understanding is critical for designing new therapies to help people impaired in self-initiating actions, as in Parkinson’s disease.
This project aims to understand the mechanisms by which the basal ganglia output circuits influence brainstem centers in the initiation, execution, and modulation of specific forms of movement. To this end, we planned to characterize and exploit the functional specialization of both the brainstem and the basal ganglia by focusing on the input to the circuit controlling forelimb-reaching movements in the Lateral Rostral Medulla (LatRM).
We found that the SNR sends direct GABAergic input to the LatRM region, where it contacts a variety of neuronal subpopulations. Furthermore, we found that these LatRM neurons also receive direct GABAergic input from a region contiguous to the SNR, yet belonging to a different brain-wide circuit. From these results, we conclude that the SNR-to-LatRM circuit can be exploited to gain a mechanistic understanding of the role of basal ganglia in action initiation and control. However, a higher-than-anticipated molecular and functional specificity level is required to restrict the investigative focus to the specific role of the basal ganglia in a single behavioral module. Finally, preliminary high-density recordings from the SNR-to-LatRM neurons in behaving mice began to unravel the dynamic profile of these neurons under physiological conditions. Such dynamics highlighted a possible role of these neurons in shaping the timing of behavior.
Anatomical experiments were performed to characterize the SNR input to LatRM. These included anterograde and retrograde viral tracing in molecularly defined cell types and transsynaptic tracing experiments starting from specific neuronal populations. A computational pipeline was developed to register all the anatomical information to the 3D Allen Common Reference Mouse Atlas. We confirmed that the SNR sends direct GABAergic input to the LatRM region, where forelimb premotor neurons are located. There, it contacts a variety of neuronal subpopulations, including GABAergic neurons and glutamatergic projection neurons. Furthermore, we found that these LatRM neurons also receive direct GABAergic input from a region contiguous to the SNR, yet belonging to a distinct brain-wide circuit.
Next, we began to investigate the physiological role of SNR-to-LatRM neurons through dense extracellular electrophysiological recordings in freely moving mice performing lever-press and reaching-for-pellet tasks. Many recorded units showed activity time-locked with events in the tasks. More specifically, many units displayed pausing of tonic firing preceding or following specific behavioral events, a characteristic pattern of activity shown initially in seminal work in primates, in relation to saccades. Other units showed increased firing in relation to the same behavioral events.
Additional experiments were planned to further specify the correlational and causal role of the SNR-to-LatRM input in controlling specific movements and to obtain data leading to publication. However, these experiments could not be carried out before the premature termination of the action.
No website has been developed for the project.
Next, we began to investigate the physiological role of SNR-to-LatRM neurons through dense extracellular electrophysiological recordings in freely moving mice performing lever-press and reaching-for-pellet tasks. Many recorded units showed activity time-locked with events in the tasks. More specifically, many units displayed pausing of tonic firing preceding or following specific behavioral events, a characteristic pattern of activity shown initially in seminal work in primates, in relation to saccades. Other units showed increased firing in relation to the same behavioral events.
Additional experiments were planned to further specify the correlational and causal role of the SNR-to-LatRM input in controlling specific movements and to obtain data leading to publication. However, these experiments could not be carried out before the premature termination of the action.
No website has been developed for the project.
The preliminary results described above were entirely novel, as only a coarse anatomical characterization of the SNR-to-LatRM has been published to date, and no physiology data are currently available from functionally and anatomically defined SNR neurons in behaving mice. Additional experiments were planned to further specify the correlational and causal role of the SNR-to-LatRM input in controlling specific movements in physiological conditions as well as in a pathology mouse model of Parkinson's disease.