Adult Plasticity in the Subcortical Auditory Pathway of the Maternal Mouse

Subcortical auditory nuclei were traditionally viewed as non-plastic in adulthood so that acoustic information could be stably conveyed to higher auditory areas. Studies in a variety of species, including humans, now suggest that prolonged acoustic training can drive long-lasting brainstem plasticity. The neurobiological mechanisms for such changes are not well understood in natural behavioral contexts due to a relative dearth of in vivo animal models in which to study this. Here, we demonstrate in a mouse model that a natural life experience with increased demands on the auditory system – motherhood – is associated with improved temporal processing in the subcortical auditory pathway. We measured the auditory brainstem response to test whether mothers and pup-naïve virgin mice differed in temporal responses to both broadband and tone stimuli, including ultrasonic frequencies found in mouse pup vocalizations. Mothers had shorter latencies for early ABR peaks, indicating plasticity in the auditory nerve and the cochlear nucleus. Shorter interpeak latency between waves IV and V also suggest plasticity in the inferior colliculus. Hormone manipulations revealed that these cannot be explained solely by estrogen levels experienced during pregnancy and parturition in mothers. In contrast, we found that pup-care experience, independent of pregnancy and parturition, contributes to shortening auditory brainstem response latencies. These results suggest that acoustic experience in the maternal context imparts plasticity on early auditory processing that lasts beyond pup weaning. In addition to establishing an animal model for exploring adult auditory brainstem plasticity in a neuroethological context, our results have broader implications for models of perceptual, behavioral and neural changes that arise during maternity, where subcortical sensorineural plasticity has not previously been considered.     

Auditory brainstem responses in ground squirrels arousing from hibernation

Summary Auditory brainstem responses (ABRs) were recorded in ground squirrels (Citellus lateralis) arousing from hibernation. Squirrels implanted with recording screws to record ABRs, and a thermistor to record brain temperature, were placed in a cold room at 9 °C on a 2L:22D light-dark cycle. Hibernating animals were moved from the cold room and ABRs recorded during arousal. The responses showed a gradual development of all brainstem peaks.At low temperatures there were very long latencies to the peaks. The amplitudes of the peaks increased (with fluctuations) as brain temperature increased. The data indicate that neural generators on the brainstem auditory pathway were all activated early in arousal.These results do not support the hypothesis that successive peaks appear and grow in amplitude only after previous peaks are fully developed.     

EphB signaling regulates target innervation in the developing and deafferented auditory brainstem

Precision in auditory brainstem connectivity underlies sound localization. Cochlear activity is transmitted to the ventral cochlear nucleus (VCN) in the mammalian brainstem via the auditory nerve. VCN globular bushy cells project to the contralateral medial nucleus of the trapezoid body (MNTB), where specialized axons terminals, the calyces of Held, encapsulate MNTB principal neurons. The VCN-MNTB pathway is an essential component of the circuitry used to compute interaural intensity differences that are used for localizing sounds. When input from one ear is removed during early postnatal development, auditory brainstem circuitry displays robust anatomical plasticity. The molecular mechanisms that control the development of auditory brainstem circuitry and the developmental plasticity of these pathways are poorly understood. In this study we examined the role of EphB signaling in the development of the VCN-MNTB projection and in the reorganization of this pathway after unilateral deafferentation. We found that EphB2 and EphB3 reverse signaling are critical for the normal development of the projection from VCN to MNTB, but that successful circuit assembly most likely relies upon the coordinated function of many EphB proteins. We have also found that ephrin-B reverse signaling repels induced projections to the ipsilateral MNTB after unilateral deafferentation, suggesting that similar mechanisms regulate these two processes.     

Sensory perception and hypothyroidism

Subjective and objective changes in smell and taste perceptionwere evaluated in 16 patients with primary hypothyroidism beforeand after thyroxine (T4) replacement and in 17 control subjects.Visual evoked responses (VER) and brainstem auditory evokedresponses (BAER) were measured in 15 patients. Although 11 ofthe patients reported subjective alterations in smell and tasteand eight of these reported resolution or improvement with euthyroidism,no improvement was found using objective measures (mean follow-up6.4 months) in smell, taste or flavour perception or in visualand auditory brainstem evoked responses. However, on a ‘scratchand sniff’ encapsulated odour identification test, hypothyroidpatients had a significant deficit in detecting and identifyingodours when compared to controls. The possibility that the deficitwas due to age differences between the two groups is discussed.     

