Brain Map Clarifies Neuronal Connectivity Behind Motor Function

Scientists at St. Jude Children’s Research Hospital traced connectivity between neurons to identify how the brain communicates with the spinal cord to control motor function. Lief Fenno, an assistant professor in the Department of Neuroscience at The University of Texas at Austin and at the Dell Medical School, contributed to the work.  

Signals relayed to motor neurons from the brain enable muscle movement, but these signals typically pass through spinal interneurons before they reach their destination. How the brain and this highly diverse group of “switchboard operator” cells are connected is poorly understood. To address this, the team created a whole-brain atlas visualizing regions of the brain that send direct inputs to V1 interneurons, a group of cells necessary for movement. The resulting atlas and accompanying three-dimensional interactive website provide a framework to further understand the anatomical landscape of the nervous system and how the brain communicates with the spinal cord. The findings were published late last month in the journal Neuron. 

“We have known for decades that the motor system is a distributed network, but the ultimate output is through the spinal cord,” said corresponding author Jay Bikoff, Ph.D. of the St. Jude Department of Developmental Neurobiology. “There, you have motor neurons which cause muscle contraction, but the motor neurons don’t act in isolation. Their activity is sculpted by networks of molecularly and functionally diverse interneurons.” 

While huge leaps have been made in understanding how different regions of the brain relate to different facets of motor control, precisely how these regions connect to specific neurons in the spinal cord has been a blind spot in the field. Interneurons are difficult to study, mainly because they come in hundreds of different, intermingled varieties. 

To dissect the circuits linking the brain to the spinal cord, the researchers used a genetically modified version of the rabies virus that is missing a key glycoprotein from its surface. This inhibited the virus’s ability to spread between neurons and essentially stranded the virus at its origin. By reintroducing this glycoprotein to a specific population of interneurons, the virus could make a single jump across synapses before becoming stuck again. The researchers used a fluorescent tag to track the virus. By tracking where the virus ends up, the researchers could pinpoint which regions of the brain were connected to these interneurons.

The researchers applied this approach to a class of interneurons called V1 interneurons, which were previously shown to play a vital role in shaping motor output. The work allowed them to accurately trace the origins of multiple signals received by these interneurons back to the brain.

Fenno and his collaborators developed the viral tools used by Bikoff and the St. Jude team to produce the brain map. 

Traditionally, single parameters have been used to describe types of neurons: e.g., this cell is a dopamine neuron, that one makes glutamate. But Fenno points out that a challenge to this tradition has come from the advent of large-scale transcriptomics (the ability to study all of an organism’s RNA transcripts at once). 

Now, Fenno said, “a single gene, neurotransmitter or other property may not be sufficient to define a functional population.” Viral tools developed by the Fenno lab played a role in the work led by Bikoff and the St. Jude team. “Clinically, this and other investigations working to provide a granular description of the nervous system’s motor wiring diagram have utility in brain-computer interfaces, spinal cord repair and movement disorders,” Fenno added. 

The study’s first authors are Phillip Chapman and Anand Kulkarni of St. Jude, and other authors are Alexandra Trevisan, Katie Han, Jennifer Hinton, Paulina Deltuvaite, Mary Patton, Lindsay Schwarz, and Stanislav Zakharenko at St. Jude and Charu Ramakrishnan and Karl Deisseroth at Stanford University.

The study was supported by a grant from the National Institutes of Health and ALSAC, the fundraising and awareness organization of St. Jude.

Adapted from a press release by St. Jude Children’s Research Hospital.