PerspectiveNeuroscience

Adult neurogenesis in mammals

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Science  31 May 2019:
Vol. 364, Issue 6443, pp. 827-828
DOI: 10.1126/science.aav6885

The first claim, in the early 1960s, that neurons could be generated in the postnatal mammalian brain was met with considerable skepticism and controversy (1). Over the next 20 years, each subsequent study reporting adult neurogenesis in the mammalian brain was greeted similarly (2, 3). A dogma had been established and accepted by the scientific community: After birth, no new neurons could be generated. Conceptually, it was thought that the structural composition of the neurons within the brain remained unchangeable after birth. However, the detection of adult neurogenesis in certain regions of the brain suggested that the adult brain exhibits more plasticity than previously thought, and this has implications for concepts of self, memory, and the pathogenesis of neurodegenerative diseases.

Neurogenesis occurs through the division of neural stem cells and subsequent maturation into neural progenitor cells; these progenitors then migrate and mature into neurons. This process was thought to be restricted to embryonic development, then ceasing postnatally, such that new neurons could not be generated after birth. Adult neurogenesis has unexpectedly been detected to occur throughout the lifetime of various mammals in certain areas of the brain, particularly in the hippocampus, a brain structure that is crucial for the acquisition of new memories as well as the accurate retrieval of older memories.

What were the arguments against adult neurogenesis? The technical part of the skeptics' argument questioned how new neurons could be generated from mature neurons that were integrated into the existing mature brain network. The more conceptual concern was that if new neurons were being generated in the mature brain, then memories and even the concept of self would be unstable. The concerns were countered by the discovery that adult rodent brains contained neural stem and progenitor cells in the regions where postnatal neurogenesis had been detected using fate-mapping methods, such as bromodeoxyuridine (BrdU) labeling of dividing cells and genetic markers (4). Moreover, adult neurogenesis was shown to occur in limited areas of the brain, and the number of new neurons being generated was clearly small.

In the 1990s, adult neurogenesis was investigated in more species, including non-human primates and humans (5). However, attention was turning away from questioning whether adult neurogenesis occurred, and toward revealing the cell and molecular mechanisms for generating these new neurons in a mature brain. This effort was particularly interesting and challenging because of the then-presumed lack of developmental signals and structures present in the mature brain to support neurogenesis. In addition, there was substantial and growing interest in whether adult neurogenesis had any consequences for animal behavior. A twist in the adult neurogenesis story emerged with the finding that environmental experiences such as learning, exercise, enriched environmental stimulation (enrichment), and stress could have marked effects on various aspects of adult neurogenesis, including proliferation, maturation, migration, differentiation, survival, and integration (6) (see the figure). Moreover, many of these environmental experiences appeared to have consequences for the behavior of animals, and they directly correlated with the rate and extent of adult neurogenesis.

Mammalian neurogenesis is regulated by many behavioral factors

Running potently induces neurogenesis, promoting the proliferation of neural progenitor cells. Enrichment has a complementary effect by increasing the survival of neurons during their maturation. By contrast, stress suppresses proliferation of neural progenitor cells. The effects of learning are more complex, suppressing neurogenesis at some stages and increasing it at others.

GRAPHIC: A. KITTERMAN/SCIENCE

In the midst of this flourishing area of research, technical concerns continued to be expressed regarding the limitations of the detection methods. In particular, questions were raised by a claim of adult neurogenesis in the neocortex of cynomolgus monkeys (7). This claim was subsequently revealed to be unlikely following the development of a radiocarbon dating method developed specifically for neurons in the postmortem brains of humans exposed to ionizing radiation during the atomic bomb testing of the 1960s (8). Using this method, adult neurogenesis was not detected in the neocortex, cerebellum, and olfactory bulb of humans. However, this method confirmed that a consistent rate of neurogenesis occurred in the human hippocampus well into the ninth decade of life. These results were supported by studies of postmortem human brains that detected, by immunostaining techniques (whereby antibodies are used to detect markers in tissue samples), various markers of proliferation and early neurogenesis in cells of the dentate gyrus, a subregion of the hippocampus thought to contribute to the formation of new memories, the exploration of new environments, and other functions. The amounts of neurogenesis were found to be dependent on the individual's age or disease states, including Alzheimer's disease (AD) and depression. However, no clear consensus was achieved from these postmortem studies because of technical challenges including differences in postmortem delay prior to tissue fixation, variation in life experience, and the use of different antibodies in immunostaining.

