A lively debate about
brain’s capacity for renewal

Two competing views of neurogenesis
are played out in the pages of Science.

Neurogenesis, an arcane and complex issue, has leaped out of scientific journals and conferences in the last few years to land in the pages of newspapers and magazines, including Newsweek and The New Yorker.

The source of this growing interest is an ongoing debate over the brain’s ability to generate new neurons in the cortex. Pasko Rakic, M.D., Ph.D., the Dorys McConnell Duberg Professor of Neuroscience and chair of the Department of Neurobiology, believes that the neocortex of primates, including humans, gets its lifetime share of neurons during development and shortly after birth.

Elizabeth Gould, Ph.D., a professor of psychology at Princeton, has published studies asserting that primates generate neurons in the neocortex well into adulthood.

The two camps have reached such different conclusions using largely the same experimental design, but with variations in their techniques and criteria for identifying new cells. Each publication on the topic rekindles the debate.

Rakic fired the latest salvo in the December 7 issue of Science when, with colleague David R. Kornack, Ph.D., his former postdoc who is now at the University of Rochester, he reported that Gould had indeed found new cells in the neocortex. They simply weren’t neurons. Instead, reports Rakic, Gould mistook glial and endothelial cells for neurons.

“Our study shows that neurons of the cerebral cortex are created in a precise sequence during restricted periods of development before birth and during the neonatal period,“ Rakic said. “Therefore we have to live our entire lives with the cortical neurons we are born with.”

With a preponderance of evidence in its favor, this view has dominated study of the brain since the 1980s, when Rakic published his findings after conducting lengthy studies of macaque monkeys. Subsequent studies with new labeling techniques found evidence of neurogenesis in other parts of the mammalian brain—the hippocampus and the olfactory bulb. But neurogenesis in the neocortex remains a controversial topic.

Gould insists she has found new neurons in the cortex. Like Rakic, she used the thymidine analog BrdU, along with other markers that would stain new cells. And she said she has factored in the possibility of false positives. When viewed through a confocal microscope and rotated, she said, it’s clear that the cells she found are neurons. Rakic counters that BrdU labeling, although essential to identify new cells, is not by itself sufficient evidence. “Incorporation of BrdU may also occur during DNA repair, cell degeneration and during cell death,” he said. And large and multiple injections of BrdU may also induce DNA synthesis, he said.

“There are lots of reasons there could be a discrepancy in the findings,” Gould said. “We don’t go about it in the same way. Our histological techniques differ. Our animals could have different experiences.” Stress, for example, limits production of neurons, while a stimulating environment encourages it, she said.

It is also unclear what function, if any, the new neurons may have in the neocortex. Gould notes that the cortex, which is associated with higher functions, is very large. The number of new neurons she has found is so small relative to the total number that their impact may be minimal. Indeed, she said, the generation of new neurons might be a vestige of a developmental process that was never turned off.

But what Gould sees as a very small number is, to Rakic, “staggering.” To accommodate these new neurons, Rakic said, the brain would have to grow or kill off existing neurons. Rakic said he has found evidence of neither.

He also believes that neurogenesis in the neocortex makes no functional or evolutionary sense. Early in their evolution humans traded the ability to grow new neurons, as seen in fish, amphibians and reptiles, for the ability to retain memory in existing neurons, he said. “We use neurons to store our life experiences and if we change neurons every season like male canaries do, then we would lose a lot of our life experiences,” Rakic said. “Neurogenesis in the neocortex could eliminate crucial, learned cognitive functions and long-term memories. We have to learn how to preserve our neurons during disease and natural aging.”

A link from sleep to pain

A neuropeptide whose absence may be a factor in sudden sleep attacks also appears to modulate pain. A team that included Anthony N. van den Pol, Ph.D., professor of neurosurgery at Yale, and colleagues at the University of North Carolina, found that hypocretin neurons provide a biochemical link from the hypothalamus—which regulates eating, drinking, sleeping, waking, body temperature, chemical balances, heart rate, hormones, sex and emotions—to the spinal cord. “We found that most cells in a region of the spinal cord responsible for detecting pain (pictured at left) show a significant physiological response to the peptide hypocretin-2,” said van den Pol, a co-author of the study published in the January issue of the Journal of Physiology. New drugs related to hypocretin, which plays a role in narcolepsy, could help in the treatment of pain.

Et Cetera

Bleach, water and HIV

Although proven effective in preventing the spread of HIV, needle exchange programs remain unfunded by the federal government, largely for political reasons. Yale scientists, whose earlier work was fundamental in proving the efficacy of needle exchange, reported recently that in a worst-case scenario in which sterile syringes are not available, rinsing syringes with a bleach solution or even plain water can provide effective protection against infection. “We found that for the type of syringe usually used by drug injectors, a solution of bleach and nine parts water disinfects the syringe if the solution is drawn in and squirted back out twice,” said Robert Heimer, Ph.D., associate professor of epidemiology and pharmacology and principal investigator of the study, published in the December issue of the Journal of Acquired Immune Deficiency Syndromes: JAIDS. “We found that rinsing three times with clean water reduced the likelihood of recovering live virus by 99 percent.” While not absolutely protective against HIV, Heimer said, “these measures reinforce the adage that prevention is never perfect and never ending.”

Cocaine and the fetus

When pregnant women use cocaine, their offspring may suffer permanent harm to an area of the brain that governs short-term memory, leading to learning impairments and symptoms resembling attention deficit disorder. According to two recent animal studies by Yale scientists Bret A. Morrow, Ph.D., John D. Elsworth, Ph.D., and Robert H. Roth, Ph.D., the effects are manifest in the prefrontal cortex. “Children exposed to cocaine in the womb may have a problem inhibiting excitable neurons in the part of the brain that helps control attention and memory,” said Morrow, associate research scientist, associate clinical professor and lead author of both studies, published in February and March in the journals Behavioral Brain Research and Neuropsychopharmacology, respectively.


			Originally published in Yale Medicine, Spring 2002. Copyright © 2002 Yale University School of Medicine. All rights reserved.

A lively debate about brain’s capacity for renewal