Visual reconstruction of synapses in the mouse somatosensory cortex

Researchers at the Stanford University School of Medicine, applying a state-of-the-art imaging system to brain-tissue samples from mice, have been able to quickly and accurately locate and count the myriad connections between nerve cells in unprecedented detail, as well as to capture and catalog those connections’ surprising variety.

A typical healthy human brain contains about 200 billion nerve cells, or neurons, linked to one another via hundreds of trillions of tiny contacts called synapses. It is at these synapses that an electrical impulse traveling along one neuron is relayed to another, either enhancing or inhibiting the likelihood that the second nerve will fire an impulse of its own. One neuron may make as many as tens of thousands of synaptic contacts with other neurons, said Stephen Smith, PhD, professor of molecular and cellular physiology and senior author of a paper describing the study, to be published Nov. 18 in Neuron.

Because synapses are so minute and packed so closely together, it has been hard to get a handle on the complex neuronal circuits that do our thinking, feeling and activation of movement. But the new method may put the mapping of these connections within scientists’ grasp. It works by combining high-resolution photography with specialized fluorescent molecules that bind to different proteins and glow in different colors. Massive computing power captures this information and converts it into imagery.

Examined up close, a synapse — less than a thousandth of a millimeter in diameter — is a specialized interface consisting of the edges of two neurons, separated by a tiny gap. Chemicals squirted out of the edge of one neuron diffuse across the gap, triggering electrical activity in the next and thus relaying a nervous signal. There are perhaps a dozen known types of synapses, categorized according to the kind of chemical employed in them. Different synaptic types differ correspondingly in the local proteins, on one abutting neuron or the other, that are associated with the packing, secretion and uptake of the different chemicals.

Synapse numbers in the brain vary over time. Periods of massive proliferation in fetal development, infancy and adolescence give way to equally massive bursts of “pruning” during which underused synapses are eliminated, and eventually to a steady, gradual decline with increasing age. The number and strength of synaptic connections in various brain circuits also fluctuate with waking and sleeping cycles, as well as with learning. Many neurodegenerative disorders are marked by pronounced depletion of specific types of synapses in key brain regions.

In particular, the cerebral cortex — a thin layer of tissue on the brain’s surface — is a thicket of prolifically branching neurons. “In a human, there are more than 125 trillion synapses just in the cerebral cortex alone,” said Smith. That’s roughly equal to the number of stars in 1,500 Milky Way galaxies, he noted.

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