Development in some parts of the brain is controlled by neural activity rather than experience.

An electrode fills an indirect pathway neuron with a red fluorophore to help measure its growth.

A newborn’s brain develops by forming and strengthening new synapses—connections between neurons—in response to sights, sounds, and experiences. But one part of the brain, the basal ganglia, doesn’t receive inputs from the external world, so how does it build its wiring shortly after birth?

Research by HHMI investigator Bernardo Sabatini suggests that self-reinforcing loops of neural activity may drive the development of synapses in the basal ganglia, a region of the brain that uses sensory and social context to direct movement.

The basal ganglia’s main input center—the striatum—orchestrates movement through two pathways: a direct pathway that stimulates movement and an indirect pathway that inhibits movement. To learn how striatal activity affects neuronal development, Sabatini and his colleagues at Harvard Medical School bred mice whose indirect or direct pathways were turned off because they were incapable of releasing the chemical messenger GABA.

Long-distance Neuronal Path-finding
Retinal axons travel across the brain, reading navigation cues, to find appropriate targets.

The scientists expected that silencing these neurons would stop them from forming connections between the striatum and receiving neurons. Instead, even with the striatum’s output signal silenced, the synapses grew normally. However, silencing the direct pathway prevented the formation of connections delivering input to the striatum, and silencing the indirect pathway increased the growth of these input synapses. The circuit was basically wiring itself—output controlled the development of input.

In a follow-up experiment, the group reduced the activity in neurons providing input to the striatum during development. When these mice reached adulthood, their brains had fewer neuronal connections in their striatum than normal mice, suggesting that wiring changes in the basal ganglia during early development can have lasting effects.

This research, says Sabatini, reveals the existence in basal ganglia development “of a very important positive feedback loop where something can establish itself by driving its own maturation into the right state.” Sabatini’s team published its results May 31, 2012, in Nature.

“We went into the study with hypotheses that were completely disproven by the study,” says Sabatini. Ready for more surprises, he will continue to engineer mice, activating and inactivating specific neurons to reveal how perturbations affect wiring later in life.

Photo: Bernardo Sabatini / Harvard Medical School