Department of Neuroscience
Mærsk Tower, room 07-4-54
Phone: +45 93565963
We study the molecular, cellular, and network diversification of locomotor circuitries in mammals with the goal of providing a unified understanding of the functional organization of neuronal circuits that execute movements.
Short research description:
A monumental challenge in neuroscience is to understand the operation of neuronal networks that are linked to execution of specific behaviors. Our lab is meeting this challenge by addressing the organization of neuronal networks that produce movements, the origin of all behaviors.
We study the molecular, cellular, and network diversification of locomotor circuitries in mammals with the goal of providing a unified understanding of the functional organization of neuronal circuits that execute movements. To this end, we apply new physiological and molecular genetic approaches, including optogenetics, RNA-seq, molecular tracing, advanced imaging, and electrophysiology.
We have deciphered the functional organization of spinal circuitries necessary for producing changes in timing and coordination of locomotion, and delineated brainstem circuits involved in gating or context-dependent selection of motor behaviors.
The lab also investigates plasticity in spinal networks and motor neurons following lesions of the spinal cord, with the goal of devising manipulations that may alleviate motor dysfunction following spinal cord injury.
In recent efforts, we also address the role of spinal interneurons in development and progression of amyotrophic lateral sclerosis.
Our work bridges the gap between neuronal circuit organization and behaviour, and has strong translational potential in development of therapies for movement disorders caused by trauma or disease.
Detailed research description:
Physiological and molecular organization of neuronal networks controlling movements in mammals
Movement takes many forms. Among movements, locomotion is one of the most fundamental—used by all animals and humans for interaction with the surroundings. Locomotion is employed episodically in many daily activities, representing an output measure for integrated brain activity involved in exploring the environment, escaping predators, and searching for food. Its activity also directly influences the state of sensory information processing.
The planning and initiation of locomotion takes place in the brain and brainstem, while the execution—which involves precise timing and coordination—is to a large part accomplished by activity within neuronal networks of the spinal cord itself.
Early work from our lab has revealed aspects of the overall organization of spinal locomotor networks, the implication of cellular properties for rhythmicity, and the nature of neuronal spike coding.
Recent work has focused on the functional organization of key neuronal elements that characterize limbed locomotion in mammals: 1) rhythm generation, 2) coordination of flexors and extensors across the same or different joints in a limb or between limbs, and 3) left/right coordination.
Rhythm generating neurons set tempo within the network, and are an elementary component of all vertebrate locomotor networks. Experiments from our lab using genetically driven expression of light-sensitive channels in excitatory and inhibitory neurons have demonstrated that excitatory neurons in the mammalian spinal cord are both sufficient and necessary for initiation and maintenance of rhythmic locomotor pattern. Using intersectional mouse genetics in combination with electrophysiology, we have identified non-overlapping subpopulations of excitatory neurons in the spinal cord that participate in rhythm generation.
We have also characterized networks involved in left-right coordination, which include commissural interneurons (CINs) whose axons cross the midline, in detail using anatomical, electrophysiological, and targeted genetic ablation techniques for molecularly defined subpopulations of CINs.
These studies have converged on a common organizational principle for circuits controlling left-right alternation in mammals, which consists of a modular organization for left-right alternating gaits (walk and trot) and synchronous gaits (gallop/bound). Moreover, we have addressed the organization of circuits controlling flexor-extensor coordination. We are now addressing the functional integration of these diverse circuit elements using both in vitro and in vivo studies.
In a general scheme of motor control, we study how spinal locomotor circuits are activated and controlled by descending command signals. Decision-making signals to locomote are conveyed from the brain to locomotor regions in the midbrain. The locomotor regions in the midbrain include the mesencephalic locomotor region (MLR)—a complex structure—that in turn is thought to activate neurons in the reticular formation (RF) in the lower brainstem, which project to locomotor networks in the spinal cord. In the first optogenetics experiments in the mammalian locomotor system, we provided direct evidence that glutamatergic neurons in the lower brainstem can provide a ‘go’- signal sufficient to activate spinal locomotor networks.
We have now implemented in vivo optogenetic and chemogenetic approaches to probe the involvement of locomotor promoting and locomotor arresting areas in the brainstem, and further explore how these brainstem circuits are selected by upstream circuitries. These experiments have defined ‘start’ neurons in the midbrain, confined to the cuneiform nucleus and pedunculopontine nucleus, which cooperate to set locomotor speed and context-dependent selection of locomotor gate.
We have also defined ‘stop’ neurons in nucleus gigantocellularis that arrest ongoing locomotion.
In future studies we will use Parkinson disease models to probe the role of different motor structures in development and encoding of disease-induced gait disturbances.
Cellular mechanism underlying spasticity after spinal cord injury
Severe muscle spasticity develops as a consequence of spinal cord injury or damage to motor pathways from the brain. We previously found evidence that the pathophysiology of spasticity after spinal cord injury is related to chronic expression of plateau properties in motor neurons. Plateau potentials in vertebrate motor neurons are caused by activation of prolonged sodium/calcium currents, and their expression is dependent on activation of noradrenergic and/or serotoninergic receptors. The normal function of motor neuron plateau potentials seems to be to maintain persistent motor output and amplify synaptic inputs during rhythmic motor activity.
To find possible targets for regulation of plateau potentials after spinal cord injury, we have performed global gene expression profiling from rat motor neurons isolated before or after injury to the cord. These studies have shown that the chronic expression of plateaux may be related to changes in genes coding for the regulatory units for persistent sodium and calcium channels. In ongoing experiments, we are investigating how changes in interneuronal network activity interact with plateaux to generate spasticity using mouse genetic, calcium imaging, and in vivo optogenetic experiments. Our long-term goal is to define new therapies for symptoms associated with spinal cord injury.