Periodic Reporting for period 4 - LocomotorIntegration (Functional connectome of brainstem circuits that control locomotion)
Reporting period: 2021-02-01 to 2021-07-31
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 ‘go’ and ‘stop’ 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 ‘go’ and ‘stop’ 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 locomotor–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.
The work has identified a region of excitatory neurons within the lower brainstem that is directly involved in providing the command for locomotion signal to the spinal locomotor circuits. The projection to the cord establish functional connections to rhythm generating neurons. These results directly build the spinal cord brainstem-spinal connectome for locomotion and reveal the precise spatiotemporal recruitment of network components during the locomotor cycle. In complementary work we defined he projection pattern in the spinal cord and the input pattern from and to brainstem ‘stop-neurons’. These neurons in addition to mediating an intended stop may mediate turning of locomotion by braking locomotion on the side of the turn when asymmetrically activated; a new mechanism used in limbed animals to make turns. Using optogenetic and chemogenetic combined with behavioral analysis we show 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. 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 the two neuronal circuits can be recruited in specific behavioural contexts. The project also describe glutamatergic neurons in rostral PPN that causes general motor immobilisation. The start and turning neuron receive inputs from many upstream regions and the studies therefore define the pathways needed to execute complex behavior as flight, finding the way, finding food etc. The functional deconstruction of the PPN and CnF organization and the turning neurons has furthermore given entry points for alleviate motor symptoms in Parkinson’s disease. We show that the akinetic locomotor phenotype induced by biasing indirect and the direct basal ganglia pathways can be reverted completely by activating of glutamatergic PPN neurons and that turning neurons play an important in motor execution from basal ganglia and are biased in basal ganglia dysfunction. Together these studies identifies new targets for alleviating Parkinsonian motor symptom. The combined effort in the granthas established the motor connectome for locomotion in mammals and pointed to strategies that will alleviate motor symptoms in the diseased brains. The results have been extensively communicate to the scientific community and public.
1. Identification of Brainstem ‘Start-neurons’: Caggiano … Kiehn Nature 2018
2. Identification of Brainstem ‘Turning-neurons’: Cregg…Kiehn Nature Neuroscience 2020
3. PPN restoration of Pakinsonian movement deficits: Masino and Kiehn Nature Communications 2021/22.
4. Identification of reticulospinal signal integration in the spinal cord (Hsu, Bertho, Kiehn)
5. Identification of glutamatergic Chx10 neurons in PPN; attentive immobilization circuits (Erro, Leiras and Kiehn).
2. Identification of Brainstem ‘Turning-neurons’: Cregg…Kiehn Nature Neuroscience 2020
3. PPN restoration of Pakinsonian movement deficits: Masino and Kiehn Nature Communications 2021/22.
4. Identification of reticulospinal signal integration in the spinal cord (Hsu, Bertho, Kiehn)
5. Identification of glutamatergic Chx10 neurons in PPN; attentive immobilization circuits (Erro, Leiras and Kiehn).