Positive Feedback in the Developing Brain
As neurons in sensory areas of the brain fire in response to sights, smells, and sounds, synapses begin to form, laying the neuronal groundwork for activity later in life
When an animal is born, its early experiences help map out the still-forming connections in its brain. Not all parts of the brain receive input directly from the external world, however, and researchers have wondered how these regions build their wiring in early development.
Now from Howard Hughes Medical Institute, investigator Bernardo Sabatini and colleagues present evidence on the basal ganglia, a region of the brain that controls motor planning, indicating that early brain development follows a different strategy.
The new findings suggest that wiring of the basal ganglia during early development is driven not only by experience, but also by a self-reinforcing loop of neuro signaling. As the loop strengthens, more synapses form.
“What we found is that silencing these neurons doesn’t really change their output patterns they still find their targets and survive but instead drastically increases their inputs.”
Bernardo L. Sabatini
Basal ganglia help an animal select its actions based on sensory and social context, as well as past experience.
These new clues on how basal ganglia get wired shortly after birth may help scientists understand what happens when things go awry Parkinson's disease reflects degradation of neurons in the basal ganglia; in drug addiction, basal ganglia are overstimulated.
Sabatini says his team’s findings also suggest the process can be easily perturbed during development, and may contribute to human disorders such as cerebral palsy and attention deficit hyperactivity disorder.
His results are described in the May 13, 2012 issue of the journal Nature.
Although basal ganglia do not receive direct messages from external sources, this region of the brain is by no means anatomically isolated. It receives signals from all over the cortex, and its output eventually returns to the cortex. Sabatini feels that to select a specific motor action, the brain likely signals through that entire loop.
“The question is, how do you lay down the circuits for those patterns?”
The basal ganglia are complex, containing many clusters of cells, some of which send excitatory and others inhibitory signals.
Sabatini’s group focused on the basal ganglia’s main input station, the striatum. The striatum uses the information it receives to help direct movement in two ways:
1) a ‘direct’ pathway stimulates motor actions and
2) an ‘indirect’ pathway inhibits them.
To learn how striatal activity affects circuit development, Sabatini’s team studied mutant mice whose indirect or direct pathways were turned off (thus unable to release the inhibitory chemical messenger, GABA).
The researchers expected that silencing/turning off, these neurons would prevent them from forming connections. To their surprise, the silenced neurons survived and continued to wire themselves to their targets. However, silencing the striatum’s direct pathway seemed to prevent formation of the connections meant to send input to the striatum. Silencing the indirect pathway increased the number of inputs.
Sabatini: “We went into this study thinking completely differently. What we found is that silencing these neurons doesn’t really change their output patterns of course they are silenced, though still finding their targets and surviving but instead drastically influences their inputs.”
To see whether individual cells help set up the basal ganglia circuit, Sabatini’s group turned off a select few striatal neurons, not whole pathways, in mice. Silencing mouse neurons did not affect excitatory connections, suggesting that circuit-level activity patterns set up the basal ganglia’s wiring, rather than individual genes or molecules within cells.
“It’s hard to believe that there are molecular cues that specify these structures, because it seems way too complicated,” Sabatini says.
The group then dampened activity in mouse neurons that project from the brain’s cortex to the striatum during development, and examined the brain when the mouse had reached early adulthood (25 days after birth). They saw fewer neuronal connections in the striatum compared to mice that had developed normally suggesting that disturbances in early development can have lasting effects.
“That experiment is what told us that it’s the ongoing activity of cortical neurons that is driving this process in the striatum,” Sabatini says.
The axons the slender processes of the neuron that carry electrical impulses stimulate striatal cells to release the excitatory neurotransmitter glutamate, to make more synapses and stabilize.
Sabatini believes that the basal ganglia tests random connection patterns after an animal is born and reinforces the correct ones. This type of plasticity of the basal ganglia probably lasts into adulthood, because animals are constantly learning new actions.
Using genetically engineered mice that allow researchers to control exactly which neurons to inactivate and when, Sabatini’s group is now studying how perturbations affect brain wiring later in life.
Sabatini expects that these results will get us a step closer to understanding human disease.
Original article: http://www.hhmi.org/news/sabatinib20120513.html