cyclin-d1 and Memory-Disorders

Advancements in fetal intervention procedures have led to increases in the number of pregnant women undergoing general anesthesia during the second trimester-a period characterized by extensive proliferation of fetal neural stem cells (NSCs). However, few studies have investigated the effects of mid-gestational sevoflurane exposure on fetal NSC proliferation or postnatal learning and memory function. In the present study, pregnant rats were randomly assigned to a control group (C group), a low sevoflurane concentration group (2%; L group), a high sevoflurane concentration group (3.5%; H group), a high sevoflurane concentration plus lithium chloride group (H + Li group), and a lithium chloride group (Li group) at gestational day 14. Rats received different concentrations of sevoflurane anesthesia for 2 h. The offspring rats were weaned at 28 days for behavioral testing (i.e., Morris Water Maze [MWM]), and fetal brains or postnatal hippocampal tissues were harvested for immunofluorescence staining, real-time PCR, and Western blotting analyses in order to determine the effect of sevoflurane exposure on NSC proliferation and the Wnt/β-catenin signaling pathway. Our results indicated that maternal exposure to 3.5% sevoflurane (H group) during the mid-gestational period impaired the performance of offspring rats in the MWM test, reduced NSC proliferation, and increased protein levels of fetal glycogen synthase kinase-3 beta (GSK-3β). Such treatment also decreased levels of β-catenin protein, CD44 RNA, and Cyclin D1 RNA relative to those observed in the C group. However, these effects were transiently attenuated by treatment with lithium chloride. Conversely, maternal exposure to 2% sevoflurane (L group) did not influence NSC proliferation or the Wnt signaling pathway. Our results suggest that sevoflurane exposure during the second trimester inhibits fetal NSC proliferation via the Wnt/β-catenin pathway and impairs postnatal learning and memory function in a dose-dependent manner.

Topics: Anesthetics, Inhalation; Animals; Cell Division; Cyclin D1; Dose-Response Relationship, Drug; Female; Fetus; Gestational Age; Glycogen Synthase Kinase 3 beta; Hippocampus; Hyaluronan Receptors; Learning Disabilities; Lithium Chloride; Maze Learning; Memory Disorders; Methyl Ethers; Nerve Tissue Proteins; Neural Stem Cells; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Sevoflurane; Spatial Behavior; Wnt Signaling Pathway

Topics: Animals; Cyclin D1; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase Inhibitor p19; Cyclooctanes; Dioxoles; Drugs, Chinese Herbal; Galactose; Gene Expression; Hippocampus; Humans; Learning Disabilities; Lignans; Male; Memory; Memory Disorders; Mice; Mice, Inbred ICR; Retinoblastoma Protein; rho GTP-Binding Proteins; Schisandra; Tumor Suppressor Protein p53

Alzheimer's disease (AD) is the most common type of dementia frequently responsible for cognitive decline in the elderly. The etiology and molecular mechanism of AD pathogenesis remain inconclusive. Aging and vascular factors are important independent causes and contributors to sporadic AD. Clinical imaging studies showed that cerebral blood flow decreases before cognitive impairment in patients with AD. To investigate the effect of chronic cerebral hypoperfusion (CCH) on cognitive impairment and morphological features, we developed a new manner of CCH mouse model by narrowing bilateral common carotid arteries. Mice started to manifest spatial memory deficits 1month after the surgery and exhibited behavioral changes in a time-dependent manner. Mice also presented memory deficits accompanied with morphological changes at the neuronal and synaptic levels. CCH damaged the normal neuronal morphology and significantly reduced the expression level of PSD95. CCH activated astrocytes, increased the co-expression of GFAP and AQP4, and destroyed the blood-brain barrier (BBB). Furthermore, CCH facilitated intracellular and extracellular Aβ deposition by up-regulating γ-secretase and β-secretase levels. Our results showed good reproducibility of post-CCH pathological processes, which are characterized by neuronal apoptosis, axonal abnormalities, glial activation, BBB damage, amyloid deposition, and cognitive dysfunction; these processes may be used to decipher the complex interplay and pathological process between CCH and AD. This study provides laboratory evidence for the prevention and treatment of cognitive malfunction and AD.

Topics: Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Aquaporin 4; Aspartic Acid Endopeptidases; Brain Ischemia; Cyclin D1; Disease Models, Animal; Disks Large Homolog 4 Protein; Enzyme-Linked Immunosorbent Assay; GAP-43 Protein; Guanylate Kinases; Maze Learning; Membrane Proteins; Memory Disorders; Mice; Mice, Inbred C57BL; Microscopy, Electron, Transmission; Nerve Tissue Proteins; Synapses; Time Factors; Tubulin

Wnt signaling has emerged as a potent regulator of hippocampal synaptic function, although no evidence yet supports a critical role for Wnt signaling in hippocampal memory. Here, we sought to determine whether canonical β-catenin-dependent Wnt signaling is necessary for hippocampal memory consolidation. Immediately after training in a hippocampal-dependent object recognition task, mice received a dorsal hippocampal (DH) infusion of vehicle or the canonical Wnt antagonist Dickkopf-1 (Dkk-1; 50, 100, or 200 ng/hemisphere). Twenty-four hours later, mice receiving vehicle remembered the familiar object explored during training. However, mice receiving Dkk-1 exhibited no memory for the training object, indicating that object recognition memory consolidation is dependent on canonical Wnt signaling. To determine how Dkk-1 affects canonical Wnt signaling, mice were infused with vehicle or 50 ng/hemisphere Dkk-1 and protein levels of Wnt-related proteins (Dkk-1, GSK3β, β-catenin, TCF1, LEF1, Cyclin D1, c-myc, Wnt7a, Wnt1, and PSD95) were measured in the dorsal hippocampus 5 min or 4 h later. Dkk-1 produced a rapid increase in Dkk-1 protein levels and a decrease in phosphorylated GSK3β levels, followed by a decrease in β-catenin, TCF1, LEF1, Cyclin D1, c-myc, Wnt7a, and PSD95 protein levels 4 h later. These data suggest that alterations in Wnt/GSK3β/β-catenin signaling may underlie the memory impairments induced by Dkk-1. In a subsequent experiment, object training alone rapidly increased DH GSK3β phosphorylation and levels of β-catenin and Cyclin D1. These data suggest that canonical Wnt signaling is regulated by object learning and is necessary for hippocampal memory consolidation.

Topics: Animals; beta Catenin; Cyclin D1; Disks Large Homolog 4 Protein; Dose-Response Relationship, Drug; Exploratory Behavior; Functional Laterality; Gene Expression Regulation; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Guanylate Kinases; Hippocampus; Intercellular Signaling Peptides and Proteins; Male; Membrane Proteins; Memory Disorders; Mice; Mice, Inbred C57BL; Phosphorylation; Recognition, Psychology; Signal Transduction; Statistics, Nonparametric; Wnt Proteins