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Effects of infrasound on hippocampus-dependent learning and memory in rats and some underlying mechanisms

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Abstract

To investigate the effect of infrasound on the hippocampus-dependent spatial learning and memory as well as its underlying mechanisms, we measured the changes of cognitive abilities, brain-derived neurotrophic factor (BDNF)-tyrosine kinase receptor B (TrkB) signal transduction pathway and neurogenesis in the hippocampus of rats. The results showed that rats exposed to infrasound of 16 Hz at 130 dB for 14 days exhibited longer escape latency from day 2 and shortened time staying in the quadrant P in Morris water maze (MWM). It was found that mRNA and protein expression levels of hippocampal BDNF and TrkB were significantly decreased in real-time PCR and Western blot, and the number of BrdU-labeled cells in hippocampus was also reduced when compared to control. These results provided novel evidences that the infrasound of a certain exposure parameter can impair hippocampus-dependent learning and memory, in which the downregulation of the neuronal plasticity-related BDNF-TrkB signal pathway and less neurogenesis in hippocampus might be involved.

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... If nothing is done to control these factors and to solve existing problems, they could potentially have some effects on health. In terms of noise, both infra-and audible sound contribute to learning, sleep and cognitive problems, as well as stress and anxiety [10,11,12,13,14]. As with other achievements of civilisation, wind turbines are perceived by local communities as a potential source of adverse effects (e.g. ...
... The self-reported health effects (sleep disorders, headaches, tinnitus, ear pressure, vertigo, nausea, visual blurring, tachycardia, irritability, problems with concentration and memory, and panic episodes) have been assumed to be associated with wind turbine infrasound. Studies where biological effects were observed due to infrasound exposure were conducted at sound pressure levels (145 dB and 165 dB [11,59]; 130 dB [13]) much greater than those produced by wind turbines [60]. Wind farms are not the only source of infrasound, it is an ever-present element of the environment generated both by natural and man-made sources, which means that residents of wind farm areas had been exposed to infrasound before the wind turbines were erected. ...
... The studies were not conducted on pure infrasound, but always combined with audible sounds. Moreover, the noise exposure in these experiments may be compared to a direct impact of wind turbines on people at a distance of less than 1 metre for many years without a break, 24 hours a day, 7 days a week, 30-31 days a month [11,13,59]. ...
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Introduction and objective: Wind power is employed worldwide as an alternative source of energy. At the same time, however, the health effects of wind turbines have become a matter of discussion. The purpose of this study is a critical review of available reports providing arguments both for and against the construction of wind farms. The authors also attempt to propose recommendations in accordance with the Evidence-Based Medicine (EBM) guidelines. In the case of exposure to wind farms, a randomized controlled trial (RCT) is impossible. To obtain the highest-level recommendations, analysis of case-control studies or cohort studies with control groups should be performed. Preferably, it should include geostatistical analysis conducted with the use of variograms and the kriging technique. Combinations of key words were entered into the Thomson Reuters Web of Knowledge (SM) and the Internet search engine Google. SHORT DESCRIPTION OF STATE OF THE ART: The nuisance caused by wind turbines is stereotypically linked with the noise that they produce. Nevertheless, the visual aspect of wind farms, opinions about them, and sensitivity to sound seem to be of the greater importance. To date, the direct correlations between the vicinity of modern wind farms, the noise that wind turbines make, and possible consequences to health have not been described in peer reviewed articles. Health effects are more probably associated with some environmental factors leading to annoyance or frustration. All types of studies share the same conclusion: wind turbines can provoke annoyance. As with any project involving changes in the local environment, a certain level of irritation among the population can be expected. There are elected officials and government representatives who should decide what level of social annoyance is acceptable, and whether wind power advantages outweigh its potential drawbacks. The influence of wind turbines on human emotional and physical health is a relatively new field of research. Further analyses of these issues are justified, especially because none of the studies published in peer-reviewed journals so far meet the criteria for cohort or case-control studies. Summary: Due to methodology, currently available research results do not allow for higher than C-level recommendations. In the case of wind farms, the ideal types of research would be: a retrospective observation of a particular group of residents before and after the wind farm construction, case-control studies or cohort studies with control groups matched in respect of socioeconomic factors, predisposition for chronic diseases, exposure to environmental risk factors, and only one variable which would differentiate cases from controls--the distance between place of residence and a wind farm.
... Infrasound has adverse effects on multiple organs of humans and rodents, and the central nervous system (CNS) is particularly vulnerable to infrasound exposure (IE) [7][8][9]. Infrasound can result in a series of symptoms in which learning and memory impairment is the most common [10]. ...
... The MWM is used widely to evaluate spatial learning and memory dependent on the hippocampus and is intimately associated with long-term potentiation (LTP) [43,44]. Damaged learning and memory increased escape latency, decreased the time in the target quadrant (C), and decreased the number of times the rat crossed the target crossing after IE, which were consistent with the results of previous studies [10,12,45]. Notably, the rat swimming speed was approximately the same speed in the pool among the groups, suggesting that their performance in the MWM was not disturbed by a locomotor factor. ...
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As a kind of environmental noise, infrasonic noise has negative effects on various human organs. To date, research has shown that infrasound impairs cognitive function, especially the ability for learning and memory. Previously, we demonstrated that impaired learning and memory induced by infrasound was closely related with glia activation; however, the underlying mechanisms remain unclear. Connexin 43 hemichannels (Cx43 HCs), which are mainly expressed in hippocampal astrocytes, are activated under pathological conditions, lending support to the hypothesis that Cx43 HCs might function in the impaired learning and memory induced by infrasound. This study revealed that that blocking hippocampal Cx43 HCs or downregulating hippocampal Cx43 expression significantly alleviated impaired learning and memory induced by infrasound. We also observed that infrasound exposure led to the abundant release of glutamate and ATP through Cx43 HCs. In addition, the abundant release of glutamate and ATP depended on proinflammatory cytokines. Our finds suggested that the enhanced release of ATP and glutamate by astroglial Cx43 HCs may be involved in the learning and memory deficits caused by infrasound exposure.
... Concerns raised, as with the emergence of any latest tech, that wind energy projects may have an effect on public health. These considerations are linked to two major issues: design of wind turbine and infrastructure (e.g., electromagnetic frequency bands from transmission system, ice throw from the blades of rotor, shadow flicker from the blades of rotor, and structural damage) and wind turbine noise [10][11][12]. Wind-power production provides a clean, environment friendly, non-toxic, and easily accessible renewable energy source. Specific criteria's must be fulfilled for efficient wind power generation, like the provision of a significant amount of wind inside a site, suitable statistical assessment of the wind to investigate the nature of wind velocity dispersion within a location, multi criteria evaluation of the location to keep the validity of the place for setup of wind-energyconversion systems (WECs), cost implications of installing the WECs, and other logistic analyses. ...
... It is evaluated in watts per meter square and is a primary determinant of the average value of airspeed available at such location. Before using wind turbines, it is essential to define the wind-power density of the specific site [1,8,9,12,13]. ...
Article
To progress toward sustainable growth, future hydro-power development must pay a bit more attention towards how changing climate may impact hydropower output, as well as make massive action to limit the environmental costs borne by people who live near dams. Long term projections help in providing data for power network risk analysis as well as identifying wind power generation potential in particular places, delivering important data for electricity planners. Hydro-electric power system is an enhanced energy process because it effectively converts mechanical power into grid power, but both are high-energy methods. The utilization of wind turbines for renewable power source has turned out to be one of the greatest viable alternate wells-prings of electricity age because of the little recompense, for instance, being profitable and efficient and environment friendly. Many foundations, organizations, associations, and experts have demonstrated that wind turbines are presumed to comprehend the imperativeness order. In compared to conventional power plants, although wind-power plants have little impact on the environment, concern exists over the noise produced by the turbine blades and visual impacts to the landscape and turbine blade. While wind turbines are connected to the small scale or isolated network, the power product from another source should be varied in reply to these variant and change in sequence to retain system density and voltage with in pre-set limit.
... Infrasound is defined as sound wave frequencies below the hearing range of humans (≤20 Hz) and ultrasound is defined as sound waves at frequencies above the hearing range for people (>20 kHz). There is evidence that extremely high levels of infrasound in rats can have adverse effects on the hippocampus, and rats exposed to infrasound also exhibited longer escape latencies in the Morris Water Maze [23]. Weight loss in rats was also attributed to infrasound produced from a faulty ventilation system [24]. ...
... Weight loss in rats was also attributed to infrasound produced from a faulty ventilation system [24]. These effects are thought to occur not due to perceiving the sound in an auditory fashion but potentially to either or both the whole-body vibration caused by the sound or due to damage caused by vibration at the inherent vibration resonance frequency (the frequency at which objects most readily vibrate) of the brain tissue, as discussed below [23]. Obviously, ultrasound is problematic because humans are not aware that it exists without measurement. ...
Article
Sound and vibration have been shown to alter animal behavior and induce physiological changes as well as to cause effects at the cellular and molecular level. For these reasons, both environmental factors have a considerable potential to alter research outcomes when the outcome of the study is dependent on the animal existing in a normal or predictable biological state. Determining the specific levels of sound or vibration that will alter research is complex, as species will respond to different frequencies and have varying frequencies where they are most sensitive. In consideration of the potential of these factors to alter research, a thorough review of the literature and the conditions that likely exist in the research facility should occur specific to each research study. This review will summarize the fundamental physical properties of sound and vibration in relation to deriving maximal level standards, consider the sources of exposure, review the effects on animals, and discuss means by which the adverse effects of these factors can be mitigated.
... Animal experiments showed that infrasound destroyed hearing, cardiac, respirational, gastrointestinal, and circulation systems [7]. Particularly, infrasound impaired the central nervous system (CNS) and cognitive abilities [8]. ...
... Infrasound impaired animal learning and memory abilities [45], inhibited adult neurogenesis in hippocampi, and induced neuronal injury [46]. Cognitive ability was affected by the infrasound of 16 Hz at 130 dB [8]. Hippocampi and PFC play an important role in behavioral and cognitive psychology [47,48]. ...
Article
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Background. Infrasound is a major threat to global health by causing injuries of the central nervous system (CNS). However, there remains no effective therapeutic agent for preventing infrasound-caused CNS injury. 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glycoside (THSG) exerts protective function against CNS injuries and may have beneficial effects on infrasound-induced CNS impairment. Methods. A mouse model with CNS (oxidative stress-induced inflammation and neuronal apoptosis) injuries was established when the mouse was exposed to the infrasound of 16 Hz at 130 dB for 2 h each day and the duration of treatment was 8 d. The mice were divided into the control (CG, healthy mice), the model (MG, model mice), and the THSG (EG, experimental group, model mice treated with THSG) groups. The learning and memory impairments caused by infrasound were examined using a Morris water maze test. Lipid profiles, antioxidant biomarkers, and inflammatory cytokines in hippocampus tissue were measured by using corresponding ELISA kits. Meanwhile, BCL-2/BAX/caspase-3 signaling pathway was measured in the hippocampi and prefrontal cortex of the mouse brain using real-time qPCR and Western blot. Nissl’s stain was used to measure neuronal necrosis in the hippocampi and prefrontal cortex of the mouse brain. Results. THSG significantly ameliorated the learning and memory impairments caused by infrasound. On the other hand, THSG improved lipid profiles, increased antioxidant properties by affecting the levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and malondialdehyde (MDA), and displayed anti-inflammatory action via the downregulation of IL- (interleukin-) 6, IL-8, IL-10, TNF- (tumor necrosis factor-) α, and hs-CRP (high-sensitivity C-reactive protein) in the hippocampal tissues of the mouse model (P
... Infrasound comes from two aspects, natural world and artificial activities, including volcanic eruptions, tsunami, aircraft flight, and weapons (Angelis et al., 2016). Infrasound can cause a systemic disease, known as vibroacoustic disease (VAD) (Ferreira et al., 2006;Mendes et al., 2006;Alves-Pereira and Castelo, 2007), which may cause damages to many systems, such as the central nervous system (CNS) (Yuan et al., 2009;Cheng et al., 2012;Zhang et al., 2016), digestion system (Da et al., 2006), cardiovascular system (Pei et al., 2009), respiratory system (Castelo et al., 2003;Branco et al., 2007), and other systems. ...
... It has been suggested that infrasound can induce neuronal axon degeneration and neuronal damage by promoting Ca 2+ influx (Cheng et al., 2012). Exposure to infrasound can remarkably impair the learning and memory ability of rats Ma et al., 2015) and increase the neuronal apoptosis in rat hippocampus because of pro-inflammatory cytokines from neuroglial cells (Yuan et al., 2009;Shi et al., 2013;Cai et al., 2014). Under the infrasound with frequency 16 Hz and sound pressures ranging from 90 to 130 dB, the average escape latency of rats was increased, indicating that the more infrasound was intensified, the more learning and memory was damaged (Shi et al., 2013). ...
Article
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Infrasound, a kind of ambient noise, can cause severe disorders to various human organs, specially to central nervous system (CNS). Our previous studies have shown that infrasound-induced CNS injury was closely related with astrocytes activation and astrocytes-mediated neuroinflammation, but the underlying molecular mechanisms are still largely unclear. FGF2/FGFR1 (Fibroblast growth factor 2/Fibroblast growth factor receptor 1) pathway was reported to play an important role in anti-inflammation in CNS disorders. To further study the possible roles of FGF2/FGFR1 pathway in infrasound-induced CNS injury, here we exposed Sprague-Dawley rats or cultured astrocytes to 16 Hz, 150 dB infrasound, and explored the effects of FGF2 on infrasound-induced astrocytes activation and neuroinflammation. Western blotting, immunofluorescence and liquid chip method were used in this experiment. Our results showed that after 3- or 7-day exposure (2 h/day) of rats as well as 2 h exposure of cultured astrocytes to 16 Hz, 150 dB infrasound, astrocyte-expressed FGFR1 was downregulated in vivo and in vitro. FGF2 pretreatment not only inhibited infrasound-induced astrocyte activation in rat hippocampal CA1 region, but also reduced the levels of pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-18, IL-6, and IFN-γ in vitro and in vivo. However, FGF2 significantly upregulated the expression of FGFR1. Furthermore, we showed that FGF2 could attenuate IκBα phosphorylation, NF-κB p65 translocation, pro-inflammatory cytokines levels, and neuronal loss in the CA1 region induced by infrasound. On the contrary, PD173074, a special antagonist of FGFR1, could reverse the effects above in vitro and in vivo. Taken together, our findings showed that FGF2/FGFR1 pathway may exert inhibitive effects on astrocyte-mediated neuroinflammation in vitro and in vivo after infrasound exposure.
... If left unchecked and unmanaged, it is possible that individually or cumulatively, these issues could lead to potential health impacts. In terms of noise, high sound pressure levels (loudness) of audible noise and infrasound have been associated with learning, sleep and cognitive disruptions as well as stress and anxiety45678. As a result, minimum setback distances have been established world-wide to reduce or avoid potential effects for people living in proximity to wind turbines. ...
... It has been hypothesized that the self reported health effects (e.g., sleep disturbance, headache, tinnitus (ringing in the ears), ear pressure, dizziness, vertigo, nausea, visual blurring, tachycardia (rapid heart rate), irritability, problems with concentration and memory, and panic episodes ) are related to infrasound emitted from wind turbines [28]. Studies where biological effects were observed due to infrasound exposure were conducted at sound pressure levels (e.g., 145 dB and 165 dB [5,16]; 130 dB [7] ) much greater than what is produced by wind turbines (e.g., see O'Neal et al. [26]). Infrasound is not unique to wind turbines but is ubiquitous in the environment due to natural and man-made sources, meaning that people living near wind turbines were exposed to infrasound prior to turbine operation. ...
Article
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Wind power has been harnessed as a source of power around the world. Debate is ongoing with respect to the relationship between reported health effects and wind turbines, specifically in terms of audible and inaudible noise. As a result, minimum setback distances have been established world-wide to reduce or avoid potential complaints from, or potential effects to, people living in proximity to wind turbines. People interested in this debate turn to two sources of information to make informed decisions: scientific peer-reviewed studies published in scientific journals and the popular literature and internet. The purpose of this paper is to review the peer-reviewed scientific literature, government agency reports, and the most prominent information found in the popular literature. Combinations of key words were entered into the Thomson Reuters Web of KnowledgeSM and the internet search engine Google. The review was conducted in the spirit of the evaluation process outlined in the Cochrane Handbook for Systematic Reviews of Interventions. Conclusions of the peer reviewed literature differ in some ways from those in the popular literature. In peer reviewed studies, wind turbine annoyance has been statistically associated with wind turbine noise, but found to be more strongly related to visual impact, attitude to wind turbines and sensitivity to noise. To date, no peer reviewed articles demonstrate a direct causal link between people living in proximity to modern wind turbines, the noise they emit and resulting physiological health effects. If anything, reported health effects are likely attributed to a number of environmental stressors that result in an annoyed/stressed state in a segment of the population. In the popular literature, self-reported health outcomes are related to distance from turbines and the claim is made that infrasound is the causative factor for the reported effects, even though sound pressure levels are not measured. What both types of studies have in common is the conclusion that wind turbines can be a source of annoyance for some people. The difference between both types is the reason for annoyance. While it is acknowledged that noise from wind turbines can be annoying to some and associated with some reported health effects (e.g., sleep disturbance), especially when found at sound pressure levels greater than 40 db(A), given that annoyance appears to be more strongly related to visual cues and attitude than to noise itself, self reported health effects of people living near wind turbines are more likely attributed to physical manifestation from an annoyed state than from wind turbines themselves. In other words, it appears that it is the change in the environment that is associated with reported health effects and not a turbine-specific variable like audible noise or infrasound. Regardless of its cause, a certain level of annoyance in a population can be expected (as with any number of projects that change the local environment) and the acceptable level is a policy decision to be made by elected officials and their government representatives where the benefits of wind power are weighted against their cons. Assessing the effects of wind turbines on human health is an emerging field and conducting further research into the effects of wind turbines (and environmental changes) on human health, emotional and physical, is warranted.
... In ähnlicher Weise wird die Blut-Retina-Schranke bei Ratten ab einem Schalldruckpegel von 130 dB bei 8 Hz destabilisiert [50]. Wie bei den erwähnten Untersuchungen an Rattenmyokard zeigten sich auch an neuronalen Strukturen infraschallinduzierte Apoptose-und Inflammationsprozesse [51,52,53,54]. Hinsichtlich der Effekte von Infraschall auf das Reproduktionssystem werden Verände-CME rungen in der Testosteronbiosynthese angenommen [55]. ...
Article
Infrasound describes ubiquitous, low-frequency sound (< 20 Hz) in the environment with a long wavelength below the median hearing threshold, which can nevertheless be heard and tactilely perceived, depending on the sound pressure level and frequency spectrum. In nature, infrasound emissions usually occur only in the low-threshold range. Nevertheless, after strong and chronic exposure to usually artificially generated infrasound emissions, various effects on the ear and the body, sometimes questionably critical to health, can be observed. Correct measurement and assessment of infrasound sources is complex and controversial. Established guidelines are scarce. Innovative research areas include infrasound monitoring for evaluation of natural events and infrasound applications in medicine. In the future, it is hoped that new insights will be gained from infrasound research and that a more extensive classification in occupational medicine will be possible.
... The Morris water maze (MWM) evaluated hippocampal-dependent spatial learning and memory (Yuan et al., 2009). The MWM consisted of a dark gray circular pool (140 cm in diameter and 60 cm in height), filled with 24 ± 1 • C water with a platform submerged 1 cm below the water's surface. ...
Article
Opioid exposure during adolescence, a crucial period of neurodevelopment, has lasting neurological and behavioral consequences and affects the cognitive functions in adulthood. This study investigated the effects of adolescent morphine exposure in spatial learning and memory and synaptic plasticity of the CA1 area of the dorsal hippocampus. Adolescent Wistar rats received increasing doses of morphine for 1, 5, and 10 days. Acute morphine group was injected 2.5 mg/kg morphine for 1 day, subchronic morphine group for 5 days, with an increasing dose of 2.5 mg/kg and reached to the dose of 12.5 mg/kg and chronic morphine group for 10 days that began with an increasing dose of 2.5 mg/kg and reached to the dose of 25 mg/kg. Then after 25 days and reaching adulthood, spatial learning and memory were evaluated via the Morris water maze (MWM) test. Moreover, we test the electrophysiological properties of dorsal hippocampal plasticity in adult rats by in vitro field potential recordings. Subchronic and chronic adolescent morphine exposure impaired spatial learning and memory in the MWM test. Baseline synaptic responses in the chronic morphine group were increased and long-term potentiation (LTP) impaired in the CA1 area in subchronic and chronic morphine groups. In adulthood, the slope of the field excitatory postsynaptic potential (fEPSP) required to elicit a half-maximal population spike (PS) amplitude was significantly larger in subchronic and chronic adolescent morphine exposure compared to the saline group. Therefore, subchronic and chronic adolescent morphine exposure altered synaptic transmission and plasticity in addition to learning and memory. Long-term morphine exposure during adolescence can interfere with neurodevelopment, making a persistent impression on plasticity and cognitive capability in adulthood.
