Telomerase mediates lymphocyte proliferation but not the atherosclerosis-suppressive potential of regulatory T-cells

Objective: Atherosclerosis is an age-related disease characterised by systemic oxidative stress and low-grade inflammation. The role of telomerase and telomere length in atherogenesis remains contentious. Short telomeres of peripheral leukocytes are predictive for coronary artery disease. Conversely, attenuated telomerase has been demonstrated to be protective for atherosclerosis. Hence a potential causative role of telomerase in atherogenesis is critically debated. Approach and Results: In this study we used multiple mouse models to investigate the regulation of telomerase under oxidative stress as well as its impact on atherogenesis in vitro and in vivo. Using primary lymphocytes and myeloid cell cultures we demonstrate that cultivation under hyperoxic conditions induced oxidative stress resulting in chronic activation of CD4+ cells and significantly reduced CD4+ T-cell proliferation. The latter was telomerase dependent, as oxidative stress had no effect on the proliferation of primary lymphocytes isolated from telomerase-knock-out mice. In contrast, myeloid cell proliferation was unaffected by oxidative stress nor reliant on telomerase. Telomerase reverse transcriptase (TERT) deficiency had no effect on Treg numbers in vivo or suppressive function ex vivo. Adoptive transfer of TERT-/- Tregs into Rag2-/- ApoE-/- double knock out mice demonstrated that telomerase function was not required for the ability of Tregs to protect against atherosclerosis. However, telomere length was critical for Treg function. Conclusions: Telomerase contributes to lymphocyte proliferation but plays no major role in Treg function, provided that telomere length is not critically short. We suggest that oxidative stress may contribute to atherosclerosis via suppression of telomerase and acceleration of telomere attrition in Tregs.This study was supported, in part, by British Heart Foundation Project Grants PG/15/85/31744 and PG/12/47/29681 (www.BHF.org.uk) as well as the Newcastle Healthcare Charity (www.newcastle-hospitals. org.uk/patient-guides/charity-matters-at-newcastle-hospitals_charitable- funds.aspx). N.M. Al Zhrany was funded by a stipend from the Government of Saudi Arabia

Electrophysiological correlates of selective attention: A lifespan comparison

<p>Abstract</p> <p>Background</p> <p>To study how event-related brain potentials (ERPs) and underlying cortical mechanisms of selective attention change from childhood to old age, we investigated lifespan age differences in ERPs during an auditory oddball task in four age groups including 24 younger children (9–10 years), 28 older children (11–12 years), 31 younger adults (18–25), and 28 older adults (63–74 years). In the Unattend condition, participants were asked to simply listen to the tones. In the Attend condition, participants were asked to count the deviant stimuli. Five primary ERP components (N1, P2, N2, P3 and N3) were extracted for deviant stimuli under Attend conditions for lifespan comparison. Furthermore, Mismatch Negativity (MMN) and Late Discriminative Negativity (LDN) were computed as difference waves between deviant and standard tones, whereas Early and Late Processing Negativity (EPN and LPN) were calculated as difference waves between tones processed under Attend and Unattend conditions. These four secondary ERP-derived measures were taken as indicators for change detection (MMN and LDN) and selective attention (EPN and LPN), respectively. To examine lifespan age differences, the derived difference-wave components for attended (MMN and LDN) and deviant (EPN and LPN) stimuli were specifically compared across the four age groups.</p> <p>Results</p> <p>Both primary and secondary ERP components showed age-related differences in peak amplitude, peak latency, and topological distribution. The P2 amplitude was higher in adults compared to children, whereas N2 showed the opposite effect. P3 peak amplitude was higher in older children and younger adults than in older adults. The amplitudes of N3, LDN, and LPN were higher in older children compared with both of the adult groups. In addition, both P3 and N3 peak latencies were significantly longer in older than in younger adults. Interestingly, in the young adult sample P3 peak amplitude correlated positively and P3 peak latency correlated negatively with performance in the Identical Picture test, a marker measure of fluid intelligence.</p> <p>Conclusion</p> <p>The present findings suggest that patterns of event-related brain potentials are highly malleable within individuals and undergo profound reorganization from childhood to adulthood and old age.</p

A Melodic Contour Repeatedly Experienced by Human Near-Term Fetuses Elicits a Profound Cardiac Reaction One Month after Birth

Human hearing develops progressively during the last trimester of gestation. Near-term fetuses can discriminate acoustic features, such as frequencies and spectra, and process complex auditory streams. Fetal and neonatal studies show that they can remember frequently recurring sounds. However, existing data can only show retention intervals up to several days after birth.Here we show that auditory memories can last at least six weeks. Experimental fetuses were given precisely controlled exposure to a descending piano melody twice daily during the 35(th), 36(th), and 37(th) weeks of gestation. Six weeks later we assessed the cardiac responses of 25 exposed infants and 25 naive control infants, while in quiet sleep, to the descending melody and to an ascending control piano melody. The melodies had precisely inverse contours, but similar spectra, identical duration, tempo and rhythm, thus, almost identical amplitude envelopes. All infants displayed a significant heart rate change. In exposed infants, the descending melody evoked a cardiac deceleration that was twice larger than the decelerations elicited by the ascending melody and by both melodies in control infants.Thus, 3-weeks of prenatal exposure to a specific melodic contour affects infants 'auditory processing' or perception, i.e., impacts the autonomic nervous system at least six weeks later, when infants are 1-month old. Our results extend the retention interval over which a prenatally acquired memory of a specific sound stream can be observed from 3-4 days to six weeks. The long-term memory for the descending melody is interpreted in terms of enduring neurophysiological tuning and its significance for the developmental psychobiology of attention and perception, including early speech perception, is discussed

