SAN DIEGO - While sessions on new drugs for mental illnesses drew big crowds at the 160th annual meeting of the American Psychiatric Association (APA), a few basic research lectures also held their own.

In particular, a talk on the formation and potential function of new neurons in the adult brain, given by Fred Gage, professor in the Laboratory of Genetics at the Salk Institute for Biological Studies and co-founder of Stem Cells Inc., drew a full house at the conference, which ended Thursday.

Gage explained that while neurons cannot divide, neural stem cells in specific sections of the brain, such as the hippocampus, can differentiate into neurons. Gage's laboratory identified a family of molecules called Wnt as a key signaling factor involved in the differentiation of neural stem cells into neurons rather than other types of cells.

Wnt is a key developmental signaling molecule, and recently has been implicated in the growth of what's on top of the skull as well as inside it (see BioWorld Today, May 17, 2007.)

Yet especially for neurons, which form enormously complex circuitry, differentiation is just part of the story - the new neurons must "find a way to integrate into the appropriate target area" in order to function and survive, Gage said.

If they don't, neurogenesis goes from repair mechanism to useless - or worse. Stroke patients often show a spike in neurogenesis as the brain attempts to repair itself, but those neurons do not survive. Epileptic patients also show massive neurogenesis, but the neurons integrate backward, which Gage said may be "causally related" to the seizures.

Correct integration appears to be achieved by the filopodia, tiny fingers that extend off a newly formed dendrite. Yet those fingers do not search for empty holes to fill; they compete with existing neurons. In fact, 95 percent of filopodia form within 50-200 nm from a pre-existing synapse.

The neurotransmitter GABA also plays a role in integration, serving to excite rather than inhibit the newly formed neurons. Gage said that while many labs are studying GABA's effects, it has proven difficult to separate its stimulatory effect on new neurons from its inhibitory effect on other synapses in the brain.

Factors such as sex, age and genetics also can affect the formation and survival of new neurons. External factors play a role as well. Acute stress transiently blocks proliferation of new neurons, while chronic stress can result in sustained suppression of neurogenesis. Exercise also can increase neurogenesis.

Gage discussed an experiment in which mice given an exercise wheel demonstrated three to four times as many new neurons as sedentary mice over a 30-day period, with two to three times as many neurons integrating and surviving. The distance the mice ran correlated to the number of new neurons formed.

But what exactly do the new neurons do? The hippocampus is important in learning and memory, as well as integrating the various sensory aspects of an experience. Experiments in mice have shown that exercise increases memory abilities, while mice without neurogenesis can learn but cannot remember.

One theory that Gage proposed as "completely theoretical" is the idea that new neurons connect our memories of experiences that occur within a few weeks of each other. He offered the example of how thinking about an event that occurred last summer will trigger memories of completely unrelated events that happened around the same time.

Another idea on exactly how new neurons in the adult hippocampus are related to learning was offered up in the May 24, 2007 issue of Neuron. Researchers from Johns Hopkins University and Taiwan's National Cheng Kung University suggested the neurons enable new learning without jettisoning old information from the brain.

The researchers used labeling studies to determine whether new neurons in the adult brain are merely there to mitigate the ravages of everything from age to heavy drinking, or whether they actually make "unique contributions to specific brain functions that could not be achieved by existing mature neurons," as the authors wrote in their paper.

The scientists labeled specific neurons in a way that allowed them to tell their exact age. They then tested how plastic, or able to change in response to stimulation, those neurons were at certain ages.

They found that in the hippocampus, neurons that are 4-6 weeks of age are the most able to change in response to stimulation.

Neurons of that age showed the most long-term potentiation, which is widely believed to be the mechanism by which neurons store memories. Finally, at that age, neurons expressed a type of receptor that also is known to be involved in memory formation.

The scientists pointed out that the period of plasticity is reminiscent of postnatal critical periods; some skills - including language in humans - need to be learned at a certain age, or they will not be learned at all.

The authors suggested that the enhanced plasticity of the young neurons may enable them to store new information, while the comparatively short time they are able to do so keeps mature circuits from being overwhelmed by too much of a good thing.