... For example, infrasound exposure is noted to be harmful in pregnant women (Castelo-Branco and Rodriguez, 1999). Furthermore, human and animal experiments have suggested that prolonged infrasound exposure can damage the central nervous system (CNS), including the hippocampus, cerebellum, limbic-corticular complex, hypothalamus, and cortex (Izmerov et al., 1997;Fei et al., 2000;Yuan et al., 2009;Shi et al., 2013;Cai et al., 2014;Ma et al., 2015). We previously confirmed that infrasound exposure activated astrocytes and induced neuronal apoptosis in the CNS, which subsequently impaired spatial learning and memory abilities (Shi et al., 2013(Shi et al., , 2018. ...
Article
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Two types of reactive astrocytes, A1 and A2 astrocytes, are induced following neuroinflammation and ischemia. In this study, we evaluated the effects of the fibroblast growth factor (FGF)2/FGF receptor (FGFR)1 pathway on A1 and A2 astrocytes in the rat hippocampus using double-labeling immunofluorescence following infrasound exposure. A1 astrocytes were induced in the CA1 region of the hippocampus after exposure to infrasound for 3 days. The number of microglial cells was also increased, and we investigated if these might be responsible for the reactivity of A1 astrocytes. Accordingly, expression levels of C3 and Iba-1, as markers of A1 astrocytes and microglial cells, respectively, were both up-regulated in rat hippocampus following infrasound exposure, as demonstrated by western blot. We also explored the effect of the FGF2/FGFR1 pathway on A1 astrocyte reactivity by pretreating rats with FGF2 or the specific FGFR1 antagonist, PD173074. A1 astrocytes were gradually down-regulated by activation of the FGF2/FGFR1 pathway and were up-regulated by inhibition of the FGF2/FGFR1 pathway after infrasound damage. These results further our understanding of the role of reactive astrocytes in infrasound-induced central nervous system injury and will thus facilitate the development of new treatments for these injuries.
... Prior studies have shown that the hippocampus is involved in learning and memory impairment, such as that seen in rodents after infrasound exposure [49]. The hippocampus-located between the cerebral hemispheres and the brainstem-was classically considered as part of the limbic system. ...
Chapter
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Within the context of noise-induced health effects, the impact of airborne acoustical phenomena on biological tissues, particularly within the lower frequency ranges, is very poorly understood. Although the human body is a viscoelastic-composite material, it is generally modeled as Hooke elastic. This implies that acoustical coupling is considered to be nonexistent at acoustical frequencies outside of the human auditory threshold. Researching the acoustical properties of mam-malian tissue raises many problems. When tissue samples are investigated as to their pure mechanical properties, stimuli are not usually in the form of airborne pressure waves. Moreover, since the response of biological tissue is dependent on frequency, amplitude, and time profile, precision laboratory equipment and relevant physiological endpoints are mandatory requirements that are oftentimes difficult to achieve. Drawing upon the viscoelastic nature of biological tissue and the tensegrity model of cellular architecture, this chapter will visit what is known to date on the biological response to a variety of different acoustic stimuli at very low frequencies.
... Yuan ym. (2009) tarkastelivat rottien avulla infraäänen vaikutuksia hippokampuksesta riippuvaan spatiaaliseen oppimiseen ja muistiin sekä niihin vaikuttaviin mekanismeihin (Yuan et al., 2009). Urosrottia (n=48) altistettiin 14 päivän ajan 6 Hz:n infraäänelle äänenpainetasolla 130 dB siten, että altistus kesti 2 tuntia päivässä. ...
Technical Report
Wind turbines produce broadband sound that also includes low frequencies. Sounds below 20 Hz are contractually referred to as infrasound. Infrasound occurs together with audible sound in both natural and built environments. Infrasound is not generally audible at levels occurring typically in the environment. The most usual effects of audible noise are annoyance and sleep disturbance. Audible sound from wind turbines is associated with annoyance, but evidence of its link to sleep disturbance is less prominent. There appears to be a difference in the prevalence of annoyance between wind power areas. In addition to sound pressure level, other factors are associated with annoyance as well. There is no scientific evidence of the effects of audible sound from wind turbines on the emergence of illnesses. Some people who reside close to wind turbines have symptoms that they associate with infrasound from wind turbines. Infrasound levels within the vicinity of wind turbines are on the same level or lower than in city centres. There is no scientific evidence that the infrasound levels present in these kinds of environments could cause negative health effects. Furthermore, in the population studies undertaken so far, symptoms have not been observed to be more prevalent close to wind turbines. However, the number of studies is relatively limited. On the other hand, strong, audible infrasound has been reported to have an effect on, for example, wakefulness. Various mechanisms have been presented through which low infrasound levels have been thought to potentially affect on health within the vicinity of wind turbines. Similar levels also appear elsewhere in built environments. It has been indicated that infrasound can cause the appearance of symptoms connected with vestibular disorders in sensitive groups of people (anomalies in the structure of the ear, hearing-related and vestibular diseases). On the other hand, in one experimental study it has been reported that infrasound also activates other brain areas than those responsible for hearing. Scientific studies on the effects of exposure to infrasound and to audible noise from wind turbines are rather limited, thus additional studies are justified.
... The CNS is vulnerable to infrasonic insults. Our previous experiments showed that exposure to a certain frequency and SPL of infrasound could impair learning and memory abilities in animals [6,7], interfere with adult neurogenesis in the hippocampus [8], cause apoptosis of the hippocampal cells [9], and induce intracellular Ca 2+ overload [9][10][11][12]. Our recent studies revealed that infrasound activated microglia and astrocytes in rat brain [12][13][14], and the activated glial cells could release proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin (IL)-1β, consequently leading to neuronal impairment [12]. ...
Article
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Excessive exposure to infrasound, a kind of low-frequency but high-intensity sound noise generated by heavy transportations and machineries, can cause vibroacoustic disease which is a progressive and systemic disease, and finally results in the dysfunction of central nervous system. Our previous studies have demonstrated that glial cell-mediated inflammation may contribute to infrasound-induced neuronal impairment, but the underlying mechanisms are not fully understood. Here, we show that cannabinoid (CB) receptors may be involved in infrasound-induced neuronal injury. After exposure to infrasound at 16 Hz and 130 dB for 1-14 days, the expression of CB receptors in rat hippocampi was gradually but significantly decreased. Their expression levels reached the minimum after 7- to 14-day exposure during which the maximum number of apoptotic cells was observed in the CA1. 2-Arachidonoylglycerol (2-AG), an endogenous agonist for CB receptors, reduced the number of infrasound-triggered apoptotic cells, which, however, could be further increased by CB receptor antagonist AM251. In animal behavior performance test, 2-AG ameliorated the infrasound-impaired learning and memory abilities of rats, whereas AM251 aggravated the infrasound-impaired learning and memory abilities of rats. Furthermore, the levels of proinflammatory cytokines tumor necrosis factor alpha and interleukin-1β in the CA1 were upregulated after infrasound exposure, which were attenuated by 2-AG but further increased by AM251. Thus, our results provide the first evidence that CB receptors may be involved in infrasound-induced neuronal impairment possibly by affecting the release of proinflammatory cytokines.
... This ratio can therefore vary from −1 to +1 with anything above zero being indicative of novelty preference. As spontaneous tasks rely on free exploration, stress may inhibit or change the nature of such exploration, and so may impair performance on such tasks (Yuan et al., 2009). For example, stress can result in neophobia (Ennaceur et al., 2009), and so even the relatively small amount of stress that may be induced through handling (which may be considerable in these one trial a day tasks as animals are repeatedly taken in and out of the apparatus) may be sufficient to drive behaviour away from the novel stimulus, thereby masking true recognition abilities. ...
Article
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This review will consider how spontaneous tasks have been applied alongside neuroscientific techniques to test complex forms of recognition memory for objects and their environmental features, e.g. the spatial location of an object or the context in which it is presented. We discuss studies that investigate the roles of the perirhinal cortex and the hippocampus in recognition memory using standard testing paradigms, and consider how these findings contribute to the ongoing debate about whether recognition memory is a single unitary process or multiple processes that can be dissociated anatomically and functionally. Due to the wide use of spontaneous tasks, the need for improved procedures that reduce animal use is acknowledged, with multiple trial paradigms discussed as a novel way of reducing variability and animal numbers in these tasks. The importance of improving translation of animal models to humans is highlighted, with emphasis on a shift away from relying on the phenomenological experience of human subjects. Copyright © 2015. Published by Elsevier Ltd.
... Measurements of IS in a typical urban setting have been reported to be up to 70 dB(G) during the daytime and 63 dB(G) at night (44). In comparison, studies reporting biological responses to IS exposure were at sound pressure levels that were above the level of auditory perception, much higher than those produced by wind turbines [e.g., 145 dB and 165 dB (68,69)]. Collectively, these reports and the measurements from the current investigation indicate that humans are regularly exposed to IS from several natural and engineered sources at levels that exceed those produced by wind turbines. ...
Article
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Setbacks for wind turbines have been established in many jurisdictions to address potential health concerns associated with audible noise. However, in recent years, it has been suggested that infrasound (IS) and low-frequency noise (LFN) could be responsible for the onset of adverse health effects self-reported by some individuals living in proximity to wind turbines, even when audible noise limits are met. The purpose of this paper was to investigate whether current audible noise-based guidelines for wind turbines account for the protection of human health, given the levels of IS and LFN typically produced by wind turbines. New field measurements of indoor IS and outdoor LFN at locations between 400 and 900 m from the nearest turbine, which were previously underrepresented in the scientific literature, are reported and put into context with existing published works. Our analysis showed that indoor IS levels were below auditory threshold levels while LFN levels at distances >500 m were similar to background LFN levels. A clear contribution to LFN due to wind turbine operation (i.e., measured with turbines on in comparison to with turbines off) was noted at a distance of 480 m. However, this corresponded to an increase in overall audible sound measures as reported in dB(A), supporting the hypothesis that controlling audible sound produced by normally operating wind turbines will also control for LFN. Overall, the available data from this and other studies suggest that health-based audible noise wind turbine siting guidelines provide an effective means to evaluate, monitor, and protect potential receptors from audible noise as well as IS and LFN.
... Some of the biological stress literature suggests that microglial activation can occur with heightened stress, but it appears to be short-lived and transitory affecting the autonomic nervous system and neuroendocrine system, resulting in multiple reported effects. To investigate the effect of infrasound on hippocampus-dependent learning and memory, Yuan et al. (2009) measure cognitive abilities and activation of molecular signaling pathways in order to determine the role of the neuronal signaling transduction pathway, BDNF-TRkB, in infrasound-induced impairment of memory and learning in the rat. Adult male Sprague-Dawley rats were exposed to infrasound of 16 Hz and 130 dB for 2 hours daily for 14 days. ...
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As the boundaries of harvesting wind energy expand to meet the ever-increasing societal energy demands, the number and size of wind turbines being constructed rises. As part of a larger project to monitor sound in an operating wind park in western New York State, a cross-sectional survey was conducted among individuals living in and around the wind park to characterize the perception, level of annoyance, and self-reported health effects of residents. We conducted the study in a 126 MW wind park consisting of 84 turbines spanning approximately 19 square miles of farmland. Short-term outdoor and indoor sound level measurements were also performed at each dwelling in which a questionnaire was administered. To our knowledge, this study is the first to collect sound measurements at individual residences. There was no apparent exposure-response relationship between an individual's level of annoyance and the short duration sound measurements collected at the time of the survey. There was a correlation between an individual's concern regarding health effects and the prevalence of sleep disturbance and stress among the study population. The siting process is unique to each community with varying degrees of success. Additional sound level measurements inside and outside homes in larger cohorts in concert with detailed questionnaires would be useful in verifying those exposure-response relationships found in studies using calculated sound level data. Additional research should include a detailed investigation of sleep patterns and possible disturbance in those living in and near operating wind turbine projects.
... Infrasonic noise, as a type of low-frequency acoustic oscillation, has been becoming an emerging public health hazard, especially detrimental to the CNS [1,7]. A battery of our previous in vivo studies have shown that infrasound impaired animal learning and memory abilities [26,27], inhibited adult neurogenesis in hippocampus [19] and induced neuronal injury of hippocampal cells [28]. More importantly, our recent findings showed that microglial cells, served as active sensors for adverse stimulus in brains [29], were activated rapidly and excessively in response to infrasound stimulation [17]. ...
... The brain is vulnerable to infrasonic insults. Our previous animal experiments showed that exposure to infrasound with a certain frequency and sound pressure level (SPl) affected animal learning and memory abilities [52, 53], impaired adult neurogenesis in hippocampus [36], induced neuronal apoptosis of hippocampal cells [37] , and triggered microglial activation in rat brain [19]. Our further studies revealed that an increased Ca 2+ influx may account for infrasoundinduced neuronal injury [16, 37, 39]. ...
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Vibroacoustic disease, a progressive and systemic disease, mainly involving the central nervous system, is caused by excessive exposure to low-frequency but high-intensity noise generated by various heavy transportations and machineries. Infrasound is a type of low-frequency noise. Our previous studies demonstrated that infrasound at a certain intensity caused neuronal injury in rats but the underlying mechanism(s) is still largely unknown. Here, we showed that glial cell-expressed TRPV4, a Ca(2+)-permeable mechanosensitive channel, mediated infrasound-induced neuronal injury. Among different frequencies and intensities, infrasound at 16 Hz and 130 dB impaired rat learning and memory abilities most severely after 7-14 days exposure, a time during which a prominent loss of hippocampal CA1 neurons was evident. Infrasound also induced significant astrocytic and microglial activation in hippocampal regions following 1- to 7-day exposure, prior to neuronal apoptosis. Moreover, pharmacological inhibition of glial activation in vivo protected against neuronal apoptosis. In vitro, activated glial cell-released proinflammatory cytokines IL-1β and TNF-α were found to be key factors for this neuronal apoptosis. Importantly, infrasound induced an increase in the expression level of TRPV4 both in vivo and in vitro. Knockdown of TRPV4 expression by siRNA or pharmacological inhibition of TRPV4 in cultured glial cells decreased the levels of IL-1β and TNF-α, attenuated neuronal apoptosis, and reduced TRPV4-mediated Ca(2+) influx and NF-κB nuclear translocation. Finally, using various antagonists we revealed that calmodulin and protein kinase C signaling pathways were involved in TRPV4-triggered NF-κB activation. Thus, our results provide the first evidence that glial cell-expressed TRPV4 is a potential key factor responsible for infrasound-induced neuronal impairment.
... As there is no other form of motivation driving behaviour in these tasks, the animals' behaviour can also be driven by other influences, such as external stimuli or initial mis-match of objects in terms of their inherent interest for animals, potentially leading, for example, to familiar but salient stimuli being more attractive for exploration than novel but relatively unsalient objects. Behaviour can be further influenced through stress induced by external stimuli which can impair performance on memory tasks (Yuan et al., 2009). In addition, stress can make animals neophobic and as such small amounts of stress through handling (which may be considerable in these tasks as animals are repeatedly taken in and out of the apparatus) may drive behaviour away from the novel stimulus, reducing the apparent memory, and masking true recognition abilities. ...
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Standard object recognition procedures assess animals' memory through their spontaneous exploration of novel objects or novel configurations of objects with other aspects of their environment. Such tasks are widely used in memory research, but also in pharmaceutical companies screening new drug treatments. However, behaviour in these tasks may be driven by influences other than novelty such as stress from handling which can subsequently influence performance. This extra-experimental variance means that large numbers of animals are required to maintain power. In addition, accumulation of data is time consuming as animals typically perform only one trial per day. The present study aimed to explore how effectively recognition memory could be tested with a new continual trials apparatus which allows for multiple trials within a session and reduced handling stress through combining features of delayed nonmatching-to-sample and spontaneous object recognition tasks. In this apparatus Lister hooded rats displayed performance significantly above chance levels in object recognition tasks (Experiments 1 and 2) and in tasks of object-location (Experiment 3) and object-in-context memory (Experiment 4) with data from only five animals or fewer per experimental group. The findings indicated that the results were comparable to those of previous reports in the literature and maintained statistical power whilst using less than a third of the number of animals typically used in spontaneous recognition paradigms. Overall, the results highlight the potential benefit of the continual trials apparatus to reduce the number of animals used in recognition memory tasks.
... Previous studies have shown that brain cognitive functions are significantly affected by infrasound (2,12,13). Similarly, impairment was also verified in the cortex and hippocampus induced by infrasound with 90 and 130 dB SPL (3,6,7). To further understand the effects of infrasound on humans and animals, we applied the same infrasonic exposure parameters once daily from 1 to 28 days for 2 h on adult rats. ...
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In the present study, we determined the effect of infrasonic exposure on apoptosis and intracellular free Ca²⁺ ([Ca²⁺]i) levels in the hippocampus of adult rats. Adult rats were randomly divided into the control and infrasound exposure groups. For infrasound treatment, animals received infrasonic exposure at 90 (8 Hz) or 130 dB (8 Hz) for 2 h per day. Hippocampi were dissected, and isolated hippocampal neurons were cultured. The [Ca²⁺]i levels in hippocampal neurons from adult rat brains were determined by Fluo-3/AM staining with a confocal microscope system on days 1, 7, 14, 21 and 28 following infrasonic exposure. Apoptosis was evaluated by Annexin V-FITC and propidium iodide double staining. Positive cells were sorted and analyzed by flow cytometry. Elevated [Ca²⁺]i levels were observed on days 14 and 21 after rats received daily treatment with 90 or 130 dB sound pressure level (SPL) infrasonic exposure (p<0.01 vs. control). The highest levels of [Ca²⁺]i were detected in the 130 dB SPL infrasonic exposure group. Meanwhile, apoptosis in hippocampal neurons was found to increase on day 7 following 90 dB SPL infrasound exposure, and significantly increased on day 14. Upon 130 dB infrasound treatment, apoptosis was first observed on day 14, whereas the number of apoptotic cells gradually decreased thereafter. Additionally, a marked correlation between cell apoptosis and [Ca²⁺]i levels was found on day 14 and 21 following daily treatment with 90 and 130 dB SPL, respectively. These results demonstrate that a period of infrasonic exposure induced apoptosis and upregulated [Ca²⁺]i levels in hippocampal neurons, suggesting that infrasound may cause damage to the central nervous system (CNS) through the Ca²⁺‑mediated apoptotic pathway in hippocampal neurons.
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Recent focus has been given on the effects of high-intensity infrasound (HII) exposure, and whether it induces changes in pancreatic morphology and glucose metabolism is still unknown. As such, we have studied the impact of HII exposure on glucose tolerance, insulin sensitivity, pancreatic islet morphology, muscle GLUT4 and plasma insulin and corticosterone levels. Normal and glucose intolerant wild-type Wistar rats were randomly divided in two groups: one group not exposed to HII and the other continuously exposed to HII. Animals were sacrificed at three timepoints of exposure (1, 6 or 12 weeks). An intraperitoneal glucose tolerance test was performed, blood samples were collected and the pancreas and the quadriceps femoris muscle were excised. Circulating insulin and corticosterone levels were determined and pancreatic and muscular tissue were routinely processed for histochemistry and immunohistochemistry with an anti-GLUT4 antibody. Animals exposed to HII had higher corticosterone levels than animals not exposed. No differences were found on insulin concerning HII exposure or glucose intolerance. Glucose intolerant animals had pancreatic islet fibrosis and no differences were found in GLUT4 ratio concerning HII exposure. In conclusion, we found that continuous exposure to HII increases stress hormone levels without inducing glucose intolerance in rats.
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Objectives: Vibroacousitic disease (VAD) is caused by excessive exposure to low-frequency but high-intensity noise. The integrity of the brain blood barrier (BBB) is essential for the brain. The study aimed to investigate the effect of noise exposure on the BBB. Methods: Healthy male Bama swine were exposed to 50, 70, 100, and 120Hz, 140dB noise for 30min. After exposure, CT brain imaging and ex vivo fluorescent imaging of parenchymal EB leakage were performed (each group consisted of N=3 swine). The human cerebral microvascular endothelial cells were exposed to 70Hz, 140dB noise for 5min. Results: The BBB permeability assay showed that 50, 70, and 100Hz with 140dB noise exposure accelerated BBB permeability, and the BBB opening at 70Hz was most serious and reversible. Additionally, CT images demonstrated that the noise-induced opening of the BBB caused no intracerebral hemorrhage. This noise-induced BBB opening was related to the downregulation of zo-1 and occludin. Finally, cysteinyl leukotriene receptor 1 (CysLT1 receptor) was found to regulate noise-induced tight junction defects in vitro. Conclusions: In conclusion, noise exposure accelerates the formation of a high-permeability BBB with leaky tight junctions through a CysLT1-mediated mechanism, which warrants additional research.
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Objective: The objective was to observe damage of hippocampus in rats after exposure to infrasound, and to assess HSP70 expression in hippocampus. Methods: SD rats in the experimental group were exposed to 140 dB (8 Hz) infrasound for 2 h per day for 3 days. The morphology of the hippocampus was examined by transmission electronic microscopic (TEM). Cell apoptosis was observed by TUNEL staining at 0 h, 24 h, 48 h, and 2 w after exposure. HSP70 expression was detected by immunohistochemistry (IHC) and Western blotting (WB). Results: TEM showed that hippocampus was significantly damaged by exposure, and exhibited recovery 1 week after exposure. The TUNEL data showed that neuronal apoptosis after exposure was significantly higher than in the control rats at 24 h and 48 h, and the apoptotic cells decreased one week after exposure. IHC and WB showed HSP70 expression was significantly higher in the exposed rats, peaked at 24 h. Conclusion: Exposure to 140 dB (8 Hz) infrasound for 2 h per day for 3 days appeared to induce damage to the hippocampus of rats, based on changes in ultrastructure and increased cell apoptosis. However, recovery from the damage occurred overtime. HSP70 expression also increased after the exposure and decreased by 48.
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Method: Cultured hippocampal astrocytes were divided into three groups: control group(Ctrl group), infrasound exposure group(IE group) and Gap26+ IE group. The astrocytes in the IE group were placed into the infrasonic chamber and exposed to infrasound(16Hz, 130dB) for different durations(15min, 30min, 60min, 90min, 120min, 240min), while Ctrl group was put into the same infrasonic chamber but without infrasonic exposure. Furthermore, in order to identify the glutamate release route under infrasound, astrocytes were pre-treated with Cx43 hemichannel blocker Gap26 before infrasound exposure. In addition, scrambled Gap26 peptide(Scrb Gap26) was used to rule out the effect of the Gap26 itself on the glutamate, which was regarded as the Scrb Gap26+IE group. After infrasound exposure, immunocytochemistry method was used to detect the expression of Cx43. At the same time, high pressure liquid chromatography(HPLC) was used to detect the extracellullar glutamate level.
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Infrasound causes functional disorders and structural injury to the central nervous system. However, few anti-infrasound drugs exist, and they are inefficient. Nitronyl nitroxide radicals have been reported to be good antioxidants that act as superoxide dismutase mimics and directly react with reactive oxygen species, such as ·OH, H2O2, and O 2 (∙) -. Our previous research showed that the nitronyl nitroxide radical L-NNNBP has good protective effects against β-amyloid deposition and memory deficits in an AD rat model of APP/PS1. The objective of the present study was to find a new group of anti-infrasound drugs and determine the underlying pharmacological actions of nitronyl nitroxide radicals against infrasound-induced neuronal impairment in vivo. We synthesized a new stable nitronyl nitroxide radical, NRbt, and characterized its crystal structure. The results of the anti-oxidative damage effects of NRbt and the positive control drug tempol showed that they could significantly increase the SOD activity, CAT activity and GSH level and decrease the MDA level in rat hippocampi compared with infrasound exposure without pretreatment. Moreover, the ability of NRbt to regulate the activity or level of these biochemical markers was better than that of tempol. Our results showed that both NRbt and tempol significantly protected against the learning and memory impairments induced by infrasound exposure in a Morris water maze, but there were no significant differences in the path length or escape latency between the rats in the tempol group and the three NRbt groups (P > 0.05). In addition, the infrasound-induced neuronal apoptosis in rat hippocampi was significantly suppressed by NRbt and tempol. The results demonstrated that compared with the infrasound exposure group, the expression of Bcl-2 was up-regulated and the expressions of Bax and caspase-3 were down-regulated in rats pretreated with NRbt (40 mg/kg) or tempol (40 mg/kg). These results showed that the newly synthesized nitronyl nitroxide radical, NRbt, may be an effective anti-infrasound drug because of its capacity to inhibit the oxidative damage of free radicals induced by infrasound exposure.
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The association between wind turbines and health effects is highly debated. Some argue that reported health effects are related to wind turbine operation [electromagnetic fields (EMF), shadow flicker, audible noise, low-frequency noise, infrasound]. Others suggest that when turbines are sited correctly, effects are more likely attributable to a number of subjective variables that result in an annoyed/stressed state. In this review, we provide a bibliographic-like summary and analysis of the science around this issue specifically in terms of noise (including audible, low-frequency noise, and infrasound), EMF, and shadow flicker. Now there are roughly 60 scientific peer-reviewed articles on this issue. The available scientific evidence suggests that EMF, shadow flicker, low-frequency noise, and infrasound from wind turbines are not likely to affect human health; some studies have found that audible noise from wind turbines can be annoying to some. Annoyance may be associated with some self-reported health effects (e.g., sleep disturbance) especially at sound pressure levels >40 dB(A). Because environmental noise above certain levels is a recognized factor in a number of health issues, siting restrictions have been implemented in many jurisdictions to limit noise exposure. These setbacks should help alleviate annoyance from noise. Subjective variables (attitudes and expectations) are also linked to annoyance and have the potential to facilitate other health complaints via the nocebo effect. Therefore, it is possible that a segment of the population may remain annoyed (or report other health impacts) even when noise limits are enforced. Based on the findings and scientific merit of the available studies, the weight of evidence suggests that when sited properly, wind turbines are not related to adverse health. Stemming from this review, we provide a number of recommended best practices for wind turbine development in the context of human health.
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Infrasonic noise/infrasound is a type of environmental noise that threatens public health as a nonspecific biological stressor. Glutamate-related excitotoxicity is thought to be responsible for infrasound-induced impairment of learning and memory. In addition to neurons, astrocytes are also capable of releasing glutamate. In the present study, to identify the effect of infrasound on astroglial glutamate release, cultured astrocytes were exposed to infrasound at 16 Hz, 130 dB for different times. We found that infrasound exposure caused a significant increase in glutamate levels in the extracellular fluid. Moreover, blocking the connexin43 (Cx43) hemichannel or gap junction, decreasing the probability of Cx43 being open or inhibiting of Cx43 expression blocked this increase. The results suggest that glutamate release by Cx43 hemichannels/gap junctions is involved in the response of cultured astrocytes to infrasound.
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In many working environments the total noise energy is dominated by infrasonic frequencies. Exposure to this type of low frequency noise has, by several authors, been correlated to different effects on human subjects. Recent laboratory experiments have thus indicated correlations between noise, perception and other effects on humans. Exposure to infrasound therefore appears to become a hygienic problem when the pressure level exceeds the threshold of perception. The present paper is a description of various laboratory experiments on perception and the physiological effects of infrasound. Subjects were exposed to pure tones and broad-band noise within the infrasonic range. Changes in perception, and physiological reactions, during different types of exposure are described. The paper also includes levels and frequency analyses of noise emanating from some of the most common infrasonic sources: buses, lorries, trains, railbuses, ships, helicopters, manoeuvre rooms and mills. The characteristics of the noise spectra are compared and related to the threshold of perception. Finally, field studies on physiological changes correlated to wakefulness in typical and authentic infrasonic noise environments are described.
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Imagine a world in which you could hear not just nearby conversations and the noise of traffic a few blocks away, but also the sound of blasting in a quarry in the next state, the rumblings of an avalanche or volcano a thousand miles away, and the roar of a typhoon halfway around the world. Fortunately, nature has spared our senses from direct exposure to this incessant din. But our relentless quest to extend our senses has yielded instruments that can do just that—and more. Waves of infrasound, sounds at frequencies too low for us to hear, permeate the atmosphere and offer us insights into natural and human‐made events on a global scale. The search for ways to monitor compliance with the Comprehensive Test Ban Treaty has sparked renewed interest in sounds with frequencies too low for humans to hear.
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New granule cells are born throughout life in the dentate gyrus of the hippocampal formation. Given the fundamental role of the hippocampus in processes underlying certain forms of learning and memory, it has been speculated that newborn granule cells contribute to cognition. However, previous strategies aiming to causally link newborn neurons with hippocampal function used ablation strategies that were not exclusive to the hippocampus or that were associated with substantial side effects, such as inflammation. We here used a lentiviral approach to specifically block neurogenesis in the dentate gyrus of adult male rats by inhibiting WNT signaling, which is critically involved in the generation of newborn neurons, using a dominant-negative WNT (dnWNT). We found a level-dependent effect of adult neurogenesis on the long-term retention of spatial memory in the water maze task, as rats with substantially reduced levels of newborn neurons showed less preference for the target zone in probe trials >2 wk after acquisition compared with control rats. Furthermore, animals with strongly reduced levels of neurogenesis were impaired in a hippocampus-dependent object recognition task. Social transmission of food preference, a behavioral test that also depends on hippocampal function, was not affected by knockdown of neurogenesis. Here we identified a role for newborn neurons in distinct aspects of hippocampal function that will set the ground to further elucidate, using experimental and computational strategies, the mechanism by which newborn neurons contribute to behavior.
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Electrophysiological studies have shown that single cells in the hippocampus respond during spatial learning and exploration1-4, some firing only when animals enter specific and restricted areas of a familiar environment. Deficits in spatial learning and memory are found after lesions of the hippocampus and its extrinsic fibre connections5,6 following damage to the medial septal nucleus which successfully disrupts the hippocampal theta rhythm7, and in senescent rats which also show a correlated reduction in synaptic enhancement on the perforant path input to the hippocampus8. We now report, using a novel behavioural procedure requiring search for a hidden goal, that, in addition to a spatial discrimination impairment, total hippocampal lesions also cause a profound and lasting placenavigational impairment that can be dissociated from correlated motor, motivational and reinforcement aspects of the procedure.
