Neural stem cells exist not only in the developing mammalian nervous system but also in the adult nervous system of all mammalian organisms, including humans. Neural stem cells can also be derived from more primitive embryonic stem cells. The location of the adult stem cells and the brain regions to which their progeny migrate in order to differentiate remain unresolved, although the number of viable locations is limited in the adult. The mechanisms that regulate endogenous stem cells are poorly understood. Potential uses of stem cells in repair include transplantation to repair missing cells and the activation of endogenous cells to provide "self-repair. " Before the full potential of neural stem cells can be realized, we need to learn what controls their proliferation, as well as the various pathways of differentiation available to their daughter cells.

https://science.sciencemag.org/content/sci/287/5457/1433.full.pdf

Mammalian neural stem cells.

Various chronic antidepressant treatments increase adult hippocampal neurogenesis, but the functional importance of this phenomenon remains unclear. Here, using genetic and radiological methods, we show that disrupting antidepressant-induced neurogenesis blocks behavioral responses to antidepressants. Serotonin 1A receptor null mice were insensitive to the neurogenic and behavioral effects of fluoxetine, a serotonin selective reuptake inhibitor. X-irradiation of a restricted region of mouse brain containing the hippocampus prevented the neurogenic and behavioral effects of two classes of antidepressants. These findings suggest that the behavioral effects of chronic antidepressants may be mediated by the stimulation of neurogenesis in the hippocampus.

https://science.sciencemag.org/content/sci/301/5634/805.full.pdf

Requirement of Hippocampal Neurogenesis for the Behavioral Effects of Antidepressants

The hippocampus shrinks in late adulthood, leading to impaired memory and increased risk for dementia. Hippocampal and medial temporal lobe volumes are larger in higher-fit adults, and physical activity training increases hippocampal perfusion, but the extent to which aerobic exercise training can modify hippocampal volume in late adulthood remains unknown. Here we show, in a randomized controlled trial with 120 older adults, that aerobic exercise training increases the size of the anterior hippocampus, leading to improvements in spatial memory. Exercise training increased hippocampal volume by 2%, effectively reversing age-related loss in volume by 1 to 2 y. We also demonstrate that increased hippocampal volume is associated with greater serum levels of BDNF, a mediator of neurogenesis in the dentate gyrus. Hippocampal volume declined in the control group, but higher preintervention fitness partially attenuated the decline, suggesting that fitness protects against volume loss. Caudate nucleus and thalamus volumes were unaffected by the intervention. These theoretically important findings indicate that aerobic exercise training is effective at reversing hippocampal volume loss in late adulthood, which is accompanied by improved memory function.

https://www.pnas.org/content/pnas/108/7/3017.full.pdf

Exercise training increases size of hippocampus and improves memory

A meta-analytic study was conducted to examine the hypothesis that aerobic fitness training enhances the cognitive vitality of healthy but sedentary older adults. Eighteen intervention studies published between 1966 and 2001 were entered into the analysis. Several theoretically and practically important results were obtained. Most important fitness training was found to have robust but selective benefits for cognition, with the largest fitness-induced benefits occurring for executive-control processes. The magnitude of fitness effects on cognition was also moderated by a number of programmatic and methodological factors, including the length of the fitness-training intervention, the type of the intervention, the duration of training sessions, and the gender of the study participants. The results are discussed in terms of recent neuroscientific and psychological data that indicate cognitive and neural plasticity is maintained throughout the life span.

https://www.jstor.org/stable/pdfplus/40063782.pdf

Fitness Effects on the Cognitive Function of Older Adults: A Meta-Analytic Study

The idea of reserve against brain damage stems from the repeated observation that there does not appear to be a direct relationship between the degree of brain pathology or brain damage and the clinical manifestation of that damage. This paper attempts to develop a coherent theoretical account of reserve. One convenient subdivision of reserve models revolves around whether they envision reserve as a passive process, such as in brain reserve or threshold, or see the brain as actively attempting to cope with or compensate for pathology, as in cognitive reserve. Cognitive reserve may be based on more efficient utilization of brain networks or of enhanced ability to recruit alternate brain networks as needed. A distinction is suggested between reserve, the ability to optimize or maximize normal performance, and compensation, an attempt to maximize performance in the face of brain damage by using brain structures or networks not engaged when the brain is not damaged. Epidemiologic and imaging data that help to develop and support the concept of reserve are presented.

