Early age-related changes in adult hippocampal neurogenesis in C57 mice

In the adult hippocampus, neural stem cells (NSCs) continuously produce new neurons that integrate into the neuronal network to modulate learning and memory. The amount and quality of newly generated neurons decline with age, which can be counteracted by increasing intrinsic Wnt activity in NSCs. However, the precise cellular changes underlying this age-related decline or its rescue through Wnt remain unclear. The present study combines development of a mathematical model and experimental data to address features controlling stem cell dynamics. We show that available experimental data fit a model in which quiescent NSCs can either become activated to divide or undergo depletion events, consisting of astrocytic transformation and apoptosis. Additionally, we demonstrate that aged NSCs remain longer in quiescence and have a higher probability to become re-activated versus being depleted. Finally, our model explains that high NSC-Wnt activity leads to longer time in quiescence while augmenting the probability of activation.

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Revealing age-related changes of adult hippocampal neurogenesis using mathematical models

Development ◽

10.1242/dev.153544 ◽

2017 ◽

Vol 145 (1) ◽

pp. dev153544 ◽

Cited By ~ 20

Author(s):

Frederik Ziebell ◽

Sascha Dehler ◽

Ana Martin-Villalba ◽

Anna Marciniak-Czochra

Keyword(s):

Mathematical Models ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Age Related ◽

Age Related Changes

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Age-related changes in spatial navigation are evident by midlife and differ by sex

10.31234/osf.io/rsfpz ◽

2020 ◽

Author(s):

Shuying Yu ◽

Alexander Paul Boone ◽

Carol He ◽

Rie Davis ◽

Mary Hegarty ◽

...

Keyword(s):

Path Integration ◽

Middle Age ◽

Spatial Navigation ◽

Spatial Knowledge ◽

Early Age ◽

Age Related ◽

Navigation Path ◽

Spatial Knowledge Acquisition ◽

Age Related Changes ◽

Navigation Strategies

Accumulating evidence suggests that distinct aspects of successful navigation—path integration, acquiring spatial knowledge, and navigation strategies—change with advanced age. Yet, few studies have established whether navigation deficits emerge early in the aging process (prior to age 65) or whether early age-related deficits vary by sex. Here, we probed healthy young (ages 18-28) and midlife (ages 43-61) adults on three essential aspects of navigation. First, path integration ability shows negligible effects of sex or age. Second, robust sex differences in spatial knowledge acquisition are observed in young adulthood and persist, but are diminished, with age. Third, by midlife, men and women show decreased ability to acquire spatial knowledge and increased reliance on taking habitual paths. Together, our findings indicate that age-related changes in navigation ability and strategy are evident as early as midlife and that path integration ability is relatively spared in the transition from youth to middle age.

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Telomere length and human hippocampal neurogenesis

Neuropsychopharmacology ◽

10.1038/s41386-020-00863-w ◽

2020 ◽

Vol 45 (13) ◽

pp. 2239-2247 ◽

Cited By ~ 1

Author(s):

Alish B. Palmos ◽

Rodrigo R. R. Duarte ◽

Demelza M. Smeeth ◽

Erin C. Hedges ◽

Douglas F. Nixon ◽

...

Keyword(s):