Good vibrations, bad vibrations: Oscillatory brain activity in the attentional blink

The attentional blink (AB) is a deficit in reporting the second (T2) of two targets (T1, T2) when presented in close temporal succession and within a stream of distractor stimuli. The AB has received a great deal of attention in the past two decades because it allows to study the mechanisms that influence the rate and depth of information processing in various setups and therefore provides an elegant way to study correlates of conscious perception in supra-threshold stimuli. Recently evidence has accumulated suggesting that oscillatory signals play a significant role in temporally coordinating information between brain areas. This review focuses on studies looking into oscillatory brain activity in the AB. The results of these studies indicate that the AB is related to modulations in oscillatory brain activity in the theta, alpha, beta, and gamma frequency bands. These modulations are sometimes restricted to a circumscribed brain area but more frequently include several brain regions. They occur before targets are presented as well as after the presentation of the targets. We will argue that the complexity of the findings supports the idea that the AB is not the result of a processing impairment in one particular process or brain area, but the consequence of a dynamic interplay between several processes and/or parts of a neural network

Electrical Brain Responses to an Auditory Illusion and the Impact of Musical Expertise

The presentation of two sinusoidal tones, one to each ear, with a slight frequency mismatch yields an auditory illusion of a beating frequency equal to the frequency difference between the two tones; this is known as binaural beat (BB). The effect of brief BB stimulation on scalp EEG is not conclusively demonstrated. Further, no studies have examined the impact of musical training associated with BB stimulation, yet musicians' brains are often associated with enhanced auditory processing. In this study, we analysed EEG brain responses from two groups, musicians and non-musicians, when stimulated by short presentation (1 min) of binaural beats with beat frequency varying from 1 Hz to 48 Hz. We focused our analysis on alpha and gamma band EEG signals, and they were analysed in terms of spectral power, and functional connectivity as measured by two phase synchrony based measures, phase locking value and phase lag index. Finally, these measures were used to characterize the degree of centrality, segregation and integration of the functional brain network. We found that beat frequencies belonging to alpha band produced the most significant steady-state responses across groups. Further, processing of low frequency (delta, theta, alpha) binaural beats had significant impact on cortical network patterns in the alpha band oscillations. Altogether these results provide a neurophysiological account of cortical responses to BB stimulation at varying frequencies, and demonstrate a modulation of cortico-cortical connectivity in musicians' brains, and further suggest a kind of neuronal entrainment of a linear and nonlinear relationship to the beating frequencies

Auditory event-related potentials

Auditory event related potentials are electric potentials (AERP, AEP) and magnetic fields (AEF) generated by the synchronous activity of large neural populations in the brain, which are time-locked to some actual or expected sound event

Neuronal correlates of auditory stream segregation - a magnetoencephalography study

Background: The ability of humans and animals to focus their attention on a single sound source among other surrounding sounds and background noises is based on the perceptual phenomenon of "fission". Using different types of stimuli (amplitude-modulated or pure tones) we investigated to which extent the percept of streaming (the perceptual segregation of auditory events into separate streams) basing on temporal cues exceeds the peripheral channeling mechanism and correlates with alterations in transient evoked brain responses. Additionally, we investigated the influence of attention on auditory stream segregation.Material and methods: Fifteen subjects (9 females) participated in the study. The stimuli were sequences of repeated triplets, either amplitude modulated (AM) or pure (PT) tone-bursts (A-B-A). Stream segregation basing on spectral cues was modeled varying the fundamental frequency of the B-tone (in PT and AM triplets). Segregation based on temporal cues was achieved varying the modulation frequency of the B-tone in AM triplets. A neuronal correlate (measured by MEG) corresponding to the change in the perception of the sequence due to changes in B-tone was assessed by P1-N1-P2 evoked complex to the B-tone in the triplets. Alterations in the component amplitudes and latencies were correlated with the perception of streaming or non-streaming.Results: We found a significant larger latency of the N1 component in the AM condition for both hemispheres in comparison to PT stimulation, whereas the P1component showed a shorter latency only in the left hemisphere. Furthermore, the amplitude of the P2 component was significantly suppressed in the AM condition compared to a PT stimulation.Discussion: These facts give an evidence for different neuronal mechanisms of auditory streaming basing on spectral and on temporal cues and on a differential specialization of both hemispheres.Conclusion: We suggest a central auditory level of streaming processing additionally to the peripheral level. This model, described as spectral vs. temporal coding of streaming could be used further for tracing the neuronal alterations in speech and hearing disorders.This project has been supported by DFG - DR 807/1-1 and FORUM - F756-201