New neurons in the hippocampus may remember the timing of events.

Even as science inches toward a fuller understanding of how memories are made, the details of how the brain associates memories temporally—that is, according to the timing by which they happened—has remained a mystery. New neurons that are born into the memory-encoding circuit of the hippocampus may provide the explanation. That is the theory posited by Fred Gage, a Salk Institute neurobiologist and one of the world’s experts on neurogenesis, the process by which new nerve cells are generated, survive, and integrate into the surrounding neural network. Gage’s 1998 Nature Medicine article reporting ongoing neuron birth in the adult human hippocampus is widely regarded as the evidence that tipped the scales in favor of neurogenesis, upending what had been a central tenet of neuroscience: that unlike cells in the rest of the body, the specialized cells of the central nervous system do not regenerate. The nerve cells you get at birth (and shortly thereafter), went the thinking, are the same ones you will have when you die. That thinking has been tossed out as reports from multiple research groups worldwide have flowed in, revealing the lifelong genesis of neurons in specific brain areas of birds, rats, mice, and nonhuman primates, in addition to the landmark human report by Gage and his colleague Peter Eriksson. As a result, a nascent area of neuroscience has exploded. A torrent of recent research has illuminated not only how these new neurons develop but also what influences their genesis, survival, and integration into the brain. Gage recalls presenting data on neurogenesis 10 years ago at the Society for Neuroscience meeting, at a time when fewer than a dozen researchers presented posters devoted to the subject and skepticism and debate about the idea of newly generated cells in the brain were widespread, he said. In contrast, the 2006 meeting had aisle after aisle of posters on adult neurogenesis, in addition to slide sessions and a mini-symposium devoted to it. A Different Question: Why? Yet even as scientists have taken the study of how neurogenesis occurs to bold new levels, the pesky question of why it occurs has stubbornly remained unanswered. What is the functional significance of these new cells in normal brain behavior? Simply put, what are they doing? Many researchers believe that the new neurons may have some particular role in learning, or, more specifically, the encoding of new experiences. The hippocampus has long been recognized as a brain area critical for laying down new memories. In rodents, research groups have found that specific types of learning that rely on the hippocampus—such as tasks that require remembering visual cues in a room to find a submerged platform in a water maze—increase the number of newly born neurons that survive. Animal studies suggest that a thousand or so new neurons may be born daily, but as many as half, and perhaps even more, die within a few weeks. However, if the animal is subjected to a learning task that depends upon the hippocampus, such as the water maze test mentioned above, many more cells survive and go on to connect with other existing cells. “I’m personally convinced that learning rescues these new cells from death,” says Tracey Shors, a neuroscientist at Rutgers University. Her team has found a close correlation between the number of new cells that survive and both the difficulty of the learning task and how well an individual animal learns. “Good learners retain more cells than poor learners, especially if the task is sufficiently difficult to learn and they learn it well,” she says. These results suggest that newly generated cells are affected by learning, Shors says, but they do not prove that the cells are actually involved in learning. “What the cells are used for once they are rescued is another question entirely,” she says. That is the question Gage’s group is now trying to answer. Toward that end, they have developed a computer model of the hippocampal neural network, an anatomically accurate representation of all that is currently known about this circuit. By introducing new neurons into the model and mimicking the actual maturation of these new cells in terms of which ones survive, how they develop connections with other cells in the circuit, and how their electrical firing patterns evolve, it should be possible to gain insight about how they function. Based on their understanding of the developmental milestones of new cells that do survive and integrate into this circuit, Gage and his colleagues postulate that newly generated cells may play a role in forming temporal associations among memories. Because the population of newborn cells is constantly changing, events that occur around the same time period may be encoded into the hippocampal circuitry by the same, or at least an overlapping, group of newborn cells, with presumably overlapping patterns of synaptic connections for memories laid down around the same time. This hypothesis, Gage argues, provides a plausible neurobiological mechanism for the long-recognized observation that remote memories are often roughly linked according to the time at which they were encoded into our brains, with memories of one event triggering other memories from that same slice of our life. If proved true, the idea that neurogenesis plays a role in the encoding of time in new memories does not rule out other possible roles for newborn neurons, in normal brain function as well as in disorders of the brain. A number of reports from the 2006 neuroscience meeting showed that the rate of neurogenesis is either increased or decreased in certain disease states, including depression, addiction, stroke, and epilepsy. For example, University of Michigan neurophysiologist Jack Parent presented new evidence that stroke induces a transient increase in neurogenesis—a finding other researchers also have reported—and that the newly generated neurons seem to contribute to recovery of function following stroke. His team is now investigating strategies to manipulate post-stroke neurogenesis to facilitate greater recovery. Epileptic seizures also trigger a burst of new neurons in the hippocampus, but in contrast to the apparent beneficial effects in stroke, neurogenesis in epilepsy may contribute to neurological problems associated with the disorder. Helen Scharfman, a neuropharmacologist at Columbia University, has found that seizure-induced neurons fail to properly integrate into the neural circuit. This “wiring problem” may underlie cognitive deficits that often do not manifest until many years later. In depression, there is mounting evidence that neurogenesis slows, which may help explain the long-recognized shrinkage of the hippocampus in people with long-lasting depression. In contrast, antidepressants increase neurogenesis, leading many experts to speculate that this mechanism may explain the therapeutic effects of antidepressant drugs. In October, Columbia neurobiologist Rene Hen added new fuel to this hypothesis, reporting evidence from an animal model of depression in which he found that young hippocampal neurons do indeed contribute to the behavioral response to antidepressants. With each new report, hope rises that this newly recognized regenerative capacity of the brain might one day be adequately harnessed to help treat neurological injury or disease, or even to counteract the normal age-related decrease in neurogenesis as a potential means of preventing or reversing cognitive decline with age.

neurogenesis, hippocampus, nerve cells, neuron, memory, memories, learning, timing, temporal