#	Pagina
attuale pagina	/open-h2020/projects/204794/results.html

Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - LocomotorIntegration (Functional connectome of brainstem circuits that control locomotion)

Teaser

Summary

Locomotion is a complex motor act that is used in many daily life activities and is the output measures of a plethora of brain behaviors. The planning and initiation of locomotion take place in the brain and brainstem, while the execution is accomplished by activity in neuronal networks in the spinal cord itself. Recent experiments have provided significant insight to the organization of the executive spinal locomotor networks. However, little is known about the brainstem control of these networks. Here, I propose to provide a unified understanding of the functional connectome of the key brainstem networks that control locomotion in mammals needed to select appropriate locomotor outputs. To obtain these goals we will develop a suite of transgenic mouse models with optogenetic or chemogenetic switches in defined populations of brainstem neurons combined with the possibility to use state-of-the-art cell-specific electrophysiological and anatomical connectivity studies. We will reveal the functional organization of â€˜goâ€™ and â€˜stopâ€™ command systems in the brainstem that are directly upstream from the spinal locomotor networks and the mechanisms for how spinal networks are selected. We will further functionally deconstruct the next network layer in midbrain structures that control the â€˜goâ€™ and â€˜stopâ€™ command systems. Our research takes a specific approach to provide mechanistic insight to the integrated movement function by building the motor matrix in a functional chain from the locomotorâ€“related spinal cord neurons that have been identified to midbrain neurons. A segment of our research will link these networks to locomotor impairments after basal ganglia dysfunction. The work has the potential to make a breakthrough in our understanding of how complex movements are generated by the brain and has translational implications for patients with movement disorders. It will push boundaries in the universal effort that aims to comprehend how brain networks create behaviors.

Work performed

We have performed research addressing all the main aims of the proposal.

We have identified a region of excitatory neurons within the lower brainstem that is directly involved in providing the â€˜goâ€™ signal to the spinal locomotor circuits. We use this information to establish functional connections to identified locomotor related interneurons in the spinal cord. For the â€˜stop-neuronsâ€™ we defined their projection patterns in the spinal cord and their input pattern. We show that these neurons in addition to stop may mediate turning of locomotion by braking locomotion on the side of the turn. This is a completely new mechanism for turning of locomotion.

For midbrain neurons we show suing optogenetic and chemogenetic combined with behavioral analysis that two separated glutamatergic nuclei neurons in the midbrain - the cuneiform nucleus (CnF) and the pedunculopontine nucleus (PPN - form command pathways that start locomotion and encode speeds of locomotion in complementary ways. Neuronal circuits in PPN and CNF both contribute to the maintenance and speed regulation of alternating locomotion. Only CNF evoke fast locomotion while PPN tends to bias very slow locomotion (Nature 2018). These results change the concept of a unitary Mesencephalic Locomotor Region (MLR) in mammals and replaced it by a model, in which the locomotor control function resides both in the PPN and CNF. The findings suggest that slow explorative locomotion is supported by PPN and fast escape behaviour by CNF and that these neuronal circuits can be recruited in specific behavioural contexts.The diversification of the MLR circuits is supported by the inputs and output matrixes in the two structure that provide a substrate for context dependent selecting of locomotor(Nature 2018).

As an extension of the functional deconstruction of the PPN and CNF organization and the stop cells we will attempt to gain an understanding of the locomotor impairments in Parkinsonâ€™s disease using the CNF/PPN and stop-neurons as entry points to the system. These experiments are in progress.

Final results

Finally, we have also used the expertise on optogenetic in this project to investigate the role of spinal interneurons for spasticity and showed that both glutamatergic and Gabaergic/glycinergic neurons contribute to the development (eLife 2017).