Inhibiting the microglia activation improves the spatial memory and adult neurogenesis in rat hippocampus during 48 h of sleep deprivation

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Abstract

Background

Sleep deprivation (SD) leads to cognitive impairment. Neuroinflammation could be a significant contributing factor in the same. An increase in regional brain pro-inflammatory cytokines induces cognitive deficits, however, the magnitude of the effect under SD is not apparent. It is plausible that microglia activation could be involved in the SD-induced cognitive impairment by modulation of neuronal cell proliferation, differentiation, and brain-derived neuronal factor (BDNF) level. The present study aimed to evaluate the possible beneficial effect of minocycline in amelioration of spatial memory decline during SD by its anti-inflammatory and neuroprotective actions. We scrutinized the effect of minocycline on the inflammatory cytokine levels associated with glial cells (microglia and astrocytes) activity and neurogenesis markers crucial for behavioral functions during SD.

Methods

Male Sprague-Dawley rats weighing 230–250 g were sleep deprived for 48 h using automated cage shaking apparatus. The spatial memory was tested using MWM apparatus immediately after completion of SD with and without minocycline. The animals were euthanized, blood was collected, and brain was extracted for neuroinflammation and neurogenesis studies. The set of experiments were also conducted with use of temozolomide, a neurogenesis blocker.

Results

Minocycline treatment increased the body weight, food intake, and spatial memory performance which declined during SD. It reduced the pro-inflammatory and increased the anti-inflammatory cytokine levels in hippocampus and plasma and inhibited the reactive gliosis in the hippocampus evidenced by improved cell count, morphology, and immunoreactivity. Additionally, minocycline administration promoted neurogenesis at different stages: proliferation (BrdU, Ki-67), differentiation (DCX) cells and growth factor (BDNF). However, no significant change was observed in maturation (NeuN) during SD. In addition, molecules related to behavior, inflammation, and neurogenesis were shown to be more affected after temozolomide administration during SD, and changes were restored with minocycline treatment. We observed a significant correlation of neurogenesis with microglial activation, cytokine levels, and spatial memory during SD.

Conclusion

The present study demonstrated that the SD-induced decline in spatial memory, neuronal cells proliferation, differentiation, and BDNF level could be attributed to upregulation of neuroinflammatory molecules, and minocycline may be an effective intervention to counteract these changes.

Graphical abstract

Microglial activation is involved in SD-induced changes in inflammatory molecules, neurogenesis, and spatial memory.

Electronic supplementary material

The online version of this article (10.1186/s12974-017-0998-z) contains supplementary material, which is available to authorized users.

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Most cited references 46

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Purification of RNA using TRIzol (TRI reagent).

Donald Rio, Manuel Ares, Gregory Hannon … (2010)

TRIzol solubilization and extraction is a relatively recently developed general method for deproteinizing RNA. This method is particularly advantageous in situations where cells or tissues are enriched for endogenous RNases or when separation of cytoplasmic RNA from nuclear RNA is impractical. TRIzol (or TRI Reagent) is a monophasic solution of phenol and guanidinium isothiocyanate that simultaneously solubilizes biological material and denatures protein. After solubilization, the addition of chloroform causes phase separation (much like extraction with phenol:chloroform:isoamyl alcohol), where protein is extracted to the organic phase, DNA resolves at the interface, and RNA remains in the aqueous phase. Therefore, RNA, DNA, and protein can be purified from a single sample (hence, the name TRIzol). TRIzol extraction is also an effective method for isolating small RNAs, such as microRNAs, piwi-associated RNAs, or endogeneous, small interfering RNAs. However, TRIzol is expensive and RNA pellets can be difficult to resuspend. Thus, the use of TRIzol is not recommend when regular phenol extraction is practical.

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Mice in an enriched environment learn more flexibly because of adult hippocampal neurogenesis

Alexander Garthe, Ingo Roeder, Gerd Kempermann (2015)

ABSTRACT We here show that living in a stimulus‐rich environment (ENR) improves water maze learning with respect to specific key indicators that in previous loss‐of‐function experiments have been shown to rely on adult hippocampal neurogenesis. Analyzing the strategies employed by mice to locate the hidden platform in the water maze revealed that ENR facilitated task acquisition by increasing the probability to use effective search strategies. ENR also enhanced the animals’ behavioral flexibility, when the escape platform was moved to a new location. Treatment with temozolomide, which is known to reduce adult neurogenesis, abolished the effects of ENR on both acquisition and flexibility, while leaving other aspects of water maze learning untouched. These characteristic effects and interdependencies were not seen in parallel experiments with voluntary wheel running (RUN), a second pro‐neurogenic behavioral stimulus. Since the histological assessment of adult neurogenesis is by necessity an end‐point measure, the levels of neurogenesis over the course of the experiment can only be inferred and the present study focused on behavioral parameters as analytical endpoints. Although the correlation of physical activity with precursor cell proliferation and of learning and the survival of new neurons is well established, how the specific functional effects described here relate to dynamic changes in the stem cell niche remains to be addressed. Nevertheless, our findings support the hypothesis that adult neurogenesis is a critical mechanism underlying the beneficial effects of leading an active live, rich in experiences. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.

