Trends in Neurosciences
OpinionThe neurogenic reserve hypothesis: what is adult hippocampal neurogenesis good for?
Introduction
The ‘neurogenic reserve’ hypothesis, proposed here, intends to explain how neurogenesis in the adult hippocampus might contribute to the maintenance and promotion of hippocampal function in health and disease across the lifespan. The theory makes explicit reference to the neural reserve theory, first proposed by R. Katzman and P. Satz and elaborated, for example, by Y. Stern 1, 2, 3, 4. A ‘neural reserve’ is sought as explanation, for example, for the observation that in cases of neurodegenerative disease, the amount of neuropathological damage shows no tight correlation with the functional impairment [5]. Apparently healthy subjects might die with a brain full of Alzheimer-like plaques, although modest plaque load in other individuals might already be associated with massive dementia [6]. The neural reserve would represent the brain's compensatory potential in the face of neurodegeneration. This reserve is thought to lie in ‘brain networks or cognitive paradigms that are less susceptible to disruption, perhaps [because] they are more efficient or have greater capacity’ [7]. The neurogenic reserve theory specifies that in the hippocampus, adult neurogenesis might activity- and experience-dependently produce a potential for sustained cellular plasticity with increasing age but from childhood onward, thereby providing such greater capacity and efficiency. The particular relevance of this special case of a reserve derives from the prominent role of the hippocampus in higher cognition, most notably learning and memory and emotional behavior. In animal experiments, both physical and cognitive ‘activity’ reduced the age-dependent decline in precursor cell proliferation in the dentate gyrus 8, 9, 10. Sustained exposure to a complex environment, even if started only in midlife, maintained neurogenesis at a higher level and also resulted in improved learning performance [9]. Thereby, adult neurogenesis might contribute to the well-known but poorly understood observation that activity – in the sense of leading an active life – is ‘good for the brain’ and promotes successful aging.
Section snippets
The local restriction of adult neurogenesis as key to its function
Adult neurogenesis, the lifelong generation of new neurons in the adult hippocampus and olfactory system, captures the scientific and public imagination with its seemingly obvious implications for regenerative medicine. This fascination is contrasted by an intriguing insecurity about what the new neurons are actually good for, although some agreement has been reached that they are involved in learning 11, 12, 13, 14, 15, 16. However, the fact that adult neurogenesis is regulated by activity and
Possible functions of adult hippocampal neurogenesis on the systems level
Our assumption is that for some reason, the mossy fiber connection has to be as lean as possible but as strong as necessary [12]. Adding new neurons to this reduced network with its sparsely firing neurons might be a way to economically optimize the projection into the hippocampus proper. Adding new neurons here might be a way to solve the so-called stability–plasticity dilemma, which is particularly pressing at a network position where constantly new information is flooding in and endangers
Functional relevance beyond the systems level and on longer timescales
The fact that ‘activity’ is an appropriate stimulus for adult neurogenesis adds another, temporal dimension to the question of what new neurons are good for. Activity-dependent regulation of adult neurogenesis shows an intriguing duality: the acute recruitment of the currently available immature cell (which is in its critical time window for activity-dependent recruitment) and the stimulation of mechanisms that increase the pool of such recruitable cells on longer timescales. In the course of
A synthesis of nonspecific and specific regulatory mechanisms
In the laboratory, we can separate physical and cognitive activity for mice to a certain degree. Both physical exercise and exposure to complex environments or learning stimuli increase adult neurogenesis 43, 46, 47, 48, 49. However, whereas physical activity acts on proliferating precursor cells and induces their division, the more cognitive stimuli rather promote the survival of newborn postmitotic cells 47, 48. These experiments have led us to the hypothesis that the activity-dependent
The cellular representation of the neurogenic reserve in the adult hippocampus
The very low levels of adult neurogenesis, together with its local restriction to the hippocampus and just one other neurogenic region in the olfactory system, its limitation to only one type of new hippocampal neuron and the tight link to hippocampal function have come as a disappointment to those who hoped that adult neurogenesis might serve as a source for restoring cellular losses. In many models of pathology, adult neurogenesis is robustly induced but this effect seems to be transient and
Testing the neurogenic reserve hypothesis
The neurogenic reserve hypothesis aims at providing an explanation of why activity-dependently controlled adult neurogenesis might be beneficial over long periods of time. The emphasis is on the fact that adult neurogenesis is regulated by activity, and functional consequences might become particularly apparent over long timescales. The hypothesis relies on certain assumptions about the functional contribution new neurons might make to a network (as outlined above and e.g. in Ref. [19]), but
Medical implications of a neurogenic reserve
If we extrapolate the animal data to the situation in humans, broad ranges of activity early in life would not only help to build a highly optimized hippocampal network adapted to a complex life, lifelong activity would also contribute to a neurogenic reserve by keeping precursor cells in cycle and thereby generating an incessant stream of immature, potentially recruitable neurons [10]. Adult neurogenesis might thus be able to contribute to primary and secondary prevention of failing cognitive
Concluding remarks
The neurogenic reserve hypothesis aims at explaining how the activity-dependent incorporation of a low number of neurons into the hippocampal network can lead to a functional benefit along the course of life of an individual. The core idea is that ‘activity’ preserves the potential for cell-based plasticity by maintaining adult neurogenesis in an activated state. To test the hypothesis, experiments following and manipulating adult neurogenesis across the lifespan while measuring an animal's
Acknowledgements
The ideas proposed in this article owe much to the intense discussions at four conferences of the Max Planck Network on Aging (Maxnet Aging) between 2004 and 2006. I would especially like to thank Ulman Lindenberger (Berlin) and Lars Bäckman (Stockholm).
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