/pdf/what-is-cognitive-reserve-theory-and-research-application-of-4bek0o9s8b.pdf

What is cognitive reserve? Theory and research application of the reserve concept.

Exposure to an enriched environment increases neurogenesis in the dentate gyrus of adult rodents. Environmental enrichment, however, typically consists of many components, such as expanded learning opportunities, increased social interaction, more physical activity and larger housing. We attempted to separate components by assigning adult mice to various conditions: water-maze learning (learner), swim-time-yoked control (swimmer), voluntary wheel running (runner), and enriched (enriched) and standard housing (control) groups. Neither maze training nor yoked swimming had any effect on bromodeoxyuridine (BrdU)-positive cell number. However, running doubled the number of surviving newborn cells, in amounts similar to enrichment conditions. Our findings demonstrate that voluntary exercise is sufficient for enhanced neurogenesis in the adult mouse dentate gyrus.

http://www.neurogenesisresearch.com/Runing_and_Neurogenesis_Nat.pdf

Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus.

There is extensive evidence indicating that new neurons are generated in the dentate gyrus of the adult mammalian hippocampus, a region of the brain that is important for learning and memory1,2,3,4,5. However, it is not known whether these new neurons become functional, as the methods used to study adult neurogenesis are limited to fixed tissue. We use here a retroviral vector expressing green fluorescent protein that only labels dividing cells, and that can be visualized in live hippocampal slices. We report that newly generated cells in the adult mouse hippocampus have neuronal morphology and can display passive membrane properties, action potentials and functional synaptic inputs similar to those found in mature dentate granule cells. Our findings demonstrate that newly generated cells mature into functional neurons in the adult mammalian brain.

Functional neurogenesis in the adult hippocampus

Neuronal plasticity is a central theme of modern neurobiology, from cellular and molecular mechanisms of synapse formation in Drosophila to behavioural recovery from strokes in elderly humans. Although the methods used to measure plastic responses differ, the stimuli required to elicit plasticity are thought to be activity-dependent. In this article, we focus on the neuronal changes that occur in response to complex stimulation by an enriched environment. We emphasize the behavioural and neurobiological consequences of specific elements of enrichment, especially exercise and learning.

Neural consequences of environmental enrichment.

Aging causes changes in the hippocampus that may lead to cognitive decline in older adults. In young animals, exercise increases hippocampal neurogenesis and improves learning. We investigated whether voluntary wheel running would benefit mice that were sedentary until 19 months of age. Specifically, young and aged mice were housed with or without a running wheel and injected with bromodeoxyuridine or retrovirus to label newborn cells. After 1 month, learning was tested in the Morris water maze. Aged runners showed faster acquisition and better retention of the maze than age-matched controls. The decline in neurogenesis in aged mice was reversed to 50% of young control levels by running. Moreover, fine morphology of new neurons did not differ between young and aged runners, indicating that the initial maturation of newborn neurons was not affected by aging. Thus, voluntary exercise ameliorates some of the deleterious morphological and behavioral consequences of aging.

https://www.jneurosci.org/content/jneuro/25/38/8680.full.pdf

Exercise Enhances Learning and Hippocampal Neurogenesis in Aged Mice

Exposure to an enriched environment and physical activity, such as voluntary running, increases neurogenesis of granule cells in the dentate gyrus of adult mice. These stimuli are also known to improve performance in hippocampus-dependent learning tasks, but it is unclear whether their effects on neurogenesis are exclusive to the hippocampal formation. In this study, we housed adult mice under three conditions (enriched environment, voluntary wheel running and standard housing), and analysed proliferation in the lateral ventricle wall and granule cell neurogenesis in the olfactory bulb in comparison to the dentate gyrus. Using bromodeoxyuridine to label dividing cells, we could not detect any difference in the number of newly generated cells in the ventricle wall. When giving the new cells time to migrate and differentiate in the olfactory bulb, we observed no changes in the number of adult-generated olfactory granule cells; however, voluntary running and enrichment produced a doubling in the amount of new hippocampal granule cells. The discrepancy between the olfactory bulb and the dentate gyrus suggests that these living conditions trigger locally through an as yet unidentified mechanism specific to neurogenic signals in the dentate gyrus.

Henriette van Praag

Papers

Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus.

Functional neurogenesis in the adult hippocampus

Neural consequences of environmental enrichment.

Exercise Enhances Learning and Hippocampal Neurogenesis in Aged Mice

Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis.