Xiaojun She

Effects of Chronic Noise Exposure on Spatial Learning and Memory of Rats in Relation to Neurotransmitters and NMDAR2B Alteration in the Hippocampus

Effects of Chronic Noise Exposure on Spatial Learning and Memory of Rats in Relation to Neurotransmitters and NMDAR2B Alteration in the Hippocampus: Bo Cui, et al. Department of Occupational Hygiene, Institute of Health and Environmental Medicine, PR China

Impulse noise exposure in rats causes cognitive deficits and changes in hippocampal neurotransmitter signaling and tau phosphorylation.

Noise exposure has been characterized as a stressor, and its non-auditory effects on the central nervous system have been established both epidemiologically and experimentally. Little is known about the impact of impulse noise on the brain, however. In this study, we examined the effects of impulse noise stress on spatial learning and memory and on associated changes in the hippocampus. Rats were exposed to 20 sound impulses with a peak sound pressure of 165 dB and duration of 100 ms. Impulse noise stress led to a temporary decrease in cognitive function as evidenced by poor spatial memory in the Morris water maze (MWM). Effects of noise on the glutamate (Glu)-N-methyl-D-aspartic acid receptor (NMDAR) signaling system and hippocampal tau phosphorylation were investigated by high performance liquid chromatography, Western blotting, and immunohistochemistry. The concentrations of Glu and aspirate (Asp) in the hippocampus were increased at 30 min after exposure and remained elevated for the entire observation period (24 h), while the content of glycine (Gly) was stable for several hours following noise but also increased by 24 h after noise stress. Impulse noise stress also caused a significant increase in NMDAR 2B subunit (NR2B) expression and a two-phase increase in tau phosphorylation in hippocampus. Immunohistochemistry confirmed tau hyperphosphorylation in hippocampus that was most prominent in the dentate gyrus (DG) and CA1 region. These findings demonstrate that impulse noise stress impairs early spatial memory, possibly by disrupting Glu-NMDAR signaling and triggering aberrant tau hyperphosphorylation in hippocampus.

Chronic noise exposure causes persistence of tau hyperphosphorylation and formation of NFT tau in the rat hippocampus and prefrontal cortex.

The non-auditory effects of noise exposure on the central nervous system have been established both epidemiologically and experimentally. Chronic noise exposure (CNE) has been associated with tau hyperphosphorylation and Alzheimers disease (AD)-like pathological changes. However, experimental evidence for these associations remains limited. The aim of the current study was to explore the effects of CNE [100 dB sound pressure level (SPL) white noise, 4 h/d×14 d] on tau phosphorylation in the rat hippocampus and the prefrontal cortex. Forty-eight male Wistar rats were randomly assigned to two groups: a noise-exposed group and a control group. The levels of radioimmunoprecipitation assay (RIPA)-soluble and RIPA-insoluble phosphorylated tau at Ser202, Ser396, Ser404, and Ser422 in the hippocampus and the prefrontal cortex were measured at different time points (days 0, 3, 7, and 14) after the end of the last noise exposure. Exposure to white noise for 14 consecutive days significantly increased the levels of tau phosphorylation at Ser202, Ser396, Ser404, and Ser422, the sites typically phosphorylated in AD brains, in the hippocampus and the prefrontal cortex. Tau hyperphosphorylation persisted for 7 to 14 d after the cessation of noise exposure. These alterations were also concomitant with the generation of pathological neurofibrillary tangle (NFT) tau 3, 7 and 14 d after the end of the stimulus. Furthermore, lasting increases in proteins involved in hyperphosphorylation, namely glycogen synthase kinase 3β (GSK3β) and protein phosphatase 2A (PP2A), were found to occur in close correspondence with increase in tau hyperphosphorylation. The results of this study show that CNE leads to long-lasting increases in non-NFT hyperphosphorylated tau and delayed formation of misfolded NFT tau in the hippocampus and the prefrontal cortex. Our results also provide evidence for the involvement of GSK3β and PP2A in these processes.

Effects of chronic noise on glucose metabolism and gut microbiota-host inflammatory homeostasis in rats.

Chronic noise exposure has been implicated in increased risk of diabetes. However, there is limited experimental evidence of the mechanisms linking chronic noise stress and glucose metabolism. We addressed this in the present study by examining glucose metabolism, immune response, and changes in gut microbiota/host inflammatory homeostasis in rats exposed to noise for 30 consecutive days. Chronic noise exposure increased blood glucose and corticosterone levels for at least 14 days after cessation of noise. Stressed rats also exhibited elevated levels of glycogen and triglyceride in the liver and impaired hepatic insulin production via insulin-induced insulin receptor/insulin receptor substrate 1/glycogen synthase kinase 3β signalling, which persisted for 3–14 days after cessation of noise exposure. Chronic noise altered the percentage of Proteobacteria and Actinobacteria in the gut, increasing Roseburia but decreasing Faecalibacterium levels in the cecum relative to controls. Immunoglobulin A, interleukin 1β, and tumor necrosis factor α levels were also elevated in the intestine of these animals, corresponding to noise-induced abnormalities in glucose regulation and insulin sensitivity. These results suggest that lifelong environmental noise exposure could have cumulative effects on diabetes onset and development resulting from alterations in gut microbiota composition and intestinal inflammation.

Changes in Guinea Pig Cochlear Hair Cells after Sound Conditioning and Noise Exposure

Changes in Guinea Pig Cochlear Hair Cells after Sound Conditioning and Noise Exposure: Hongyan Zuo, et al. Department of Occupational Hygiene, Institute of Health and Environmental Medicine of Tianjin, PR China—Sound conditioning has reduced noise‐induced hearing loss in experimental mammalian animals and in clinical observation. Forty guinea pigs were grouped as: A, control; B, conditioning noise exposure group; C, high level noise exposure group; and D, conditioning noise exposure followed by a high level noise exposure group. Auditory brainstem response thresholds were measured. The cochlear sensory epithelia surface was observed microscopically. Calmodulin, F‐actin and heat shock protein 70 (HSP70) in hair cells were immunohistochemistrically stained. The intracellular free calcium was stained for confocal microscopy. The ABR threshold shift after noise exposure was higher in group C than D, and showed a quicker and better recovery in group D than C. Stereocilia loss and the disarrangement of outer hair cells were observed, with the greatest changes seen in group C, followed by groups D and B. The most intensive immunohistochemical intracellular expressions of calmodulin, F‐actin, and HSP70 were found in group D, followed by groups C, B and A. The highest intensity of the fluorescent intracellular free Ca2+ staining in the isolated outer hair cells was observed in group C. The ABR and morphological studies confirmed the protective effect from noise trauma of sound conditioning. The protective mechanism of hair cells during sound conditioning was enforced through the increase of cellular cytoskeleton proteins and through the relieving of intracellular calcium overloading caused by the traumatic noise.

Overexpression of S100A4 is closely associated with the progression and prognosis of gastric cancer in young patients

The aim of this study was to determine the correlation of S100A4 expression with the progression, prognosis and clinical pathology of gastric cancer (GC) in young pateints. A total of 85 tumor tissues with corresponding adjacent normal tissues and 62 non-metastatic lymph nodes (LNs) with corresponding metastatic LNs were obtained from young GC patients (<40 years old) who underwent surgery between January 2001 and December 2006. The expression of S100A4 was detected by RT-PCR and immunohistochemistry. Differences in the expression of S100A4 mRNA or protein were observed among the GC tissues, matched normal gastric mucosa, non-metastatic LNs and metastatic LNs. The expression of S100A4 mRNA and protein in GC tissues and metastatic LNs was significantly higher compared with that in the matched normal gastric mucosa and non-metastatic LNs, respectively (P<0.05). The overexpression of S100A4 was significantly associated with parameters involved in tumor progression and poor prognosis, including tumor size (P=0.017), Lauren classification (P=0.002), histological classification (P= 0.010), histological differentiation (P= 0.000), Borrmann classification (P=0.020), tumor-node-metastasis (TNM) stage (P=0.000), LN metastasis (P=0.000) and distant metastasis (P=0.024). Multivariate analysis suggested that patient age (P=0.035), tumor size (P=0.002), TNM stage (P=0.001) and S100A4 upregulation (P=0.000) were independent prognostic indicators for the disease. The overexpression of S100A4 in young GC patients is significantly associated with the clinicopathological characteristics. S100A4 may be used as a biomarker to predict the progression and poor prognosis of GC in young patients.

Chronic Noise Exposure Acts Cumulatively to Exacerbate Alzheimer’s Disease-Like Amyloid-β Pathology and Neuroinflammation in the Rat Hippocampus

A putative etiological association exists between noise exposure and Alzheimer’s disease (AD). Amyloid-β (Aβ) pathology is thought to be one of the primary initiating factors in AD. It has been further suggested that subsequent dysregulation of Aβ may play a mechanistic role in the AD-like pathophysiology associated with noise exposure. Here, we used ELISA, immunoblotting, cytokine arrays, and RT-PCR, to examine both hippocampal Aβ pathology and neuroinflammation in rats at different time points after noise exposure. We found that chronic noise exposure significantly accelerated the progressive overproduction of Aβ, which persisted for 7 to 14 days after the cessation of exposure. This effect was accompanied by up-regulated expression of amyloid precursor protein (APP) and its cleavage enzymes, β- and γ-secretases. Cytokine analysis revealed that chronic noise exposure increased levels of tumor necrosis factor-α and the receptor for advanced glycation end products, while decreasing the expression of activin A and platelet-derived growth factor- AA. Furthermore, we found persistent elevations of glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1 expression that closely corresponded to the noise-induced increases in Aβ and neuroinflammation. These studies suggest that lifelong environmental noise exposure may have cumulative effects on the onset and development of AD.