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Neurotrophins acting at the trkB receptor have been shown to be important modulators of activity-dependent plasticity in the hippocampus, but the mechanisms underlying these effects are not yet well understood. To identify the cellular and subcellular targets of trkB ligands in the adult rat hippocampal formation, full-length trkB receptor immunoreactivity (trkB-IR) was localized using electron microscopy. trkB-IR was present in the glutamatergic pyramidal and granule cells. Labeling in these neurons appeared as discrete clusters and was primarily in axons, excitatory-type axon terminals, and dendritic spines and to a lesser extent in somata and dendritic shafts. trkB-IR was commonly found on the plasma membrane of dendritic spines, whereas in other subcellular regions trkB-IR was often intracellular. Labeling was strikingly dense within axon initial segments, suggesting extensive receptor trafficking. trkB-IR was not confined to pyramidal and granule cells. Dense trkB-IR was found in occasional interneuron axon initial segments, some axon terminals forming inhibitory-type synapses onto somata and dendritic shafts, and excitatory-type terminals likely to originate extrahippocampally. This suggests that trkB is contained in some GABAergic interneurons, neuromodulatory (e.g., cholinergic, dopaminergic, and noradrenergic) afferents, and/or glutamatergic afferents. These data indicate that full-length trkB receptor activation may modulate glutamatergic pathways of the trisynaptic circuit both presynaptically at axon terminals and initial segments and postsynaptically at dendritic spines and shafts. Signaling via catalytic trkB may also presynaptically affect inhibitory and modulatory neurons. A pan-trkB antibody labeled the same neuronal populations as the full-length-specific trkB antiserum, but the labels differed in density at various subcellular sites. These findings provide an ultrastructural foundation for further examining the mechanisms through which neurotrophins acting at trkB receptors contribute to synaptic plasticity.
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Brain-derived neurotrophic factor (BDNF) and other neurotrophins are critically involved in long-term potentiation (LTP). Previous reports point to a presynaptic site of neurotrophin action. By imaging dentate granule cells in mouse hippocampal slices, we identified BDNF-evoked Ca2+ transients in dendrites and spines, but not at presynaptic sites. Pairing a weak burst of synaptic stimulation with a brief dendritic BDNF application caused an immediate and robust induction of LTP. LTP induction required activation of postsynaptic Ca2+ channels and N-methyl-d-aspartate receptors and was prevented by the blockage of postsynaptic Ca2+ transients. Thus, our results suggest that BDNF-mediated LTP is induced postsynaptically. Our finding that dendritic spines are the exclusive synaptic sites for rapid BDNF-evoked Ca2+ signaling supports this conclusion.
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One of the most rigorously investigated problems in modern neuroscience is to decipher the mechanisms by which experience-induced changes in the central nervous system are translated into behavioral acquisition, consolidation, retention, and subsequent recall of information. Brain-derived neurotrophic factor (BDNF) has recently emerged as one of the most potent molecular mediators of not only central synaptic plasticity, but also behavioral interactions between an organism and its environment. Recent experimental evidence indicates that BDNF modulates synaptic transmission and plasticity by acting across different spatial and temporal domains. BDNF signaling evokes both short- and long-term periods of enhanced synaptic physiology in both pre- and postsynaptic compartments of central synapses. Specifically, BDNF/TrkB signaling converges on the MAP kinase pathway to enhance excitatory synaptic transmission in vivo, as well as hippocampal-dependent learning in behaving animals. Emerging concepts of the intracellular signaling cascades involved in synaptic plasticity induced through environmental interactions resulting in behavioral learning further support the contention that BDNF/TrkB signaling plays a fundamental role in mediating enduring changes in central synaptic structure and function. Here we review recent literature showing the involvement of BDNF/TrkB signaling in hippocampal-dependent learning paradigms, as well as in the types of cellular plasticity proposed to underlie learning and memory.
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Activity-dependent changes in synaptic strength are considered mechanisms underlying learning and memory. Brain-derived neurotrophic factor (BDNF) plays an important role in activity-dependent synaptic plasticity such as long-term potentiation. Recent experimental evidence supports the role of BDNF in memory processes: Memory acquisition and consolidation are associated with an increase in BDNF mRNA expression and the activation of its receptor TrkB. Genetic as well as pharmacologic deprivation of BDNF or TrkB impairs learning and memory. In a positively motivated radial arm maze test, activation of the TrkB/phosphatidylinositol-3 kinase (PI3-K) signaling pathway in the hippocampus is associated with consolidation of spatial memory through an activation of translational processes. In a negatively motivated passive avoidance test, mitogen-activated protein kinase (MAPK) is activated during acquisition of fear memory. Furthermore, recent findings suggest the importance of interaction between BDNF/TrkB signaling and NMDA receptors for spatial memory. A Src-family tyrosine kinase, Fyn plays a role in this interaction by linking TrkB with NR2B. These findings suggest that BDNF/TrkB signaling in the hippocampus plays a crucial role in learning and memory.
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Definitions of infrasound and low-frequency noise are discussed and the fuzzy boundary between them described. Infrasound, in its popular definition as sound below a frequency of 20 Hz, is clearly audible, the hearing threshold having been measured down to 1.5 Hz. The popular concept that sound below 20 Hz is inaudible is not correct. Sources of infrasound are in the range from very low-frequency atmospheric fluctuations up into the lower audio frequencies. These sources include natural occurrences, industrial installations, low-speed machinery, etc. Investigations of complaints of low-frequency noise often fail to measure any significant noise. This has led some complainants to conjecture that their perception arises from non-acoustic sources, such as electromagnetic radiation. Over the past 40 years, infrasound and low-frequency noise have attracted a great deal of adverse publicity on their effects on health, based mainly on media exaggerations and misunderstandings. A result of this has been that the public takes a one-dimensional view of infrasound, concerned only by its presence, whilst ignoring its low levels.
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Throughout adulthood, new neurons are continuously added to the dentate gyrus, a hippocampal subregion that is important in spatial learning. Whether these adult-generated granule cells become functionally integrated into memory networks is not known. We used immunohistochemical approaches to visualize the recruitment of new neurons into circuits supporting water maze memory in intact mice. We show that as new granule cells mature, they are increasingly likely to be incorporated into circuits supporting spatial memory. By the time the cells are 4 or more weeks of age, they are more likely than existing granule cells to be recruited into circuits supporting spatial memory. This preferential recruitment supports the idea that new neurons make a unique contribution to memory processing in the dentate gyrus.
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The N-methyl-D-aspartate receptor (NMDAR), brain-derived neurotrophic factor (BDNF), postsynaptic density protein 95 (PSD-95) and phosphatidylinositol 3-kinase (PI3K) have all been implicated in long-term potentiation. Here we show that these molecules are involved in a single pathway for synaptic potentiation. In visual cortical neurons in young rodents, the neurotrophin receptor TrkB is associated with PSD-95. When BDNF is applied to cultured visual cortical neurons, PSD-95-labeled synaptic puncta enlarge, and fluorescent recovery after photobleaching (FRAP) reveals increased delivery of green fluorescent protein-tagged PSD-95 to the dendrites. The recovery of fluorescence requires TrkB, signaling through PI3K and the serine-threonine kinase Akt, and an intact Golgi apparatus. Stimulation of NMDARs mimics the PSD-95 trafficking that is induced by BDNF but requires active BDNF and PI3K. Furthermore, local dendritic contact with a BDNF-coated microsphere induces PSD-95 FRAP throughout the dendrites of the stimulated neuron, suggesting that this mechanism induces rapid neuron-wide synaptic increases in PSD-95 and refinement whenever a few robust inputs activate the NMDAR-BDNF-PI3K pathway.
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The dentate gyrus of the hippocampus is one of the few regions of the mammalian brain where new neurons are generated throughout adulthood. This adult neurogenesis has been proposed as a novel mechanism that mediates spatial memory. However, data showing a causal relationship between neurogenesis and spatial memory are controversial. Here, we developed an inducible transgenic strategy allowing specific ablation of adult-born hippocampal neurons. This resulted in an impairment of spatial relational memory, which supports a capacity for flexible, inferential memory expression. In contrast, less complex forms of spatial knowledge were unaltered. These findings demonstrate that adult-born neurons are necessary for complex forms of hippocampus-mediated learning.
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In many working environments the total noise energy is dominated by infrasonic frequencies. Exposure to this type of low frequency noise has, by several authors, been correlated to different effects on human subjects. Recent laboratory experiments have thus indicated correlations between noise, perception and other effects on humans. Exposure to infrasound therefore appears to become a hygienic problem when the pressure level exceeds the threshold of perception. The present paper is a description of various laboratory experiments on perception and the physiological effects of infrasound. Subjects were exposed to pure tones and broad-band noise within the infrasonic range. Changes in perception, and physiological reactions, during different types of exposure are described. The paper also includes levels and frequency analyses of noise emanating from some of the most common infrasonic sources: buses, lorries, trains, railbuses, ships, helicopters, manoeuvre rooms and mills. The characteristics of the noise spectra are compared and related to the threshold of perception. Finally, field studies on physiological changes correlated to wakefulness in typical and authentic infrasonic noise environments are described.
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Aim: To observe the changes of learning and memory abilities and ultrastructural changes of medial septal nucleus (MS) and diagonal band (DB) nucleus in rats after long-term exposure to infrasound so as to explore the mechanism of infrasound in learning and memory abilities. Methods: After the rats were exposed to 16 Hz and 130 dB infrasound for 42 days (2 hours per day), the changes of learning and memory abilities were assessed by dark avoidance reaction. Transmission electron microscope technique was used to detect the ultrastructural changes of MS and DB in the rats. Results: After 42-day exposure to infrasound stimulation (16 Hz, 130 dB), the error times of dark avoidance task in the experimental group (2.9 ± 1.9) increased significantly as compared with that in the control group (0.8 ± 0.8), and the average latency in the experimental group[(153 ± 22) s] was shorter than that in the control group [(290 ± 15)s] (t=3.61, P < 0.01). In the injured neurons, mitochondria were damaged, and the levels of ribosome and glycogen were reduced. Increased levels of lysosome and lipofuscin were observed in the plasma of the injured neurons. Conclusion: Long-term infrasound exposure may disturb septus-hipocampus cholinergic pathway, which is related with the decrease of learning and memory abilities in rats.
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The drivers of long distance transport trucks exposed to infrasound vibration (about 115dBA). We studied the effects of infrasound with a questionnaire survey of long distance transport trucks. The questions dealt with general fatigue, yawning, sleepiness, vertigo, tinnitus, headache, sensation of being stifled, hearing impairment, abdominal symptoms and hypertension.We analyzed statistically the incidence of each symptom in relation to exposure to infrasound, the duration of work, the hours of driving and the hours of rest.The results were not statistical by significant. Exposure to about 115dBA of infrasound has no effect on humans.
