Thrombin-induced microglial activation impairs hippocampal neurogenesis and spatial memory ability in mice

Abstract Background: Our recent studies reported the opposite effects of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) on neuron survival after traumatic brain injury (TBI). However, as a mixed agonist for MR and GR, whether short term use of high-dose endogenous glucocorticoids exerts neurotoxic effects by excessive activation of GR, what is the set-point, and the possible signaling pathways remain unclear. This study examined the dose-dependent dual effects of corticosterone (CORT) on the spatial memory, the survival of hippocampal neurons and the possible receptor-mediated downstream signaling pathways after TBI.Methods: Based on controlled cortical impact (CCI) and CORT treatments, Sprague-Dawley rats (n=168) were randomly divided into the sham, CCI, CCI + CORT1 (0.3 mg/kg), CCI + CORT2 (3 mg/kg), CCI + CORT3 (30 mg/kg), CCI + CORT1 + spirolactone (spirolactone: 50 mg/kg/d), and CCI + CORT3 + RU486 (RU486: 50 mg/kg/d) groups. Brain tissues were collected on postinjury day 3 and processed for histology and western blot analysis.Results: On postinjury day 3, we tested the learning and memory ability, neuronal apoptosis in the hippocampus, activation levels of MR and GR, Bcl-2 family proteins, and apoptosis-related intracellular signaling pathways. We found that different doses of CORT exhibited dual effects on the survival of hippocampal neurons and the spatial memory. Lower doses of CORT (0.3, 3 mg/kg) significantly increased the activation of MR, upregulated the phosphorylation of Akt/CREB/Bad and the Bcl-2 expression, reduced the number of apoptotic neurons, and subsequently improved the spatial memory. In contrast, higher dose of CORT (30 mg/kg) exerted opposite effect by over activating GR, upregulating the expressions of P53/Bax, and inhibiting the Erk/CREB activities. Conclusion: The results suggest that there is a threshold between the neuroprotective and neurotoxic effects of endogenous GC, higher dose of which, even for short-term use, should also be avoided after TBI.

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Long term exposure to combination paradigm of environmental enrichment, physical exercise and diet reverses the spatial memory deficits and restores hippocampal neurogenesis in ventral subicular lesioned rats

Neurobiology of Learning and Memory ◽

10.1016/j.nlm.2016.01.013 ◽

2016 ◽

Vol 130 ◽

pp. 61-70 ◽

Cited By ~ 9

Author(s):

Vijayakumar Kapgal ◽

Neethi Prem ◽

Preethi Hegde ◽

T.R. Laxmi ◽

Bindu M. Kutty

Keyword(s):

Physical Exercise ◽

Spatial Memory ◽

Environmental Enrichment ◽

Memory Deficits ◽

Hippocampal Neurogenesis

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Water-Soluble Arginyl–Diosgenin Analog Attenuates Hippocampal Neurogenesis Impairment Through Blocking Microglial Activation Underlying NF-κB and JNK MAPK Signaling in Adult Mice Challenged by LPS

Molecular Neurobiology ◽

10.1007/s12035-019-1496-3 ◽

2019 ◽

Vol 56 (9) ◽

pp. 6218-6238 ◽

Cited By ~ 2

Author(s):

Bangrong Cai ◽

Kyung-Joo Seong ◽

Sun-Woong Bae ◽

Min Suk Kook ◽

Changju Chun ◽

...

Keyword(s):

Microglial Activation ◽

Mapk Signaling ◽

Hippocampal Neurogenesis ◽

Water Soluble ◽

Adult Mice

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The intellectual disability PAK3 R67C mutation impacts cognitive functions and adult hippocampal neurogenesis

Human Molecular Genetics ◽

10.1093/hmg/ddz296 ◽

2020 ◽

Vol 29 (12) ◽

pp. 1950-1968

Author(s):

Charlotte Castillon ◽

Laurine Gonzalez ◽

Florence Domenichini ◽

Sandrine Guyon ◽

Kevin Da Silva ◽

...