Cognitive Function ◽

Psychiatric Disorder ◽

Telomere Length ◽

Gene Networks ◽

Hippocampal Neurogenesis ◽

Telomere Maintenance ◽

Adult Hippocampal Neurogenesis ◽

Telomere Shortening ◽

Age Related

Abstract Short telomere length is a risk factor for age-related disease, but it is also associated with reduced hippocampal volumes, age-related cognitive decline and psychiatric disorder risk. The current study explored whether telomere shortening might have an influence on cognitive function and psychiatric disorder pathophysiology, via its hypothesised effects on adult hippocampal neurogenesis. We modelled telomere shortening in human hippocampal progenitor cells in vitro using a serial passaging protocol that mimics the end-replication problem. Serially passaged progenitors demonstrated shorter telomeres (P ≤ 0.05), and reduced rates of cell proliferation (P ≤ 0.001), with no changes in the ability of cells to differentiate into neurons or glia. RNA-sequencing and gene-set enrichment analyses revealed an effect of cell ageing on gene networks related to neurogenesis, telomere maintenance, cell senescence and cytokine production. Downregulated transcripts in our model showed a significant overlap with genes regulating cognitive function (P ≤ 1 × 10−5), and risk for schizophrenia (P ≤ 1 × 10−10) and bipolar disorder (P ≤ 0.005). Collectively, our results suggest that telomere shortening could represent a mechanism that moderates the proliferative capacity of human hippocampal progenitors, which may subsequently impact on human cognitive function and psychiatric disorder pathophysiology.

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Age-Related Changes in Spatial Navigation Are Evident by Midlife and Differ by Sex

Psychological Science ◽

10.1177/0956797620979185 ◽

2021 ◽

pp. 095679762097918

Author(s):

Shuying Yu ◽

Alexander P. Boone ◽

Chuanxiuyue He ◽

Rie C. Davis ◽

Mary Hegarty ◽

...

Keyword(s):

Knowledge Acquisition ◽

Path Integration ◽

Spatial Knowledge ◽

Early Age ◽

Age Related ◽

Navigation Path ◽

Spatial Knowledge Acquisition ◽

Midlife Adults ◽

Age Related Changes ◽

Navigation Strategies

Accumulating evidence suggests that distinct aspects of successful navigation—path integration, spatial-knowledge acquisition, and navigation strategies—change with advanced age. Yet few studies have established whether navigation deficits emerge early in the aging process (prior to age 65) or whether early age-related deficits vary by sex. Here, we probed healthy young adults (ages 18–28) and midlife adults (ages 43–61) on three essential aspects of navigation. We found, first, that path-integration ability shows negligible effects of sex or age. Second, robust sex differences in spatial-knowledge acquisition are observed not only in young adulthood but also, although with diminished effect, at midlife. Third, by midlife, men and women show decreased ability to acquire spatial knowledge and increased reliance on taking habitual paths. Together, our findings indicate that age-related changes in navigation ability and strategy are evident as early as midlife and that path-integration ability is spared, to some extent, in the transition from youth to middle age.

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Environmental enrichment preserves a young DNA methylation landscape in the aged mouse hippocampus

Nature Communications ◽

10.1038/s41467-021-23993-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Sara Zocher ◽

Rupert W. Overall ◽

Mathias Lesche ◽

Andreas Dahl ◽

Gerd Kempermann

Keyword(s):

Dna Methylation ◽

Brain Function ◽

Environmental Enrichment ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Aged Mouse ◽

Lifestyle Interventions ◽

Epigenetic Changes ◽

Aging Effects ◽

Age Related

AbstractThe decline of brain function during aging is associated with epigenetic changes, including DNA methylation. Lifestyle interventions can improve brain function during aging, but their influence on age-related epigenetic changes is unknown. Using genome-wide DNA methylation sequencing, we here show that experiencing a stimulus-rich environment counteracts age-related DNA methylation changes in the hippocampal dentate gyrus of mice. Specifically, environmental enrichment prevented the aging-induced CpG hypomethylation at target sites of the methyl-CpG-binding protein Mecp2, which is critical to neuronal function. The genes at which environmental enrichment counteracted aging effects have described roles in neuronal plasticity, neuronal cell communication and adult hippocampal neurogenesis and are dysregulated with age-related cognitive decline in the human brain. Our results highlight the stimulating effects of environmental enrichment on hippocampal plasticity at the level of DNA methylation and give molecular insights into the specific aspects of brain aging that can be counteracted by lifestyle interventions.