Article
To investigate some bioeffects of infrasound on copulation as well as underlying mechanisms, we inspected the changes of sexual behavior, serum testosterone concentration and mRNA expression levels of steroidogenic factor 1 (SF-1), steroidogenic acute regulatory protein (StAR) and cytochrome P450 cholesterol side chain cleavage enzyme (P450scc) in testes of rats exposed to infrasound of 8Hz at 90 or 130dB for 1, 7, 14 and 21 days (2h/day), respectively. Rats exposed to 90dB exhibited significant decrement in sexual behavior, serum testosterone levels and mRNA expression levels of StAR and P450scc at the time point of 1 day but not at the rest time points, and no significantly change of SF-1 mRNA expression was observed over the period of 21 days in spite of mild fluctuation. Rats exposed to 130dB exhibited significant decrement in all aspects above, which became more profound with prolonged exposure. Our conclusion is that adverse bioeffects of infrasound on reproduction depend on some exposure parameters, the mechanism of which could involve in the decreased expression of some key enzymes or regulator for testosterone biosynthesis.
Article
Adult neurogenesis in the hippocampus leads to the incorporation of thousands of new granule cells into the dentate gyrus every month, but its function remains unclear. Here, we present computational evidence that indicates that adult neurogenesis may make three separate but related contributions to memory formation. First, immature neurons introduce a degree of similarity to memories learned at the same time, a process we refer to as pattern integration. Second, the extended maturation and change in excitability of these neurons make this added similarity a time-dependent effect, supporting the possibility that temporal information is included in new hippocampal memories. Finally, our model suggests that the experience-dependent addition of neurons results in a dentate gyrus network well suited for encoding new memories in familiar contexts while treating novel contexts differently. Taken together, these results indicate that new granule cells may affect hippocampal function in several unique and previously unpredicted ways.
Article
Adult hippocampal neurogenesis is stimulated by chronic administration of antidepressants (ADs) and by voluntary exercise. Neural progenitor cells (NPCs) in the dentate gyrus (DG) that are capable of continuous proliferation and neuronal differentiation are the source of such structural plasticity. Here we report that mice lacking the receptor tyrosine kinase TrkB in hippocampal NPCs have impaired proliferation and neurogenesis. When exposed to chronic ADs or wheel-running, no increase in proliferation or neurogenesis is observed. Ablation of TrkB also renders these mice behaviorally insensitive to antidepressive treatment in depression- and anxiety-like paradigms. In contrast, mice lacking TrkB only in differentiated DG neurons display typical neurogenesis and respond normally to chronic ADs. Thus, our data establish an essential cell-autonomous role for TrkB in regulating hippocampal neurogenesis and behavioral sensitivity to antidepressive treatments, and support the notion that impairment of the neurogenic niche is an etiological factor for refractory responses to an antidepressive regimen.
Article
The use of an exogenously administered thymidine analog, 5-bromo-2'-deoxyuridine (BrdU), for studies of the proliferation, migration and time of origin of cells in the cerebral cortex was investigated and compared with [3H]thymidine [( 3H]dT) autoradiography. Pregnant rats or mice were injected with BrdU and/or [3H]dT and processed by standard immunohistochemical techniques using a primary antibody directed against BrdU in single-stranded DNA, autoradiographic methods, or both. In animals that survived only 1 h after the injection, BrdU-positive cells were distributed in the proliferative zones throughout the central nervous system (CNS). In animals killed 1-3 days after the BrdU injection, intensely immunoreactive cells were in the superficial cortical plate and less intensely labeled cells were scattered throughout the deep cortical plate, the intermediate zone, and the germinal zones. In adult animals, 60 days or more after an injection of BrdU on GD 19, BrdU-positive cells were located in layer II/III of neocortex, the hippocampal pyramidal layer, and the granule layer of the dentate gyrus. In the double-labeling studies, the distribution of BrdU-immunoreactive cells was identical to that of autoradiographically labeled cells, and all autoradiographically labeled neurons were BrdU positive. Thus, BrdU immunohistochemistry is suitable for developmental studies of the CNS; moreover, it provides several advantages over [3H]dT autoradiography.
Article
The application of focused, pulsed ultrasound was studied as a method of modifying the activity of a local neural circuit of the mammalian brain. An in vitro hippocampal preparation was used to facilitate delivery, dosimetry and assessment of mechanisms of ultrasound effects. Extracellular evoked potentials were recorded from cell and dendritic layers of the rat hippocampal dentate gyrus. Focused pulses of ultrasound with center frequency of 500 kHz and repetition rate of 200 kHz were studied and found both to enhance and to depress electrically evoked field potentials. The fiber volley and cell population potentials were depressed, whereas the dendritic potential was enhanced. Results suggest a simultaneous mechanical and thermal mechanism of ultrasound in modifying evoked field potentials of dentate local circuits.
Article
Exposure to an enriched environment increases neurogenesis in the dentate gyrus of adult rodents. Environmental enrichment, however, typically consists of many components, such as expanded learning opportunities, increased social interaction, more physical activity and larger housing. We attempted to separate components by assigning adult mice to various conditions: water-maze learning (learner), swim-time-yoked control (swimmer), voluntary wheel running (runner), and enriched (enriched) and standard housing (control) groups. Neither maze training nor yoked swimming had any effect on bromodeoxyuridine (BrdU)-positive cell number. However, running doubled the number of surviving newborn cells, in amounts similar to enrichment conditions. Our findings demonstrate that voluntary exercise is sufficient for enhanced neurogenesis in the adult mouse dentate gyrus.
Article
Slices of rat hippocampus were exposed to 700 MHz continuous wave radiofrequency (RF) fields (25.2-71.0 V m(-1), 5-15 min exposure) in a stripline waveguide. At low field intensities, the predominant effect on the electrically evoked field potential in CA1 was a potentiation of the amplitude of the population spike by up to 20%, but higher intensity fields could produce either increases or decreases of up to 120 and 80%, respectively, in the amplitude of the population spike. To eliminate the possibility of RF-induced artefacts due to the metal stimulating electrode, the effect of RF exposure on spontaneous epileptiform activity induced in CA3 by 4-aminopyridine (50-100 microM) was investigated. Exposure to RF fields (50.0 V m(-1)) reduced or abolished epileptiform bursting in 36% of slices tested. The maximum field intensity used in these experiments, 71.0 V m(-1), was calculated to produce a specific absorption rate (SAR) of between 0.0016 and 0.0044 W kg(-1) in the slices. Measurements with a Luxtron fibreoptic probe confirmed that there was no detectable temperature change (+/- 0.1 degrees C) during a 15 min exposure to this field intensity. Furthermore, imposed temperature changes of up to 1 degrees C failed to mimic the effects of RF exposure. These results suggest that low-intensity RF fields can modulate the excitability of hippocampal tissue in vitro in the absence of gross thermal effects. The changes in excitability may be consistent with reported behavioural effects of RF fields.
Article
In addition to its actions on neuronal survival and differentiation, brain-derived neurotrophic factor (BDNF) has a role in the regulation of synaptic strength. Long-term potentiation, a form of synaptic plasticity, is markedly impaired in BDNF mutant mice, but the changes were restored by the re-expression of BDNF. BDNF also influences the development of patterned connections and the growth and complexity of dendrites in the cerebral cortex. These results suggest a role for BDNF in learning and memory processes, since memory acquisition is considered to involve both short-term changes in electrical properties and long-term structural alterations in synapses. Memory acquisition is associated with an increase in BDNF mRNA and TrkB receptor activation in specific brain areas. Moreover, the pharmacologic and genetic deprivation of BDNF or its receptor TrkB results in severe impairment of learning and memory in mice, rats and chicks. The effect of BDNF on learning and memory may be linked to the modulation of NMDA and non-NMDA receptor functions as well as the expression of synaptic proteins required for exocytosis. Activation of the mitogen-associated protein kinase and/or phosphatidylinositol 3-kinase signaling pathways may be involved in BDNF-dependent learning and memory formation. It is concluded that BDNF/TrkB signaling plays an important role in learning and memory.
Article
Neurons are continually born from endogenous stem cells and added to the dentate gyrus throughout life, but adult hippocampal neurogenesis declines precipitously with age. Short-term exposure to an enriched environment leads to a striking increase in new neurons, along with a substantial improvement in behavioral performance. Could this plastic response be relevant for explaining the beneficial effects of leading "an active life" on brain function and pathology? Adult hippocampal neurogenesis in mice living in an enriched environment from the age of 10 to 20 months was fivefold higher than in controls. Relatively, the increase in neuronal phenotypes was entirely at the expense of newly generated astrocytes. This cellular plasticity occurred in the context of significant improvements of learning parameters, exploratory behavior, and locomotor activity. Enriched living mice also had a reduced lipofuscin load in the dentate gyrus, indicating decreased nonspecific age-dependent degeneration. Therefore, in mice signs of neuronal aging can be diminished by a sustained active and challenging life, even if this stimulation started only at medium age. Activity exerts not only an acute but also a sustained effect on brain plasticity.
Article
We have investigated the biochemical, physiological, and behavioral properties of transgenic mice overexpressing the full-length neurotrophin receptor trkB (trkB.TK+). The highest trkB.TK+ mRNA overexpression was achieved in the cerebral cortex and hippocampal subfields, both areas also showing strongly increased trkB.TK+ receptor protein expression and phosphorylation. Furthermore, as a result of trkB.TK+ overexpression, partial activation of trkB downstream signaling was observed. Phosphorylation of phospholipaseCgamma-1 was increased but unexpectedly, the expression and phosphorylation levels of signaling molecules Shc and mitogen-activated protein kinase (MAPK) were unaltered. Behavioral studies revealed improved learning and memory in the water maze, contextual fear conditioning, and conditioned taste aversion tests, and reduced anxiety in the elevated plus maze (EPM) and light-dark exploration tests in trkB.TK+ transgenic mice. Electrophysiological studies revealed a reduced long-term potentiation (LTP) at the Schaffer collateral-CA1 synapse in trkB.TK+ mice. Altogether, overexpression of the trkB.TK+ receptor postnatally leads to selective activation of trkB signaling pathways and enhanced learning and memory.
