Nerve cells in your brain and spinal cord connect to one another
much like electronic circuits. And just as electronic circuits consist
of many components, the nervous system contains a dizzying array of
neurons, often resulting in networks with many hundreds of thousands of
breathing to walking to chewing, our days are filled with repetitive
actions that depend on the rhythmic firing of neurons. Yet the neural
circuitry underpinning such seemingly ordinary behaviors is not fully
understood, even though better insights could lead to new therapies for
disorders such as Parkinson's disease, ALS and autism.
‘Varying the ratios of excitatory to inhibitory neurons within networks may be a way that real brains create complex but flexible circuits to govern rhythmic activity.’
Recently, neuroscientists at the Salk Institute used stem cells to
generate diverse networks of self-contained spinal cord systems in a
dish, dubbed circuitoids, to study this rhythmic pattern in neurons. The
work, which appears online in eLife
reveals that some of the circuitoids - with no external
prompting - exhibited spontaneous, coordinated rhythmic activity of the
kind known to drive repetitive movements.
"It's still very difficult to contemplate how large groups of
neurons with literally billions if not trillions of connections take
information and process it," says the work's senior author, Salk
Professor Samuel Pfaff, who is also a Howard Hughes Medical Institute
investigator and holds the Benjamin H. Lewis Chair. "But we think that
developing this kind of simple circuitry in a dish will allow us to
extract some of the principles of how real brain circuits operate. With
that basic information maybe we can begin to understand how things go
awry in disease."
To model the complex neural circuits, the Pfaff lab prompted
embryonic stem cells from mice to grow into clusters of spinal cord
neurons, which they named circuitoids. Each circuitoid typically
contained 50,000 cells in clumps just large enough to see with the naked
eye, and with different ratios of neuronal subtypes.
With molecular tools, the researchers tagged four key subtypes of
both excitatory (promoting an electrical signal) and inhibitory
(stopping an electrical signal) neurons vital to movement, called V1,
V2a, V3 and motor neurons. Observing the cells in the circuitoids in
real time using high-tech microscopy, the team discovered that
circuitoids composed only of V2a or V3 excitatory neurons or excitatory
motor neurons (which control muscles) spontaneously fired rhythmically,
but that circuitoids comprising only inhibitory neurons did not.
Interestingly, adding inhibitory neurons to V3 excitatory circuitoids
sped up the firing rate, while adding them to motor circuitoids caused
the neurons to form sub-networks, smaller independent circuits of neural
activity within a circuitoid.
"These results suggest that varying the ratios of excitatory to
inhibitory neurons within networks may be a way that real brains create
complex but flexible circuits to govern rhythmic activity," says Pfaff.
"Circuitoids can reveal the foundation for complex neural controls that
lead to much more elaborate types of behaviors as we move through our
world in a seamless kind of way."
Because these circuitoids contain neurons that are actively
functioning as an interconnected network to produce patterned firing,
Pfaff believes that they will more closely model a normal aspect of the
brain than other kinds of cell culture systems. Aside from more
accurately studying disease processes that affect circuitry, the new
technique also suggests a mechanism by which dysfunctional brain
activity could be treated by altering the ratios of cell types in