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Vangl2, a core component of the WNT/PCP pathway, regulates adult hippocampal neurogenesis and age-related decline in cognitive flexibility

10.1101/2021.01.05.425435 ◽

2021 ◽

Author(s):

M Koehl ◽

E Ladevèze ◽

M Montcouquiol ◽

DN Abrous

Keyword(s):

Episodic Memory ◽

Dentate Gyrus ◽

Cognitive Flexibility ◽

Adult Neurogenesis ◽

Continuous Production ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Core Component ◽

Dominant Negative Mutation ◽

Age Related

AbstractDecline in episodic memory is one of the hallmarks of aging and represents one of the most important health problems facing western societies. A key structure in episodic memory is the hippocampal formation and the dentate gyrus in particular, as the continuous production of new dentate granule neurons in this brain region was found to play a crucial role in memory and in age-related decline in memory. As such, understanding the molecular processes that regulate the relationship between adult neurogenesis and aging of memory function holds great therapeutic potential. Recently, we found that Vang-gogh like 2 (Vangl2), a core component of the planar cell polarity signaling pathway, is enriched in the dentate gyrus of adult mice. In this context, we sought to evaluate the involvement of this effector of the Wnt/PCP pathway in both adult neurogenesis and memory abilities in adult and middle-aged mice. Using a heterozygous mouse model carrying a dominant negative mutation in Vangl2 gene, we show that alteration in Vangl2 expression decreases the survival of adult-born granule cells and advances the onset of decrease in cognitive flexibility. Inability of mutant mice to erase old irrelevant information to the benefit of new relevant ones highlights a key role of Vangl2 in interference-based forgetting. Taken together, our findings show for the first that Vangl2 activity may constitute an interesting target to prevent age-related decline in hippocampal plasticity and memory.

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Age-related decline in BubR1 impairs adult hippocampal neurogenesis

Aging Cell ◽

10.1111/acel.12594 ◽

2017 ◽

Vol 16 (3) ◽

pp. 598-601 ◽

Cited By ~ 21

Author(s):

Zhongxi Yang ◽

Heechul Jun ◽

Chan-II Choi ◽

Ki Hyun Yoo ◽

Chang Hoon Cho ◽

...

Keyword(s):

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Age Related

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α2-Antiplasmin as a potential regulator of the spatial memory process and age-related cognitive decline

Molecular Brain ◽

10.1186/s13041-020-00677-3 ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Eri Kawashita ◽

Keiichi Ishihara ◽

Haruko Miyaji ◽

Yu Tanishima ◽

Akiko Kiriyama ◽

...

Keyword(s):

Oxidative Stress ◽

Spatial Memory ◽

Cognitive Decline ◽

Brain Aging ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Negative Regulator ◽

Memory Process ◽

Age Related ◽

Brain Oxidative Stress

Abstract α2-Antiplasmin (α2AP), a principal physiological plasmin inhibitor, is mainly produced by the liver and kidneys, but it is also expressed in several parts of the brain, including the hippocampus and cerebral cortex. Our previous study demonstrated that α2AP knockout mice exhibit spatial memory impairment in comparison to wild-type mice, suggesting that α2AP is necessary for the fetal and/or neonatal development of the neural network for spatial memory. However, it is still unclear whether α2AP plays a role in the memory process. The present study demonstrated that adult hippocampal neurogenesis and remote spatial memory were enhanced by the injection of an anti-α2AP neutralizing antibody in WT mice, while the injection of α2AP reduced hippocampal neurogenesis and impaired remote spatial memory, suggesting that α2AP is a negative regulator in memory processing. The present study also found that the levels of α2AP in the brains of old mice were higher than those in young mice, and a negative correlation between the α2AP level and spatial working memory. In addition, aging-dependent brain oxidative stress and hippocampal inflammation were attenuated by α2AP deficiency. Thus, an age-related increase in α2AP might cause cognitive decline accompanied by brain oxidative stress and neuroinflammation. Taken together, our findings suggest that α2AP is a key regulator of the spatial memory process, and that it may represent a promising target to effectively regulate healthy brain aging.

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