Mouse model shines light on locomotor circuits

Laura S. Marshall, laura.marshall@photonics.com

A new genetically modified mouse in which certain neurons respond to light stimulation could mean good things for patients with spinal cord injuries that impair their ability to walk. When the mouse’s neurons were exposed to blue light, walkinglike motor activity was demonstrated.

“This new mouse model will impact the way in which future studies examining the organization of neurons involved in walking are performed,” said Dr. Ole Kiehn, a professor in the department of neuroscience at Karolinska Institute, who led the study. “We hope that our findings can provide insight that eventually will contribute to treatments for spinal-cord-injured patients.”

Although it has been suggested that activation of excitatory neurons is important and even essential for the initiation and maintenance of walking, there has been no direct demonstration supporting this. So Kiehn’s team set out to test the hypothesis.

The mouse model expresses Channelrhodopsin-2 (ChR2), a light-sensitive protein, in excitatory neurons. ChR2 is found in algae; when exposed to blue light, it activates the cell in which it is expressed.

The researchers inserted ChR2 into nerve cells expressing Vglut2, a vesicular glutamate transporter found in most excitatory neurons in the brain stem and spinal cord as well as in many excitatory neurons in regions of the brain.

With the new Vglut2-ChR2 mouse, they had hoped to achieve selective activation of the excitatory neurons in specific regions of the brain stem and spinal cord that are believed to be important for initiating locomotion.

They shone blue light directly on the spinal cord, recording activity from the motor nerves leaving the cord, and found that walkinglike activity began and was maintained for the duration of the light pulse. They reported in Nature Neuroscience that this proved that activating Vglut2-expressing excitatory neurons in the spinal cord is sufficient for walking. They also found that locomotorlike activity could be initiated by shining blue light on the lower brain stem.

The investigators noted that they carried out all of their experiments in vitro in the laboratory and not on living animals. The research focus at Kiehn’s laboratory is on the molecular, cellular and network properties of spinal locomotor circuitries in mammals. The lab also works on characterizing plasticity in interneuron and motor neurons following lesions of the spinal cord.

The mouse model in the current study, Kiehn said, “will be important not only for spinal cord research but for all circuitries where Vglut2-positive cells are found in the brain and might be involved in behavior.” He noted that this includes respiration, thalamic cells and cerebellar function.

It will have a more indirect impact on the treatment of people with spinal cord injuries, he said. “[It] has to do with the fact that if we can identify the function and integration of the descending inputs to the locomotor circuits in the spinal cord, we will be able to devise more specific treatments of this debilitating disease by targeting regeneration of these pathways and by using drugs that specifically target these pathways.”

Kiehn and his colleagues currently are designing a mouse model that will express ChR2 in specific subpopulations in the brain stem and spinal cord, enabling them to dissect the circuit organization in more detail.