Keyword(s):

Intellectual Disability ◽

Mouse Model ◽

Spatial Memory ◽

Adult Neurogenesis ◽

Hippocampal Neurons ◽

Memory Task ◽

Clinical Signs ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Adult Born Neurons

Abstract The link between mutations associated with intellectual disability (ID) and the mechanisms underlying cognitive dysfunctions remains largely unknown. Here, we focused on PAK3, a serine/threonine kinase whose gene mutations cause X-linked ID. We generated a new mutant mouse model bearing the missense R67C mutation of the Pak3 gene (Pak3-R67C), known to cause moderate to severe ID in humans without other clinical signs and investigated hippocampal-dependent memory and adult hippocampal neurogenesis. Adult male Pak3-R67C mice exhibited selective impairments in long-term spatial memory and pattern separation function, suggestive of altered hippocampal neurogenesis. A delayed non-matching to place paradigm testing memory flexibility and proactive interference, reported here as being adult neurogenesis-dependent, revealed a hypersensitivity to high interference in Pak3-R67C mice. Analyzing adult hippocampal neurogenesis in Pak3-R67C mice reveals no alteration in the first steps of adult neurogenesis, but an accelerated death of a population of adult-born neurons during the critical period of 18–28 days after their birth. We then investigated the recruitment of hippocampal adult-born neurons after spatial memory recall. Post-recall activation of mature dentate granule cells in Pak3-R67C mice was unaffected, but a complete failure of activation of young DCX + newborn neurons was found, suggesting they were not recruited during the memory task. Decreased expression of the KCC2b chloride cotransporter and altered dendritic development indicate that young adult-born neurons are not fully functional in Pak3-R67C mice. We suggest that these defects in the dynamics and learning-associated recruitment of newborn hippocampal neurons may contribute to the selective cognitive deficits observed in this mouse model of ID.

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N-Docosahexaenoylethanolamine Attenuates Neuroinflammation and Improves Hippocampal Neurogenesis in Rats with Sciatic Nerve Chronic Constriction Injury

Marine Drugs ◽

10.3390/md18100516 ◽

2020 ◽

Vol 18 (10) ◽

pp. 516 ◽

Cited By ~ 1

Author(s):

Anna A. Tyrtyshnaia ◽

Evgenia L. Egorova ◽

Anna A. Starinets ◽

Arina I. Ponomarenko ◽

Ekaterina V. Ermolenko ◽

...

Keyword(s):

Neuropathic Pain ◽

Microglial Activation ◽

Lipid Analysis ◽

Hippocampal Neurogenesis ◽

Raw Material ◽

Long Term Memory ◽

Inflammatory Factor ◽

Behavioral Experiments ◽

Chronic Neuropathic Pain ◽

The Brain

Chronic neuropathic pain is a condition that causes both sensory disturbances and a variety of functional disorders, indicating the involvement of various brain structures in pain pathogenesis. One of the factors underlying chronic neuropathic pain is neuroinflammation, which is accompanied by microglial activation and pro-inflammatory factor release. N-docosahexaenoylethanolamine (DHEA, synaptamide) is an endocannabinoid-like metabolite synthesized endogenously from docosahexaenoic acid. Synaptamide exhibits anti-inflammatory activity and improves neurite outgrowth, neurogenesis, and synaptogenesis within the hippocampus. This study aims to evaluate the effects of synaptamide obtained by the chemical modification of DHA, extracted from the Far Eastern raw material Berryteuthis magister on neuroinflammatory response and hippocampal neurogenesis changes during neuropathic pain. The study of microglial protein and cytokine concentrations was performed using immunohistochemistry and ELISA. The brain lipid analysis was performed using the liquid chromatography-mass spectrometry technique. Behavioral experiments showed that synaptamide prevented neuropathic pain-associated sensory and behavioral changes, such as thermal allodynia, impaired locomotor activity, working and long-term memory, and increased anxiety. Synaptamide attenuated microglial activation, release of proinflammatory cytokines, and decrease in hippocampal neurogenesis. Lipid analysis revealed changes in the brain N-acylethanolamines composition and plasmalogen concentration after synaptamide administration. In conclusion, we show here that synaptamide may have potential for use in preventing or treating neuropathic cognitive pain and emotional effects.

