Fluoxetine Promotes Hippocampal Oligodendrocyte Maturation and Delays Learning and Memory Decline in APP/PS1 Mice

Oligodendrogenesis dysfunction impairs memory consolidation in adult mice, and an oligodendrocyte abnormality is an important change occurring in Alzheimer's disease (AD). While fluoxetine (FLX) is known to delay memory decline in AD models, its effects on hippocampal oligodendrogenesis are unclear. Here, we subjected 8-month-old male amyloid precursor protein (APP)/presenilin 1 (PS1) mice to the FLX intervention for 2 months. Their exploratory behaviors and general activities in a novel environment, spatial learning and memory and working and reference memory were assessed using the open-field test, Morris water maze, and Y maze. Furthermore, changes in hippocampal oligodendrogenesis were investigated using stereology, immunohistochemistry, immunofluorescence staining, and Western blotting techniques. FLX delayed declines in the spatial learning and memory, as well as the working and reference memory of APP/PS1 mice. In addition, APP/PS1 mice exhibited immature hippocampal oligodendrogenesis, and FLX increased the numbers of 2′3′cyclic nucleotide 3′-phosphodiesterase (CNPase)+ and newborn CNPase+ oligodendrocytes in the hippocampi of APP/PS1 mice. Moreover, FLX increased the density of SRY-related HMG-box 10 protein (SOX10)+ cells and reduced the percentage of oligodendrocyte lineage cells displaying the senescence phenotype (CDKN2A/p16INK4a) in the hippocampus of APP/PS1 mice. Moreover, FLX had no effect on the serotonin (5-HT) 1A receptor (5-HT1AR) content or number of 5-HT1AR+ oligodendrocytes, but it reduced the content and activity of glycogen synthase kinase 3β (GSK3β) in the hippocampus of APP/PS1 transgenic mice. Taken together, FLX delays the senescence of oligodendrocyte lineage cells and promotes oligodendrocyte maturation in the hippocampus of APP/PS1 mice. FLX may regulate GSK3β through a mechanism other than 5-HT1AR and then inhibit the negative effect of GSK3β on oligodendrocyte maturation in the hippocampus of an AD mouse model.

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GABAB receptor antagonist promotes hippocampal neurogenesis and facilitates cognitive function recovery following acute cerebral ischemia in mice

Stem Cell Research & Therapy ◽

10.1186/s13287-020-02059-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Dan Song ◽

Yaohua Chen ◽

Cheng Chen ◽

Lili Chen ◽

Oumei Cheng

Keyword(s):

Cognitive Function ◽

Cerebral Ischemia ◽

Learning And Memory ◽

Spatial Learning ◽

Hippocampal Neurogenesis ◽

Morris Water Maze Test ◽

Spatial Learning And Memory ◽

In Vitro Experiments ◽

Adult Mice

Abstract Purpose and background Previous studies have suggested that promoting endogenous neurogenesis has great significance for the recovery of cognitive dysfunction caused by cerebral ischemia (CI). Pharmacological inhibition of GABAB receptor can enhance neurogenesis in adult healthy and depressed mice. In the study, we intended to investigate the effects of GABAB receptor antagonists on cognitive function and hippocampal neurogenesis in mice following CI. Methods Adult mice were subjected to bilateral common carotid artery occlusion (BCCAO) for 20 min to induce CI and treated with CGP52432 (antagonist of GABAB receptor, CGP, 10 mg/kg intraperitoneal injection) starting 24 h after CI. The Morris water maze test was performed to test spatial learning and memory at day 28. Immunofluorescence was applied to detect neurogenesis in the DG region at day 14 and 28. In in vitro experiments, cell proliferation was detected by CCK8 and immunofluorescence, and the expression of cAMP/CREB signaling pathway-related proteins was detected by ELISA assay and Western blot. Results CGP significantly improved spatial learning and memory disorders caused by CI, and it enhanced the proliferation of neural stem cells (NSCs), the number of immature neurons, and the differentiation from newborn cells to neurons. In vitro experiments further confirmed that CGP dose-dependently enhanced the cell viability of NSCs, and immunofluorescence staining showed that CGP promoted the proliferation of NSCs. In addition, treatment with CGP increased the expression of cAMP, PKA, and pCREB in cultured NSCs. Conclusion Inhibition of GABAB receptor can effectively promote hippocampal neurogenesis and improve spatial learning and memory in adult mice following CI.

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Ganglioside GQ1b improves spatial learning and memory of rats as measured by the Y-maze and the Morris water maze tests

Neuroscience Letters ◽

10.1016/j.neulet.2008.05.020 ◽

2008 ◽

Vol 439 (2) ◽

pp. 220-225 ◽

Cited By ~ 32

Author(s):

Woo Ram Jung ◽

Hong Gi Kim ◽

Kil Lyong Kim

Keyword(s):

Learning And Memory ◽

Morris Water Maze ◽

Spatial Learning ◽

Water Maze ◽

Spatial Learning And Memory ◽

Y Maze

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Milk Exosomes Cross the Blood-Brain Barrier in Murine Cerebral Cortex Endothelial Cells and Promote Dendritic Complexity in the Hippocampus and Brain Function in C57BL/6J Mice

10.1101/2021.11.24.469889 ◽

2021 ◽

Author(s):

Fang Zhou ◽

Pearl Ebea ◽

Ezra Mutai ◽

Sonal Sukreet ◽

Shya Navazesh ◽

...

