Early-life midazolam exposure persistently changes chromatin accessibility to impair adult hippocampal neurogenesis and cognition

Linkage between early-life exposure to anesthesia and subsequent learning disabilities is of great concern to children and their families. Here we show that early-life exposure to midazolam (MDZ), a widely used drug in pediatric anesthesia, persistently alters chromatin accessibility and the expression of quiescence-associated genes in neural stem cells (NSCs) in the mouse hippocampus. The alterations led to a sustained restriction of NSC proliferation toward adulthood, resulting in a reduction of neurogenesis that was associated with the impairment of hippocampal-dependent memory functions. Moreover, we found that voluntary exercise restored hippocampal neurogenesis, normalized the MDZ-perturbed transcriptome, and ameliorated cognitive ability in MDZ-exposed mice. Our findings thus explain how pediatric anesthesia provokes long-term adverse effects on brain function and provide a possible therapeutic strategy for countering them.

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Ablation of proliferating neural stem cells during early life is sufficient to reduce adult hippocampal neurogenesis

10.1101/308387 ◽

2018 ◽

Author(s):

Mary Youssef ◽

Varsha S. Krish ◽

Greer S. Kirshenbaum ◽

Piray Atsak ◽

Tamara J. Lass ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Neural Stem Cells ◽

Early Life ◽

Cell Function ◽

Cell Lineage ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Stem Cell Lineage

AbstractEnvironmental exposures during early life, but not during adolescence or adulthood, lead to persistent reductions in neurogenesis in the adult hippocampal dentate gyrus (DG). The mechanisms by which early life exposures lead to long-term deficits in neurogenesis remain unclear. Here, we investigated whether targeted ablation of dividing neural stem cells during early life is sufficient to produce long-term decreases in DG neurogenesis. Having previously found that the stem cell lineage is resistant to long-term effects of transient ablation of dividing stem cells during adolescence or adulthood (Kirshenbaum et al., 2014), we used a similar pharmacogenetic approach to target dividing neural stem cells for elimination during early life periods sensitive to environmental insults. We then assessed the Nestin stem cell lineage in adulthood. We found that the adult neural stem cell reservoir was depleted following ablation during the first postnatal week, when stem cells were highly proliferative, but not during the third postnatal week, when stem cells were more quiescent. Remarkably, ablating proliferating stem cells during either the first or third postnatal week led to reduced adult neurogenesis out of proportion to the changes in the stem cell pool, indicating a disruption of the stem cell function or niche following stem cell ablation in early life. These results highlight the first three postnatal weeks as a series of sensitive periods during which elimination of dividing stem cells leads to lasting alterations in adult DG neurogenesis and stem cell function. These findings contribute to our understanding of the relationship between DG development and adult neurogenesis, as well as suggest a possible mechanism by which early life experiences may lead to lasting deficits in adult hippocampal neurogenesis.

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Adult Hippocampal Neurogenesis along the Dorsoventral Axis Contributes Differentially to Environmental Enrichment Combined with Voluntary Exercise in Alleviating Chronic Inflammatory Pain in Mice

Journal of Neuroscience ◽

10.1523/jneurosci.3333-16.2017 ◽

2017 ◽

Vol 37 (15) ◽

pp. 4145-4157 ◽

Cited By ~ 41

Author(s):

Jie Zheng ◽

Ying-Ying Jiang ◽

Ling-Chi Xu ◽

Long-Yu Ma ◽

Feng-Yu Liu ◽

...

Keyword(s):

Inflammatory Pain ◽

Environmental Enrichment ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Voluntary Exercise ◽

Dorsoventral Axis ◽

Chronic Inflammatory Pain

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Potential Role of Adult Hippocampal Neurogenesis in Traumatic Brain Injury

Current Medicinal Chemistry ◽

10.2174/0929867328666210923143713 ◽

2021 ◽

Vol 28 ◽

Author(s):

Lucas Alexandre Santos Marzano ◽

Fabyolla Lúcia Macedo de Castro ◽

Caroline Amaral Machado ◽

João Luís Vieira Monteiro de Barros ◽

Thiago Macedo e Cordeiro ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Clinical Studies ◽

Molecular Mechanisms ◽

Hippocampal Neurogenesis ◽

Cognitive Outcomes ◽

Adult Hippocampal Neurogenesis ◽

The Brain

: Traumatic brain injury (TBI) is a serious cause of disability and death among young and adult individuals, displaying complex pathophysiology including cellular and molecular mechanisms that are not fully elucidated. Many experimental and clinical studies investigated the potential relationship between TBI and the process by which neurons are formed in the brain, known as neurogenesis. Currently, there are no available treatments for TBI’s long-term consequences being the search for novel therapeutic targets, a goal of highest scientific and clinical priority. Some studies evaluated the benefits of treatments aimed at improving neurogenesis in TBI. In this scenario, herein, we reviewed current pre-clinical studies that evaluated different approaches to improving neurogenesis after TBI while achieving better cognitive outcomes, which may consist in interesting approaches for future treatments.

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Voluntary exercise induces adult hippocampal neurogenesis and BDNF expression in a rodent model of fetal alcohol spectrum disorders

European Journal of Neuroscience ◽

10.1111/j.1460-9568.2011.07676.x ◽

2011 ◽

Vol 33 (10) ◽

pp. 1799-1811 ◽

Cited By ~ 51

Author(s):

Fanny Boehme ◽

Joana Gil-Mohapel ◽

Adrian Cox ◽

Anna Patten ◽

Erica Giles ◽

...

Keyword(s):

Fetal Alcohol Spectrum Disorders ◽

Hippocampal Neurogenesis ◽

Rodent Model ◽

Adult Hippocampal Neurogenesis ◽

Voluntary Exercise ◽

Fetal Alcohol ◽

Bdnf Expression ◽

Spectrum Disorders ◽

Fetal Alcohol Spectrum

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Estrogenic Regulation of Hippocampal Neurogenesis Throughout the Lifespan

Estrogens and Memory ◽

10.1093/oso/9780190645908.003.0016 ◽

2020 ◽

pp. 253-281

Author(s):

Shunya Yagi ◽

Rand S. Eid ◽

Wansu Qiu ◽

Paula Duarte-Guterman ◽

Liisa A. M. Galea

Keyword(s):

Steroid Hormones ◽

Cognitive Training ◽

Adult Female ◽

Ovarian Hormones ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Maternal Experience ◽

Number Of Factors ◽

Estrogenic Regulation

Neurogenesis in the hippocampus exists across a number of species, including humans. Steroid hormones, such as estrogens, modulate neurogenesis dependent on age, reproductive experience and sex. Findings are discussed in the chapter with reference to how neurogenesis in the hippocampus is related to learning and memory. Natural fluctuations in ovarian hormones or removal of ovaries modulate neurogenesis in the short term but not in the long term. Maternal experience has long-lasting effects on neurogenesis in the hippocampus. Acute estrogens increase proliferation in adult female rodents, but influence survival of new neurons dependent on a number of factors including sex, cognitive training, type of estrogen, and whether or not cells were produced under estrogens. This chapter outlines findings indicating that estrogens can be strong modulators of adult hippocampal neurogenesis, which may have implications for disorders involving hippocampal dysfunction that target women.

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