Article
The medial temporal lobe includes a system of anatomically related structures that are essential for declarative memory (conscious memory for facts and events). The system consists of the hippocampal region (CA fields, dentate gyrus, and subicular complex) and the adjacent perirhinal, entorhinal, and parahippocampal cortices. Here, we review findings from humans, monkeys, and rodents that illuminate the function of these structures. Our analysis draws on studies of human memory impairment and animal models of memory impairment, as well as neurophysiological and neuroimaging data, to show that this system (a) is principally concerned with memory, (b) operates with neocortex to establish and maintain long-term memory, and (c) ultimately, through a process of consolidation, becomes independent of long-term memory, though questions remain about the role of perirhinal and parahippocampal cortices in this process and about spatial memory in rodents. Data from neurophysiology, neuroimaging, and neuroanatomy point to a division of labor within the medial temporal lobe. However, the available data do not support simple dichotomies between the functions of the hippocampus and the adjacent medial temporal cortex, such as associative versus nonassociative memory, episodic versus semantic memory, and recollection versus familiarity.
Article
Brain-derived neurotrophic factor (BDNF) and its receptor TrkB play important roles in learning and memory. Memory acquisition is associated with an increase in BDNF mRNA and TrkB activation in specific brain areas. Pharmacologic and genetic deprivation of BDNF or TrkB results in an impairment of memory. Activation of the mitogen-associated protein kinase and phosphatidylinositol 3-kinase signaling pathways is involved in BDNF-dependent learning and memory. A frequent single nucleotide polymorphism in the targeting region of the human BDNF gene (val66met) is associated with poorer episodic memory and abnormal hippocampal neuronal function in humans. The interaction of BDNF/TrkB signaling with N-methyl-D-aspartate receptors is important for spatial learning and memory, and an Src-family tyrosine kinase Fyn may play a key role in this interaction by linking TrkB with NR2B.
Article
Synaptic actions of brain-derived neurotrophic factor (BDNF) are 'gated' by cyclic AMP (cAMP), but the underlying molecular mechanisms remain unclear. Here we report that cAMP regulates BDNF function in mature hippocampal neurons by modulating the signaling and trafficking of its receptor TrkB. cAMP gated the TrkB tyrosine kinase with three characteristic features: BDNF-induced TrkB phosphorylation was attenuated by inhibitors of cAMP signaling, it was potentiated by cAMP analogs, and activation of the cAMP pathway alone had no effect. In addition, cAMP facilitated trafficking of TrkB to dendritic spines, possibly by promoting its interaction with synaptic scaffolding protein PSD-95. Norepinephrinergic and dopaminergic agonists, which elevate intracellular cAMP concentration, also enhanced TrkB phosphorylation and its translocation to spines. cAMP gated long-term modulation by BDNF of spine density, but not the number of primary dendrites. These results reveal a specific role of cAMP in controlling BDNF actions in the brain, and provide new insights into the molecular mechanism underlying cAMP gating.
Article
There is evidence that BDNF influences the birth of granule cells in the dentate gyrus, which is one of the few areas of the brain that demonstrates neurogenesis throughout life. However, studies to date have not examined this issue directly. To do so, we compared the effects of BDNF, phosphate-buffered saline (PBS), or bovine serum albumin (BSA) on neurogenesis after infusion into the hippocampus of the normal adult rat, using osmotic pumps that were implanted unilaterally in the dorsal hilus. BDNF, PBS, and BSA were infused for 2 weeks. The mitotic marker bromodeoxyuridine (BrdU) was administered twice daily during the 2-week infusion period. At least 1 month after infusion ended, brains were processed immunocytochemically using antibodies to BrdU, a neuronal nuclear protein (NeuN), or calbindin D28K (CaBP), which labels mature granule cells. Stereology was used to quantify BrdU-labeled cells in the dorsal hippocampus that were double-labeled with NeuN or CaBP. There was a statistically significant increase in BrdU(+)/NeuN(+) double-labeled cells in the granule cell layer after BDNF infusion relative to controls. The values for BrdU(+)/NeuN(+) cells were similar to BrdU(+)/CaBP(+) cells, indicating that most new neurons were likely to be granule cells. In addition, BrdU(+)/NeuN(+)-labeled cells developed in the hilar region after BDNF infusion, which have previously only been identified after severe continuous seizures (status epilepticus) and associated pathological changes. Remarkably, neurogenesis was also increased contralaterally, but BDNF did not appear to spread to the opposite hemisphere. Thus, infusion of BDNF to a local area can have widespread effects on hippocampal neurogenesis. The results demonstrate that BDNF administration to the dentate gyrus leads to increased neurogenesis of granule cells. They also show that ectopic granule cells develop after BDNF infusion, which suggests that ectopic migration is not necessarily confined to pathological conditions. These results are discussed in light of the evidence that BDNF increases neuronal activity in hippocampus. Thus, the mechanisms underlying neurogenesis following BDNF infusion could be due to altered activity as well as direct effects of BDNF itself, and this is relevant to studies of other growth factors because many of them have effects on neuronal excitability that are often not considered.
Article
The neuroprotective effect and molecular mechanisms underlying preconditioning with N-methyl-D-aspartate (NMDA) in cultured hippocampal neurons have not been described. Pre-incubation with subtoxic concentrations of the endogenous neurotransmitter glutamate protects vulnerable neurons against NMDA receptor-mediated excitotoxicity. As a result of physiological preconditioning, NMDA significantly antagonizes the neurotoxicity resulting from subsequent exposure to an excitotoxic concentration of glutamate. The protective effect of glutamate or NMDA is time- and concentration-dependent, suggesting that sufficient agonist and time are required to establish an intracellular neuroprotective state. In these cells, the TrkB ligand, brain-derived neurotrophic factor (BDNF) attenuates glutamate toxicity. Therefore, we tested the hypothesis that NMDA protects neurons via a BDNF-dependent mechanism. Exposure of hippocampal cultures to a neuroprotective concentration of NMDA (50 microM) evoked the release of BDNF within 2 min without attendant changes in BDNF protein or gene expression. The accumulated increase of BDNF in the medium is followed by an increase in the phosphorylation (activation) of TrkB receptors and a later increase in exon 4-specific BDNF mRNA. The neuroprotective effect of NMDA was attenuated by pre-incubation with a BDNF-blocking antibody and TrkB-IgG, a fusion protein known to inhibit the activity of extracellular BDNF, suggesting that BDNF plays a major role in NMDA-mediated survival. These results demonstrate that low level stimulation of NMDA receptors protect neurons against glutamate excitotoxicity via a BDNF autocrine loop in hippocampal neurons and suggest that activation of neurotrophin signaling pathways plays a key role in the neuroprotection of NMDA.
Article
The neurotrophin brain-derived neurotrophic factor (BDNF) plays an important role in the activity-dependent regulation of synaptic structure and function, particularly of the glutamatergic synapses. BDNF may be released in the mature form, which activates preferentially TrkB receptors, or as proBDNF, which is coupled to the stimulation of the p75NTR. In the mature form BDNF induces rapid effects on glutamate release, and may induce short- and long-term effects on the postsynaptic response to the neurotransmitter. BDNF may affect glutamate receptor activity by inducing the phosphorylation of the receptor subunits, which may also affect the interaction with intracellular proteins and, consequently, their recycling and localization to defined postsynaptic sites. Stimulation of the local protein synthesis and transcription activity account for the delayed effects of BDNF on glutamatergic synaptic strength. Several evidences show impaired synaptic plasticity of glutamatergic synapses in diseases where compromised BDNF function has been observed, such as Huntington's disease, depression, anxiety, and the BDNF polymorphism Val66Met, suggesting that upregulating BDNF-activated pathways may be therapeutically relevant. This review focuses on recent advances in the understanding of the regulation of the glutamatergic synapse by BDNF, and its implications in synaptic plasticity. British Journal of Pharmacology (2008) 153, S310–S324; doi:10.1038/sj.bjp.0707509; published online 3 December 2007
Article
A diet high in total fat (HF) reduces hippocampal levels of brain-derived neurotrophic factor (BDNF), a crucial modulator of synaptic plasticity, and a predictor of learning efficacy. We have evaluated the capacity of voluntary exercise to interact with the effects of diet at the molecular level. Animal groups were exposed to the HF diet for 2 months with and without access to voluntary wheel running. Exercise reversed the decrease in BDNF and its downstream effectors on plasticity such as synapsin I, a molecule with a key role in the modulation of neurotransmitter release by BDNF, and the transcription factor cyclic AMP response element binding protein (CREB), important for learning and memory. Furthermore, we found that exercise influenced the activational state of synapsin as well as of CREB, by increasing the phosphorylation of these molecules. In addition, exercise prevented the deficit in spatial learning induced by the diet, tested in the Morris water maze. Furthermore, levels of reactive oxygen species increased by the effects of the diet were decreased by exercise. Results indicate that exercise interacts with the same molecular systems disrupted by the HF diet, reversing their effects on neural function. Reactive oxygen species, and BDNF in conjunction with its downstream effectors on synaptic and neuronal plasticity, are common molecular targets for the action of the diet and exercise. Results unveil a possible molecular mechanism by which lifestyle factors can interact at a molecular level, and provide information for potential therapeutic applications to decrease the risk imposed by certain lifestyles.
Article
Flattening the diurnal corticosterone rhythm prevented the stimulating action of L-NAME (a nitric oxide synthase, NOS, inhibitor) on progenitor cell proliferation in the dentate gyrus in Lister-Hooded adult male rats. The increased expression of brain-derived neurotrophic factor (BDNF) and trkB mRNA in the dentate gyrus which otherwise occurred after L-NAME was also prevented by clamping the corticoid rhythm in adrenalectomized rats, but was restored by daily additional injections of corticosterone (which replicates the diurnal rhythm). Unilateral infusions of BDNF into the lateral ventricle increased proliferation in the dentate gyrus on the side of the infusion, but this was not observed following implantation of subcutaneous corticosterone, which flattened the diurnal corticosterone rhythm. 5HT1A mRNA in the dentate gyrus was increased on both sides of the brain by unilateral BDNF infusions, but this was also prevented by subcutaneous corticosterone pellets. These results show that the diurnal rhythm of corticosterone regulates the stimulating action of NOS inhibitors on BDNF as well as on neurogenesis in the dentate gyrus, and that BDNF becomes ineffective on both proliferation rates and 5HT1A expression in the absence of a rhythm in corticosterone. This, together with our previous findings, suggests that corticoid rhythms permit both serotonin and NO access to BDNF, and the latter to regulate progenitor cell activity.
BDNF signaling during olfactory bulb neurogenesis Infrasound-induced changes on sexual behav-ior in male rats and some underlying mechanisms
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Role of brain-derived neurotrophic factor in learning and memory
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Role of the brain-derived neurotrophic factor at glutamatergic synapses
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