Survival, migration, and differentiation of Sox1-GFP embryonic stem cells in coculture with an auditory brainstem slice preparation

The poor regeneration capability of the mammalian hearing organ has initiated different approaches to enhance its functionality after injury. To evaluate a potential neuronal repair paradigm in the inner ear and cochlear nerve we have previously used embryonic neuronal tissue and stem cells for implantation in vivo and in vitro. At present, we have used in vitro techniques to study the survival and differentiation of Sox1-green fluorescent protein (GFP) mouse embryonic stem (ES) cells as a monoculture or as a coculture with rat auditory brainstem slices. For the coculture, 300 microm-thick brainstem slices encompassing the cochlear nucleus and cochlear nerve were prepared from postnatal SD rats. The slices were propagated using the membrane interface method and the cochlear nuclei were prelabeled with DiI. After some days in culture a suspension of Sox1 cells was deposited next to the brainstem slice. Following deposition Sox1 cells migrated toward the brainstem and onto the cochlear nucleus. GFP was not detectable in undifferentiated ES cells but became evident during neural differentiation. Up to 2 weeks after transplantation the cocultures were fixed. The undifferentiated cells were evaluated with antibodies against progenitor cells whereas the differentiated cells were determined with neuronal and glial markers. The morphological and immunohistochemical data indicated that Sox1 cells in monoculture differentiated into a higher percentage of glial cells than neurons. However, when a coculture was used a significantly lower percentage of Sox1 cells differentiated into glial cells. The results demonstrate that a coculture of Sox1 cells and auditory brainstem present a useful model to study stem cell differentiation.     

Sequential mapping favours the hypothesis of distinct generators for Na and Pa middle latency auditory evoked potentials

The temporo-spatial organization of Na and Pa middle latency auditory components evoked by monaural clicks delivered separately to right and left ears was assessed by sequential mapping of scalp potentials. The potential field distribution was found to be different for the two components and was assessed by calculating the maximal potential differences in the Na/Pa time period. These data are compatible with the hypothesis that distinct generators are responsible for the two components. Scalp potential field configuration observed for Na suggests a deep generator, which could be situated at the mesencephalic or diencephalic level. Bilateral cortical generators tangentially orientated satisfactorily account for the distribution of the Pa potential field, which could be related to simultaneous activation of both supratemporal auditory cortices in response to monaural stimulation.     

Approche empirique pour déterminer les générateurs neurophysiologiques sous-jacents des potentiels évoqués auditifs engendrés par des sons de parole (Speech ABR)

Auditory evoked potentials to speech (Speech auditory brainstem response [Speech ABR]) are a non-invasive way to investigate neurophysiological activity, at the level of the brainstem. The Speech ABR precise neurophyiological generators remain poorly defined. However, latencies and low-pass spectrum both suggest that these generators might lie in the upper brainstem (roughly between the cochlear nucleus and the inferior colliculus). Having considered the particular functional pattern of cells along the auditory pathway, specific stimuli have been synthesized to make out the acoustic sensitivity of Speech ABR components. Accordingly, hypotheses have been made on the probable neurophysiological generators, most likely to have elicited both Speech ABR components: onset response and frequency following response. Speech ABR have been recorded to pure tones, harmonic complex tones, /ba/ and /pa/ syllables, and their analogues (calculated as a sum of five weighted sine waves at the formant frequencies and amplitudes, and modulated by the syllables temporal envelopes). In addition, the Auditory Image Model (Patterson et al., 1995 [17]), simulating the neural activity at the auditory periphery, i.e. inferior colliculus input, suggests that both analogues and syllables elicit the same amount of energy, in contrast to the recorded FFR. This contradiction means that the neurophysiological signal processing leading to FFR is made beyond auditory periphery. Indeed, FFR synchronisation on F0 seems to be the result of an overall processing of the whole stimulus spectrum. This behaviour reminds the functional characteristics of disc-shape cells in the inferior colliculus, as described in a previous study of physiological periodicity coding (Periodicity analysis network, Voutsas et al., 2005 [42]).     