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Multiparity-induced enhancement of hippocampal neurogenesis and spatial memory depends on ovarian hormone status in middle age

Neurobiology of Aging ◽

10.1016/j.neurobiolaging.2015.04.007 ◽

2015 ◽

Vol 36 (8) ◽

pp. 2391-2405 ◽

Cited By ~ 39

Author(s):

Cindy K. Barha ◽

Stephanie E. Lieblich ◽

Carmen Chow ◽

Liisa A.M. Galea

Keyword(s):

Spatial Memory ◽

Middle Age ◽

Hippocampal Neurogenesis ◽

Ovarian Hormone ◽

Hormone Status

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Early-Life Stress Does Not Aggravate Spatial Memory or the Process of Hippocampal Neurogenesis in Adult and Middle-Aged APP/PS1 Mice

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2018.00061 ◽

2018 ◽

Vol 10 ◽

Cited By ~ 1

Author(s):

Lianne Hoeijmakers ◽

Anna Amelianchik ◽

Fleur Verhaag ◽

Janssen Kotah ◽

Paul J. Lucassen ◽

...

Keyword(s):

Spatial Memory ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Hippocampal Neurogenesis ◽

Middle Aged

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Transcriptional Coactivator and Chromatin Protein PC4 Is Involved in Hippocampal Neurogenesis and Spatial Memory Extinction

Journal of Biological Chemistry ◽

10.1074/jbc.m116.744169 ◽

2016 ◽

Vol 291 (39) ◽

pp. 20303-20314 ◽

Cited By ~ 11

Author(s):

Amrutha Swaminathan ◽

Hélène Delage ◽

Snehajyoti Chatterjee ◽

Laurence Belgarbi-Dutron ◽

Raphaelle Cassel ◽

...

Keyword(s):

Spatial Memory ◽

Hippocampal Neurogenesis ◽

Transcriptional Coactivator ◽

Chromatin Protein ◽

Memory Extinction

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N-Docosahexanoylethanolamine Reduces Microglial Activation and Improves Hippocampal Plasticity in a Murine Model of Neuroinflammation

International Journal of Molecular Sciences ◽

10.3390/ijms21249703 ◽

2020 ◽

Vol 21 (24) ◽

pp. 9703

Author(s):

Anna Tyrtyshnaia ◽

Anatoly Bondar ◽

Sophia Konovalova ◽

Ruslan Sultanov ◽

Igor Manzhulo

Keyword(s):

Synaptic Plasticity ◽

Microglial Activation ◽

Hippocampal Slices ◽

Morphological Characteristics ◽

Long Term Potentiation ◽

Structural Analog ◽

Neuronal Morphology ◽

Hippocampal Neurogenesis ◽

Inflammatory Factors ◽

Negative Effect

Chronic neuroinflammation is a common pathogenetic link in the development of various neurological and neurodegenerative diseases. Thus, a detailed study of neuroinflammation and the development of drugs that reduce or eliminate the negative effect of neuroinflammation on cognitive processes are among the top priorities of modern neurobiology. N-docosahexanoylethanolamine (DHEA, synaptamide) is an endogenous metabolite and structural analog of anandamide, an essential endocannabinoid produced from arachidonic acid. Our study aims to elucidate the pharmacological activity of synaptamide in lipopolysaccharide (LPS)-induced neuroinflammation. Memory deficits in animals were determined using behavioral tests. To study the effects of LPS (750 µg/kg/day, 7 days) and synaptamide (10 mg/kg/day, 7 days) on synaptic plasticity, long-term potentiation was examined in the CA1 area of acute hippocampal slices. The Golgi–Cox method allowed us to assess neuronal morphology. The production of inflammatory factors and receptors was assessed using ELISA and immunohistochemistry. During the study, functional, structural, and plastic changes within the hippocampus were identified. We found a beneficial effect of synaptamide on hippocampal synaptic plasticity and morphological characteristics of neurons. Synaptamide treatment recovered hippocampal neurogenesis, suppressed microglial activation, and significantly improved hippocampus-dependent memory. The basis of the phenomena described above is probably the powerful anti-inflammatory activity of synaptamide, as shown in our study and several previous works.

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