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New neurons in the adult brain: the role of sleep and consequences of sleep loss.

Peter Meerlo, Ralph Mistlberger, Barry Jacobs … (2009)

Research over the last few decades has firmly established that new neurons are generated in selected areas of the adult mammalian brain, particularly the dentate gyrus of the hippocampal formation and the subventricular zone of the lateral ventricles. The function of adult-born neurons is still a matter of debate. In the case of the hippocampus, integration of new cells in to the existing neuronal circuitry may be involved in memory processes and the regulation of emotionality. In recent years, various studies have examined how the production of new cells and their development into neurons is affected by sleep and sleep loss. While disruption of sleep for a period shorter than one day appears to have little effect on the basal rate of cell proliferation, prolonged restriction or disruption of sleep may have cumulative effects leading to a major decrease in hippocampal cell proliferation, cell survival and neurogenesis. Importantly, while short sleep deprivation may not affect the basal rate of cell proliferation, one study in rats shows that even mild sleep restriction may interfere with the increase in neurogenesis that normally occurs with hippocampus-dependent learning. Since sleep deprivation also disturbs memory formation, these data suggest that promoting survival, maturation and integration of new cells may be an unexplored mechanism by which sleep supports learning and memory processes. Most methods of sleep deprivation that have been employed affect both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Available data favor the hypothesis that decreases in cell proliferation are related to a reduction in REM sleep, whereas decreases in the number of cells that subsequently develop into adult neurons may be related to reductions in both NREM and REM sleep. The mechanisms by which sleep loss affects different aspects of adult neurogenesis are unknown. It has been proposed that adverse effects of sleep disruption may be mediated by stress and glucocorticoids. However, a number of studies clearly show that prolonged sleep loss can inhibit hippocampal neurogenesis independent of adrenal stress hormones. In conclusion, while modest sleep restriction may interfere with the enhancement of neurogenesis associated with learning processes, prolonged sleep disruption may even affect the basal rates of cell proliferation and neurogenesis. These effects of sleep loss may endanger hippocampal integrity, thereby leading to cognitive dysfunction and contributing to the development of mood disorders.

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Author and article information

Contributors

Meetu Wadhwa: m2wadhwa28@gmail.com

Amit Prabhakar: amit.jhbt@gmail.com

Koushik Ray: kraydipas@rediffmail.com

Koustav Roy: koustavroy001@gmail.com

Punita Kumari: punii10585@gmail.com

Prabhash Kumar Jha: prabhash161@gmail.com

Krishna Kishore: kishu16in@gmail.com

Sanjeev Kumar: sanjeev.dipas@gmail.com

Usha Panjwani: +91-11 23883203 , +91-11 23883206 , +91-11 23883205 , neurophysiolab.dipas@gmail.com , usha_dipas@rediffmail.com

Journal

Journal ID (nlm-ta): J Neuroinflammation

Journal ID (iso-abbrev): J Neuroinflammation

Title: Journal of Neuroinflammation

Publisher: BioMed Central (London )

ISSN (Electronic): 1742-2094

Publication date (Electronic): 15 November 2017

Publication date PMC-release: 15 November 2017

Publication date Collection: 2017

Volume: 14

Electronic Location Identifier: 222

Affiliations

[1 ]Defence Institute of Physiology and Allied Sciences (DIPAS), Defence Research and Development Organization (DRDO), Lucknow Road, Timarpur, Delhi, India

[2 ]Neurophysiology Division, Defence Institute of Physiology and Allied Sciences (DIPAS), Defence Research and Development Organization (DRDO), Lucknow Road, Timarpur, Delhi, -110 054 India

Article

Publisher ID: 998

DOI: 10.1186/s12974-017-0998-z

PMC ID: 5688670

PubMed ID: 29141671

SO-VID: 8f5b2976-0b7e-4aa6-8b52-b1971f2cd621

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 21 July 2017

Date accepted : 8 November 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001849, Defence Research and Development Organisation;

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ScienceOpen disciplines: Neurosciences

Keywords: sleep deprivation,minocycline,spatial memory,microglia,cytokines,neuroinflammation,neurogenesis

Data availability:

ScienceOpen disciplines: Neurosciences

Keywords: sleep deprivation, minocycline, spatial memory, microglia, cytokines, neuroinflammation, neurogenesis

Inhibiting the microglia activation improves the spatial memory and adult neurogenesis in rat hippocampus during 48 h of sleep deprivation

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Most cited references 46

Purification of RNA using TRIzol (TRI reagent).

Mice in an enriched environment learn more flexibly because of adult hippocampal neurogenesis

New neurons in the adult brain: the role of sleep and consequences of sleep loss.

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