15 July 2009. Each person is born into this world with a specific purpose, some say, and the same appears true for adult-born nerve cells, according to a study published in the 10 July issue of Science. Researchers led by Fred Gage, Salk Institute for Biological Studies, La Jolla, California, and Tim Bussey, University of Cambridge, U.K., report that adult mice with disrupted hippocampal neurogenesis have trouble discriminating spatial patterns. While prior research had suggested that neurons born in adult brains function in learning and memory more generally, the current study provides the first clear experimental evidence for a precise role of these new cells.
The work follows previous studies by Gage and others showing that adult-born neurons can join existing memory circuits in the hippocampus (Kee et al., 2007 and ARF related news story) and, in fact, seem more prone to doing so than older neurons (Toni et al., 2007 and ARF related news story). Earlier this year, the Gage laboratory published several investigations of the dentate gyrus, a hippocampal region that pumps out new neurons throughout adulthood and that plays a critical role in memory. One report, based on rat studies (Jessberger et al., 2009), put forth the idea that new cells in the dentate gyrus contribute to spatial and object recognition memory. The other (Aimone et al., 2009) described a computational model that predicted that new dentate gyrus cells function in pattern separation, a process crucial for memory accuracy because it forms distinct representations from similar inputs.
To test this idea, first author Claire Clelland and colleagues knocked down neurogenesis in adult mice and put them through two behavioral tasks that they designed to gauge the animals’ ability to remember specific spatial locations. The researchers blocked neurogenesis with focused low-dose x-rays or by using lentiviruses to express dominant-negative Wnt, thereby inhibiting a key pathway involved in generating newborn neurons.
Two months after irradiation, the mice faced the first of two spatial memory tests—an eight-arm radial maze that rewarded animals for correctly choosing which two of eight arms held a previously presented object. The second task measured two-choice pattern discrimination using a mouse touch screen. “The important thing about both tasks is that the stimuli could be moved closer or farther apart,” Clelland said, by decreasing the angle between the radial arms, for example. The distance between touch screen stimuli could vary in similar fashion.
Mice with disrupted neurogenesis by either method did fine on the radial arm task as long as the stimuli were presented farther apart in space. However, when the stimuli were placed closer together, the mice began performing worse than their untreated counterparts. “We concluded from this that adult hippocampal neurogenesis plays an important role in spatial memory formation when there is a high reliance on spatial pattern separation—when memories to be formed are derived from very similar input, in this case, similar spatial locations,” wrote Clelland in an e-mail to ARF.
Blocking generation of newborn neurons did not seem to affect global hippocampus-dependent memory function, though. Irradiated mice could still form spatial memories at similar rates and to a similar extent as control mice given a difficult paired-associates learning task that involved learning the correct location (right, middle, or left) of a picture on a touch screen but did not rely so much on spatial pattern separation. “This is interesting because it highlights the fact that ablating adult neurogenesis does not lead to general hippocampal deficits but rather to more selective deficits,” Clelland wrote. “Newborn neurons appear to play very precise roles in memory formation.”
The findings may be relevant to neurodegenerative disease because they raise the possibility that reduced neurogenesis due to disease pathology may lead to specific types of memory impairment. According to David Greenberg at the Buck Institute for Age Research in Novato, California, the new data "suggest that treatments directed at increasing neurogenesis might have the capacity to restore cognitive functions that are impaired in these disorders." However, Clelland noted, it is not clear whether disrupted production of newborn neurons would result from or contribute to disease progression. In addition, “it remains to be investigated whether immature neurons contribute to pattern separation directly or whether they contribute in more complex ways to a circuit necessary for normal dentate gyrus function…and whether the function of immature neurons is distinct from that of mature granule cells,” the authors write.—Esther Landhuis.
Clelland CD, Choi M, Romberg C, Clemenson GD Jr, Fragniere A, Tyers P, Jessberger S, Saksida LM, Barker RA, Gage FH, Bussey TJ. A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science. 2009 Jul 10;325(5937):210-3. Abstract