Recording Single Neurons and the Patch Clamp

From Adrian's single nerve fibres to microelectrodes in behaving animals, the patch clamp that captured single ion channels, Neuropixels probes recording thousands of cells, and calcium imaging with glowing proteins.

Single fibres and single cells

In the 1920s Edgar Adrian recorded impulses from single sensory nerve fibres and discovered that stimulus strength is coded by firing rate. With fine glass microelectrodes filled with salt solution, researchers in the mid-20th century could record inside single cells (intracellular recording) or just outside them (extracellular recording). In the 1950s and 60s, extracellular recordings in anaesthetised and then awake animals produced landmark discoveries: Hubel and Wiesel's orientation-tuned cells, O'Keefe's place cells, and monkey neurons linked to decisions and memory.

The patch clamp

In 1976 Erwin Neher and Bert Sakmann pressed a fire-polished glass pipette with a tip about a micrometre across against a cell membrane. With gentle suction, the glass formed an extremely tight seal (a "gigaseal") with the membrane, isolating a tiny patch containing just one or a few ion channels. They could see the current through a single channel switching between open and closed — direct proof that ion channels exist as individual molecules. They shared the 1991 Nobel Prize. Variations of the patch clamp (whole-cell, inside-out, outside-out) remain central to studying channels, synapses and drugs.

Many neurons at once

The brain computes with populations, so researchers developed ways to record many neurons simultaneously. Multi-electrode arrays such as the Utah array (used in human brain-computer interfaces) record from around 100 sites. Neuropixels probes, introduced around 2017, pack nearly a thousand recording sites along a needle-thin shank, letting researchers record from thousands of neurons across many brain areas in mice simultaneously.

Seeing neurons fire

Calcium imaging uses fluorescent indicators — especially genetically encoded proteins such as GCaMP — that glow more brightly when calcium rises as a neuron fires. With two-photon microscopy, researchers can watch thousands of individual neurons in the living brain of a behaving mouse, identifying each cell over days and weeks. Voltage indicators that report membrane potential directly are improving.