Effects of chronic noise on mRNA and protein expression of CRF family molecules and its relationship with p-tau in the rat prefrontal cortex

Chronic noise exposure has been associated with Alzheimers disease (AD)-like pathological changes, such as tau hyperphosphorylation and β-amyloid peptide accumulation in the prefrontal cortex (PFC). Corticotropin-releasing factor (CRF) is the central driving force in the stress response and a regulator of tau phosphorylation via binding to CRF receptors (CRFR). Little is known about the CRF system in relation to noise-induced AD-like changes in the PFC. The aim of this study was to explore the effects of chronic noise exposure on the CRF system in the PFC of rats and its relationship to tau phosphorylation. Male Wistar rats were randomly divided into control and noise exposure groups. The CRF system was evaluated following chronic noise exposure (95dB sound pressure level white noise, 4h/day×30days). Chronic noise significantly accelerated the progressive overproduction of corticosterone and upregulated CRF and CRFR1 mRNA and protein, both of which persisted 7-14days after noise exposure. In contrast, CRFR2 was elevated 3-7days following the last stimulus. Double-labeling immunofluorescence co-localized p-tau with CRF in PFC neurons. The results suggest that chronic noise exposure elevates the expression of the CRF system, which may contribute to AD-like changes.

Role of NMDA receptors in noise-induced tau hyperphosphorylation in rat hippocampus and prefrontal cortex☆

Chronic noise exposure has been associated with abnormalities in glutamate (Glu)-NMDAR signaling and tau hyperphosphorylation. However, further studies are necessary to clarify potential causal relationships. The aim of the present study was to evaluate the role of NMDA receptors in noise-induced tau hyperphosphorylation in the rat hippocampus and prefrontal cortex. Male Wistar rats were randomly divided into three groups in the present study: control with isotonic saline instillation (n=10); noise exposure (100 dB SPL white noise, 4h/d × 14d) and treated with saline (n=10); and noise exposure and treated with MK-801 (0.5mg/kg, intraperitoneally; n=10). The levels of tau phosphorylated at Ser202 and Ser396, and proteins involved in hyperphosphorylation, namely glycogen synthase kinase 3β (GSK3β) and protein phosphatase 2A (PP2A), were measured in the hippocampus and prefrontal cortex (PFC) after the last noise exposure. We showed that phosphorylated tau levels were enhanced in noise-exposed-rat hippocampus and PFC. MK-801 decreased the hyperphosphorylation of tau at Ser202 and Ser396 sites in the hippocampus and PFC. Furthermore, MK-801 reversed noise-induced GSK3β overexpression but had no significant effect on PP2A levels. This suggests that MK-801 protects against chronic-noise-induced tau hyperphosphorylation in the hippocampus and PFC. These findings demonstrate that Glu-NMDAR signaling may be involved in triggering aberrant tau hyperphosphorylation in the hippocampus and PFC after chronic noise exposure.

Effects of chronic noise exposure on the microbiome-gut-brain axis in senescence-accelerated prone mice: implications for Alzheimer’s disease

BackgroundChronic noise exposure is associated with neuroinflammation and gut microbiota dysregulation and increases the risk of Alzheimer’s disease (AD). Environmental hazards are also thought to be associated with genetic susceptibility factors that increase AD pathogenesis. However, there is limited experimental evidence regarding the link between chronic noise stress and microbiome-gut-brain axis alterations, which may be closely related to AD development.MethodsThe aim of the present study was to systematically investigate the effects of chronic noise exposure on the microbiome-gut-brain axis in the senescence-accelerated mouse prone 8 (SAMP8) strain. We established SAMP8 mouse models to examine the consequences of noise exposure on the microbiome-gut-brain axis. Hippocampal amyloid-β (Aβ) assessment and the Morris water maze were used to evaluate AD-like changes, 16S ribosomal RNA sequencing analyses were used for intestinal flora measurements, and assessment of endothelial tight junctions and serum neurotransmitter and inflammatory mediator levels, as well as fecal microbiota transplant, was conducted to explore the underlying pathological mechanisms.ResultsChronic noise exposure led to cognitive impairment and Aβ accumulation in young SAMP8 mice, similar to that observed in aging SAMP8 mice. Noise exposure was also associated with decreased gut microbiota diversity and compositional alterations. Axis-series studies showed that endothelial tight junction proteins were decreased in both the intestine and brain, whereas serum neurotransmitter and inflammatory mediator levels were elevated in young SAMP8 mice exposed to chronic noise, similar to the observations made in the aging group. The importance of intestinal bacteria in noise exposure-induced epithelial integrity impairment and Aβ accumulation was further confirmed through microbiota transplantation experiments. Moreover, the effects of chronic noise were generally intensity-dependent.ConclusionChronic noise exposure altered the gut microbiota, accelerated age-related neurochemical and inflammatory dysregulation, and facilitated AD-like changes in the brain of SAMP8 mice.