Keyword(s):

Gene Expression ◽

Endothelial Cells ◽

Brain Development ◽

Learning And Memory ◽

Kainic Acid ◽

Spatial Learning ◽

Granule Cells ◽

Spatial Learning And Memory ◽

Adult Mice ◽

Dendritic Complexity

Background: Human milk contains large amounts of exosomes (MEs) and their regulatory microRNA cargos, whereas infant formulas contain only trace amounts of MEs and microRNAs. Breastfeeding has been implicated in optimal brain development but experimental evidence linking ME intake with brain development is limited. Objectives: We assessed the transport of MEs across the blood-brain barrier (BBB) and ME accumulation in distinct regions of the brain in brain endothelial cells and suckling mice. We further assessed BME-dependent gene expression profiles and effects on the dendritic complexity of hippocampal granule cells and phenotypes of BME depletion in neonate, juvenile and adult mice. Methods: The transfer of MEs across the BBB was assessed by using bovine MEs labeled with FM4-64 or loaded with IRDye-labeled miR-34a in murine brain endothelial bEnd.3 cell monolayers and dual chamber systems, and in wild-type newborn pups fostered to exosome and cargo tracking (ECT) dams that express MEs endogenously labeled with a CD63-eGFP fusion protein for subsequent analysis by serial two-photon tomography and staining with anti-eGFP antibodies. Effects of MEs on gene expression and dendritic architecture of granule cells was analyzed in hippocampi from juvenile mice fed exosome and RNA-depleted (ERD) and exosome and RNA-sufficient (ERS) diets by using RNA-sequencing analysis and Golgi-Cox staining followed by integrated neuronal tracing and morphological analysis of neuronal dendrites, respectively. Spatial learning and severity of kainic acid-induced seizures were assessed in mice fed ERD and ERS diets. Results: bEnd.3 cells internalized MEs by using a saturable transport mechanism and secreted miR-34a across the basal membrane. MEs penetrated the entire brain in fostering experiments; major regions of accumulation included the hippocampus, cortex and cerebellum. Two hundred ninety-five genes were differentially expressed in hippocampi from male mice fed ERD and ERS diets; high-confidence gene networks included pathways implicated in axon guidance and calcium signaling. Only one gene was differentially expressed in females fed the experimental diets. Juvenile pups fed the ERD diet had reduced dendritic complexity of dentate granule cells in the hippocampus, scored nine-fold lower in the Barnes maze test of spatial learning and memory (P < 0.01), and the severity of seizures was 5-fold higher following kainic acid administration in adult mice fed the ERD diet compared to mice fed the ERS diet (P < 0.01). Conclusions: MEs cross the BBB and contribute toward optimal neuronal development, spatial learning and memory, and resistance to kainic acid-induced seizures in mice.

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Tanshinone IIA Ameliorates Spatial Learning and Memory Deficits by Inhibiting the Activity of ERK and GSK-3β

Journal of Geriatric Psychiatry and Neurology ◽

10.1177/0891988719837373 ◽

2019 ◽

Vol 32 (3) ◽

pp. 152-163 ◽

Cited By ~ 5

Author(s):

Li Lin ◽

Sarmad Sheraz Jadoon ◽

Shang-Zhi Liu ◽

Ru-Yi Zhang ◽

Fan Li ◽

...

Keyword(s):

Learning And Memory ◽

Spatial Learning ◽

Glycogen Synthase ◽

Memory Deficits ◽

Tanshinone Iia ◽

Control Group ◽

Spatial Learning And Memory ◽

Intragastric Administration ◽

Learning And Memory Deficits ◽

Gsk 3Β

Background: Alzheimer disease (AD) is the most common type of dementia which is becoming a primary problem in the present society, but it lacks effective treatment methods and means of AD. Tanshinone IIA (Tan IIA) has been reported to have neuroprotective effects to restrain the Aβ25 -35-mediated apoptosis. However, few studies try to understand how Aβ1-42 affects hyperphosphorylation of tau and how Tan IIA regulates this process at the molecular level. Methods: Fifty male Sprague-Dawley rats were randomly divided into 5 groups and infused through the lateral ventricle with Aβ1-42 except the control group. Then the rats were treated with Tan IIA through intragastric administration for 4 weeks. After the ability of learning and memory being measured, histomorphological examination and Western blot were used to detect the possible mechanism in the AD-associated model rats. Results: We observed that Aβ1-42 infusion could induce spatial learning and memory deficits in rats. Simultaneously, Aβ1-42 also could reduce the neuron in cornu ammonis 1 and dentate gyrus of hippocampus, as well as increase the levels of cleaved caspase 3, hyperphosphorylated tau at the sites Ser396, Ser404, and Thr205 with enhancing staining of black granules in brain. We also found that Aβ1-42 could increase the activity of extracellular signal-regulated protein kinase (ERK) and glycogen synthase kinase-3β (GSK-3β). Meanwhile, these phenomena could be ameliorated when Tan IIA was used. Conclusion: We concluded that Tan IIA might have neuroprotective effect and improving learning and memory ability to be a viable candidate in AD therapy with mechanisms involving the ERK and GSK-3β signal pathway.

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