Structural Changes and Lack of HCN1 Channels in the Binaural Auditory Brainstem of the Naked Mole-Rat (Heterocephalus glaber)

Naked mole-rats (Heterocephalus glaber) live in large eu-social, underground colonies in narrow burrows and are exposed to a large repertoire of communication signals but negligible binaural sound localization cues, such as interaural time and intensity differences. We therefore asked whether monaural and binaural auditory brainstem nuclei in the naked mole-rat are differentially adjusted to this acoustic environment. Using antibody stainings against excitatory and inhibitory presynaptic structures, namely the vesicular glutamate transporter VGluT1 and the glycine transporter GlyT2 we identified all major auditory brainstem nuclei except the superior paraolivary nucleus in these animals. Naked mole-rats possess a well structured medial superior olive, with a similar synaptic arrangement to interaural-time-difference encoding animals. The neighboring lateral superior olive, which analyzes interaural intensity differences, is large and elongated, whereas the medial nucleus of the trapezoid body, which provides the contralateral inhibitory input to these binaural nuclei, is reduced in size. In contrast, the cochlear nucleus, the nuclei of the lateral lemniscus and the inferior colliculus are not considerably different when compared to other rodent species. Most interestingly, binaural auditory brainstem nuclei lack the membrane-bound hyperpolarization-activated channel HCN1, a voltage-gated ion channel that greatly contributes to the fast integration times in binaural nuclei of the superior olivary complex in other species. This suggests substantially lengthened membrane time constants and thus prolonged temporal integration of inputs in binaural auditory brainstem neurons and might be linked to the severely degenerated sound localization abilities in these animals.     

Deletion of Fmr1 Alters Function and Synaptic Inputs in the Auditory Brainstem

Fragile X Syndrome (FXS), a neurodevelopmental disorder, is the most prevalent single-gene cause of autism spectrum disorder. Autism has been associated with impaired auditory processing, abnormalities in the auditory brainstem response (ABR), and reduced cell number and size in the auditory brainstem nuclei. FXS is characterized by elevated cortical responses to sound stimuli, with some evidence for aberrant ABRs. Here, we assessed ABRs and auditory brainstem anatomy in Fmr1^-/- mice, an animal model of FXS. We found that Fmr1^-/- mice showed elevated response thresholds to both click and tone stimuli. Amplitudes of ABR responses were reduced in Fmr1^-/- mice for early peaks of the ABR. The growth of the peak I response with sound intensity was less steep in mutants that in wild type mice. In contrast, amplitudes and response growth in peaks IV and V did not differ between these groups. We did not observe differences in peak latencies or in interpeak latencies. Cell size was reduced in Fmr1^-/- mice in the ventral cochlear nucleus (VCN) and in the medial nucleus of the trapezoid body (MNTB). We quantified levels of inhibitory and excitatory synaptic inputs in these nuclei using markers for presynaptic proteins. We measured VGAT and VGLUT immunolabeling in VCN, MNTB, and the lateral superior olive (LSO). VGAT expression in MNTB was significantly greater in the Fmr1^-/- mouse than in wild type mice. Together, these observations demonstrate that FXS affects peripheral and central aspects of hearing and alters the balance of excitation and inhibition in the auditory brainstem.     

Distribution of metabolic activity (cytochrome oxidase) and immunoreactivity to calcium-binding proteins in turtle brainstem auditory nuclei

Using histochemical and immunohistochemical techniques, distribution of activity of oxidative mitochondrial enzyme cytochrome oxidase (CO) and of immunoreactivity to calcium-binding proteins has been studied in spiral ganglion and auditory nuclei of brainstem in two turtle species. It has been shown that immunoreactivity to calbindin, parvalbumin, and calretinin in neurons and neuropil of nuclei of cochlear and superior olivary complexes, in nucleus of lateral lemniscus, and in spiral ganglion neurons coincides topographically with the high CO activity. The similarity of the studied metabolic and neurochemical characteristics of these auditory centers in reptiles, birds, and mammals indicates the existence of some common principles of their organization in amniotes in spite of phylogenetic differences and peculiarities of specialization of the auditory system in different species.     

Loss of Central Auditory Processing in a Mouse Model of Canavan Disease

Canavan Disease (CD) is a leukodystrophy caused by homozygous null mutations in the gene encoding aspartoacylase (ASPA). ASPA-deficiency is characterized by severe psychomotor retardation, and excessive levels of the ASPA substrate N-acetylaspartate (NAA). ASPA is an oligodendrocyte marker and it is believed that CD has a central etiology. However, ASPA is also expressed by Schwann cells and ASPA-deficiency in the periphery might therefore contribute to the complex CD pathology. In this study, we assessed peripheral and central auditory function in the Aspa^lacZ/lacZ rodent model of CD using auditory brainstem response (ABR). Increased ABR thresholds and the virtual loss of waveform peaks 4 and 5 from Aspa^lacZ/lacZ mice, indicated altered central auditory processing in mutant mice compared with Aspa^wt/wt controls and altered central auditory processing. Analysis of ABR latencies recorded from Aspa^lacZ/lacZ mice revealed that the speed of nerve conduction was unchanged in the peripheral part of the auditory pathway, and impaired in the CNS. Histological analyses confirmed that ASPA was expressed in oligodendrocytes and Schwann cells of the auditory system. In keeping with our physiological results, the cellular organization of the cochlea, including the organ of Corti, was preserved and the spiral ganglion nerve fibres were normal in ASPA-deficient mice. In contrast, we detected substantial hypomyelination in the central auditory system of Aspa^lacZ/lacZ mice. In summary, our data suggest that the lack of ASPA in the CNS is responsible for the observed hearing deficits, while ASPA-deficiency in the cochlear nerve fibres is tolerated both morphologically and functionally.     

