Using an inventive new method in which mice run through a virtual reality environment based on the video game Quake, researchers from Princeton University have made the first direct measurements of the cellular activity associated with spatial navigation. The method will allow for investigations of the neural circuitry underlying navigation, and should lead to a better understanding of how spatial information is encoded at the cellular level.
In mice, spatial navigation involves at least four different cell types located in the hippocampus and surrounding regions. Place cells increase their activity when the animal is in a specific location within its environment, called the place field. Grid cells, by contrast, fire periodically as the animal traverses a space; each has a unique periodicity, and apparently measures out the space using its own scale. Head direction cells, as their name implies, fire when the animal is facing a particular direction and border cells, which were identified only last year, encode the animal’s distance from the borders within its environment.
Place cells were discovered almost 40 years ago and are the most extensively studied of these cell types. Their activity is typically recorded using small arrays of microelectrodes implanted within the hippocampus of a freely moving rodent. The arrays can remain in place for days or weeks, during which time they can be used to monitor changes in place cell firing rates, and how the acitivty of cells is related to the animal’s movements within its environment. They record from afar, because the animal’s movements prevent them from coming into, and maintaining, close contact with the cells.
In the ingenious set-up devised by members of David Tank‘s laboratory, the mice were restrained, and ran on a spherical treadmill supported by a jet of air. Information about the rotation of the treadmill was used to control the animals’ movements along a computer-generated track which was projected onto a surrounding screen.
In this virtual environment, the place cells behaved as expected. All the cells from which recordings were made generated short, regular bursts of nervous impulses, separated by intervals of about one tenth of a second,. This produced a low level of background activity called the theta oscillation, which has a frequency of 6-10 cycles per second, and which is characteristic of the hippocampus. The actvity of individual place cells was modulated by location. As the animal entered a given place field, the corresponding place cell increased its firing rate almost five-fold, to generate a rhythmic discharge with a higher frequency than the background.
Because the animals were stationary, the electrodes could be used to record directly from the place cells, enabling the researchers to measure their dynamical electrical properties. This revealed how their firing rate increases: as the mouse approached a place field, the corresponding cell would ramp up its resting membrane voltage. This would cause the cell to increase the frequency of its impulses while the mouse ran through the field. When the animal emerged from the other side of the field, the membrane voltage would go back down to its normal level, and the frequency of impulses would decrease again. The background activity of single cells was also found to increase while the animal was in the appropriate location.
These findings are consistent with the predictions of a model which states that place cell activity is modulated by interactions between two separate oscillating inputs. The data do not exclude other possibilities, however, and the availablity of this virtual reality system will enable researchers to study the activity of place cells in greater detail, because it offers researchers the ability to design highly customized environments, and can be used in combination with other techniques such as two-photon laser scanning microscopy.
Reference: Harvey, C., et al. (2009). Intracellular dynamics of hippocampal place cells during virtual navigation. Nature 461: 941-946. DOI: 10.1038/nature08499.
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