During this period of the 1990s, researchers were conducting experiments in which they hoped to demonstrate causal and functional roles for adult neurogenesis in the rodent hippocampus by increasing the rate of neurogenesis or blocking it in a time-dependent, regulated manner. Although the results increasingly indicated that adult neurogenesis in rodents was required for some forms of learning and memory, the interpretations of the results and the theoretical (computational) framework for understanding the role of adult neurogenesis in hippocampal function continued to be points of contention. Nonetheless, these studies defined a number of diverse potential functions of the new neurons, including enhancing resilience against stress (affective resilience) (9), regulating the ability to discriminate among similar experiences (pattern separation) (10), incorporating time into episodic memories, and enabling the forgetting of old memories (11). Theoretical models continue to aid investigators to reconcile different interpretations based on the behavioral task used and on when the task was administered in experiments compared to the experiences the rodents had prior to and after performance of the task (12). There is now more consensus than contention regarding the existence of a functional role of adult hippocampal neurogenesis in the mammalian brain, but more research is needed to establish a common language to describe the role(s) of adult hippocampal neurogenesis in the behavior of the adult organism.

However, the debate continues, as two recent studies have reported contradictory findings of undetectable levels of hippocampal neurogenesis in adult human brains (13) versus persistent human hippocampal neurogenesis throughout aging (14). Both studies were based on the same premise that if neurogenesis occurs in humans, specific markers of neural stem and progenitor cells should be expressed in the dentate gyrus.

The anatomical and molecular features of the neural stem and progenitor cells in the dentate gyrus had been defined in the adult mouse hippocampus. Both studies used a variety of similar antibodies to immunostain for markers of neural stem and progenitor cells, proliferating cells, migrating neural progenitors, and markers expressed at various stages of neuron maturation. The underlying thesis for both studies was that if neurogenesis is occurring in the hippocampus, then some combination of these markers and cells should be present there. Both studies detected marker-positive cells in the adult human hippocampus, but they used different criteria for concluding that the immunostaining was adequate, relevant, or accurate to define the cells as neurogenic. It is clear that there are a variety of technical and methodological issues that can add to the variability in immunostaining between samples in these postmortem human studies. These issues include postmortem delay, tissue fixation, and the physical and psychological state of the subject before death, adding to the difficulty of establishing invariant criteria for calling an immunostained cell a neural stem or progenitor cell (15).

Currently, the argument that adult neurogenesis persists in the human hippocampus is more convincing because of evidence using fate markers such as BrdU and carbon dating, as well as the more rigorously controlled studies with shorter postmortem times and extensive information about the individual, well-characterized fixation protocols, and accepted cell-counting methods (16). But how can the conditions for studying adult neurogenesis in humans be improved to resolve the debate? Ideally, more work should be done to validate and extend the methods that have already been used to detect indirect indicators of neurogenesis, such as functional magnetic resonance imaging in living humans. More direct measures of adult neurogenesis using, for example, proton magnetic resonance spectroscopy or probes could be developed for positron emission tomography brain imaging. In addition, single-cell RNA sequencing studies from postmortem brains are now under way and should add valuable information for more sophisticated understanding of the cellular components in neurogenic regions.

A more universal approach to consider is the creation of open-access brain banks with tissues more ideally suited to these types of studies. Such brain banks would have clear, consistent, and reliable record-keeping for postmortem brain tissue, and the tissue would be stored in optimal conditions for preservation in standardized locations so that multiple researchers from different institutions could use their unique staining methods and antibodies on the same tissues.

One reason why it is important to establish reliable and consistent methods is highlighted by the recent finding that adult neurogenesis persists into the ninth decade of life in the human hippocampus and that there is a significant decline in neurogenesis in patients with AD (16). The hippocampus and its functions, such as learning, memory, and emotional resilience, have been consistently implicated as a brain area that is affected early in the pathogenesis of AD. This study is notable for using short postmortem delay, clinically characterized subjects, well-tested tissue fixation protocols, and state-of-the-art quantitative methods.

Neural stem and progenitor cells persist in the adult mammalian brain and can faithfully integrate into the adult brain circuitry; this constitutes the most robust form of adult structural plasticity at the cellular level. Brain plasticity, in this context, refers to the anatomical and functional changes that can occur in brain cells in response to environmental stimulation. Even more extraordinary is that the fate and functions of adult-born neural stem and progenitor cells and their progeny are regulated by an individual organism's internal and external environmental experiences. Contradictions and controversy generally drive science to develop better and more reliable methods and procedures; this process is already under way in this remarkable field. These new tools will help to further our knowledge of the mechanisms and function of adult mammalian neurogenesis.

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