Neurodynamics, tonality, and the auditory brainstem response

Tonal relationships are foundational in music, providing the basis upon which musical structures, such as melodies, are constructed and perceived. A recent dynamic theory of musical tonality predicts that networks of auditory neurons resonate nonlinearly to musical stimuli. Nonlinear resonance leads to stability and attraction relationships among neural frequencies, and these neural dynamics give rise to the perception of relationships among tones that we collectively refer to as tonal cognition. Because this model describes the dynamics of neural populations, it makes specific predictions about human auditory neurophysiology. Here, we show how predictions about the auditory brainstem response (ABR) are derived from the model. To illustrate, we derive a prediction about population responses to musical intervals that has been observed in the human brainstem. Our modeled ABR shows qualitative agreement with important features of the human ABR. This provides a source of evidence that fundamental principles of auditory neurodynamics might underlie the perception of tonal relationships, and forces reevaluation of the role of learning and enculturation in tonal cognition.     

Brain-stem auditory evoked response: normative values in children

Normative values of brain-stem auditory evoked response (BAER) derived from a large (N = 174) normal school age sample are presented. In our 4–14 years of age sample we found a significant influence of sex on some BAER components, and a significant influence of age on others. The norms have been computed according to these influences. Particular aspects of the influence of age and sex are also discussed.     

耳蜗微音电位数学模型及其应用——一种分离听神经动作电位的新方法

本文用生物控制论方法研究声波—耳蜗微音电位系统,建立了该系统的数学模型,提出了一种以此为基础的分离听神经动作电位的新方法.在耳蜗电位中将该模型预测出的微音电位成份减掉,便得到单独的听神经动作电位.与国内外通行使用的声音交替倒相迭加法相比,本文提出的方法有不改变听神经发放时间,可用于较复杂声音引起的耳蜗电位分析等优点,对听觉生理基础研究和耳科临床实践都有实用意义,对人工耳蜗声电特性的设计也提供了依据.     

A Connectionist Model of Left-Right Sound Discrimination by the Mauthner System

Artificial neural networks were used to explore the auditory function of the Mauthner system, the brainstem circuit in teleost fishes that initiates fast-start escape responses. The artificial neural networks were trained with backpropagation to assign connectivity and receptive fields in an architecture consistent with the known anatomy of the Mauthner system. Our first goal was to develop neurally specific hypotheses for how the Mauthner system discriminates right from left in the onset of a sound. Our model was consistent with the phase model for directional hearing underwater, the prevalent theory for sound source localization by fishes. Our second goal was to demonstrate how the neural mechanisms that permit sound localization according to the phase model can coexist with the mechanisms that permit the Mauthner system to discriminate between stimuli based on amplitude. Our results indicate possible computational roles for elements of the Mauthner system, which has provided us a theoretical context within which to consider past and future experiments on the cellular physiology. Thus, these findings demonstrate the potential significance of this approach in generating experimentally testable hypotheses for small systems of identified cells.     

On the Relevance of Natural Stimuli for the Study of Brainstem Correlates: The Example of Consonance Perception

Some combinations of musical tones sound pleasing to Western listeners, and are termed consonant, while others sound discordant, and are termed dissonant. The perceptual phenomenon of consonance has been traced to the acoustic property of harmonicity. It has been repeatedly shown that neural correlates of consonance can be found as early as the auditory brainstem as reflected in the harmonicity of the scalp-recorded frequency-following response (FFR). “Neural Pitch Salience” (NPS) measured from FFRs—essentially a time-domain equivalent of the classic pattern recognition models of pitch—has been found to correlate with behavioral judgments of consonance for synthetic stimuli. Following the idea that the auditory system has evolved to process behaviorally relevant natural sounds, and in order to test the generalizability of this finding made with synthetic tones, we recorded FFRs for consonant and dissonant intervals composed of synthetic and natural stimuli. We found that NPS correlated with behavioral judgments of consonance and dissonance for synthetic but not for naturalistic sounds. These results suggest that while some form of harmonicity can be computed from the auditory brainstem response, the general percept of consonance and dissonance is not captured by this measure. It might either be represented in the brainstem in a different code (such as place code) or arise at higher levels of the auditory pathway. Our findings further illustrate the importance of using natural sounds, as a complementary tool to fully-controlled synthetic sounds, when probing auditory perception.     

耳蜗电图慢波电位

采用同极双道同步记录法对比观察了豚鼠耳蜗电图慢波电位和快波电位的波形;测量了慢波电位的潜伏期、波幅和阈值;并与快波电位的阈值进行了比较。结果表明,慢波电位不但对高频声音反应好,而且对低频声音反应也很好,反应闽都在OdBnHL以下,因而弥补了快波电位对低频声音反应闽值高的缺陷,解决了耳蜗电图低频检测的难题。作者认为,慢波电位主要来源于听神经动作电位的慢成分,其次是听觉脑干诸核团的慢成分。慢波电位是反映频率和强度特性的理想指标,在科研及临床实践中应用将是很有前途的。     

Differential impact of hypothermia and pentobarbital on brain-stem auditory evoked responses

Two experiments were conducted to determine the effects of hypothermia and pentobarbital anesthesia, alone and in combination, on the brain-stem auditory evoked responses (BAERs) of rats. In experiment I, unanesthetized rats were cooled to colonic temperatures 0.5 and 1.0°C below normal. In experiment II, 2 groups of rats were cooled and tested at 37.5, 36.0, 34.5 and 31.5°C. One group was anesthetized during testing and the other group was awake. The rat BAER was sensitive to cooling of 1°C or less. Peak latencies were prolonged and peak-to-peak amplitudes were increased by hypothermia alone. The effect on amplitude may be related to the time course of temperature change or to stimulus level. Pentobarbital significantly affected both latencies and amplitudes over and above the effects of cooling. The specific effects of pentobarbital differed by BAER peak and by temperature. The findings point up the importance of the potential confound of anesthetic drugs in most of the evoked potential literature on hypothermia and, for the first time, quantify the complex interactions between pentobarbital and temperature which affect the BAER wave form.     

促红细胞生成素对脑损伤早产儿NBNA评分、肝肾功能以及脑干听觉诱发电位的影响

目的:探讨促红细胞生成素(EPO)对脑损伤早产儿新生儿神经行为测定(NBNA)评分、肝肾功能以及脑干听觉诱发电位的影响。方法:选取2015年2月~2018年7月期间我院收治的脑损伤早产儿117例,将上述研究对象根据随机数字表法将其分为对照组(n=58)和观察组(n=59),对照组患儿给予常规对症治疗,观察组在对照组的基础上联合EPO治疗,比较两组NBNA评分、肝肾功能以及脑干听觉诱发电位,记录两组患儿治疗期间并发症发生情况。结果:观察组纠正胎龄40周时NBNA评分高于对照组(P<0.05)。两组患儿治疗后峰间期(Ⅰ~Ⅲ波、Ⅲ~Ⅳ波、Ⅰ~Ⅳ波)、潜伏期(Ⅰ波、Ⅲ波、Ⅳ波)均较治疗前降低,且观察组低于对照组(P<0.05)。两组患儿治疗前、后尿素氮(BUN)、肌酐(Cr)、血清谷丙转氨酶(SGPT)、总胆红素(TBIL)比较差异均无统计学意义(P>0.05)。两组患儿动脉导管未闭、新生儿败血症发生率比较差异无统计学意义(P>0.05),而观察组支气管肺发育不良、颅内出血、脑干听觉诱发电位异常等发生率低于对照组(P<0.05)。结论:EPO对脑损伤早产儿具有一定的神经保护作用,能够有效保护受损神经细胞与听觉神经通路,降低脑损伤并发症的发生率,且不影响患儿的肝肾功能。     

The role of transients in auditory processing

Enhancement of auditory transients is well documented in the auditory periphery and mid-brain, and single unit investigations have identified units with responses which may underlie this sensitivity. It is also known that transients are important in psychophysics in, for example, speech comprehension and object recognition and grouping. In this work we use a simple phenomenological model of auditory transient extraction, based on the skewness of the distribution of energy inside a frequency dependent time window, and show that this view is consistent with electrophysiological measurements of auditory brainstem responses. In addition, we present evidence that this representation may provide a positive biological advantage in processing classes of sound that are behaviourlly relevant.