Coding of envelope modulation in the auditory nerve and anteroventral cochlear nucleus.

We have investigated responses of the auditory nerve fibres (ANFS) and anteroventral cochlear nucleus (AVCN) units to narrowband 'single-formant' stimuli (SFSS). We found that low and medium spontaneous rate (SR) ANFS maintain greater amplitude modulation (AM) in their responses at high sound levels than do high SR units when sound level is considered in dB SPL. However, this partitioning of high and low SR units disappears if sound level is considered in dB relative to unit threshold. Stimuli with carrier frequencies away from unit best frequency (BF) were found to generate higher AM in responses at high sound levels than that observed even in most low and medium SR units for stimuli with carrier frequencies near BF. AVCN units were shown to have increased modulation depth in their responses when compared with high SR ANFS with similar BFS and to have increased or comparable modulation depth when compared with low SR ANFS. At sound levels where AM almost completely disappears in high SR ANFS, most AVCN units we studied still show significant AM in their responses. Using a dendritic model, we investigated possible mechanisms of enhanced AM in AVCN units, including the convergence of inputs from different SR groups of ANFS and a postsynaptic threshold mechanism in the soma.     

Multidimensional characterization and differentiation of neurons in the anteroventral cochlear nucleus

Multiple parallel auditory pathways ascend from the cochlear nucleus. It is generally accepted that the origin of these pathways are distinct groups of neurons differing in their anatomical and physiological properties. In extracellular in vivo recordings these neurons are typically classified on the basis of their peri-stimulus time histogram. In the present study we reconsider the question of classification of neurons in the anteroventral cochlear nucleus (AVCN) by taking a wider range of response properties into account. The study aims at a better understanding of the AVCN's functional organization and its significance as the source of different ascending auditory pathways. The analyses were based on 223 neurons recorded in the AVCN of the Mongolian gerbil. The range of analysed parameters encompassed spontaneous activity, frequency coding, sound level coding, as well as temporal coding. In order to categorize the unit sample without any presumptions as to the relevance of certain response parameters, hierarchical cluster analysis and additional principal component analysis were employed which both allow a classification on the basis of a multitude of parameters simultaneously. Even with the presently considered wider range of parameters, high number of neurons and more advanced analytical methods, no clear boundaries emerged which would separate the neurons based on their physiology. At the current resolution of the analysis, we therefore conclude that the AVCN units more likely constitute a multi-dimensional continuum with different physiological characteristics manifested at different poles. However, more complex stimuli could be useful to uncover physiological differences in future studies.     

Model of discharge patterns of units in the cochlear nucleus in response to steady state and time-varying sounds

A model for the coding of sounds in the discharge pattern of single neurons in the auditory periphery is described. The model consists of a non-linear differential equation and a conventional diffusion neuron model. The same model describes 1) the unit interspike interval distribution in response to continuous stimulation, 2) the response to tone bursts, as well as 3) the responses to sinusoidally amplitude-modulated stimuli. The parameters of the model are determined quantitatively for each neuron. The responses of a certain unit can be described by 5 parameters.     

Frequency sensitivity of auditory neurons in the Caiman cochlear nucleus

Summary The characteristic frequencies of single auditory neurons in Caiman crocodilus (South American Alligator) range from 70 to 2,900 Hz. These neurons in the cochlear nuclei show a striking tonotopic organization which parallels that in birds. The sensitivity curve of all neurons and the number of neurons in each frequency range show features similar to those of birds and mammals.Supported by NSF. grant GB 5697. I thank Dr. Mark Konishi for overseeing this work.     

Harmonic analysis of two-tone discharge patterns in cochlear nerve fibers

Discharges in cochlear nerve fibers evoked by low frequency phase-locked sinusoidal acoustic stimuli are synchronized to the stimulus waveform. Excitation and suppression regions of single units were explored using a stimulus composed of either a fixed intensity test tone at the characteristic frequency, a variable intensity interfering tone with a simple integer frequency relation to the characteristic frequency, or both. Compound period histograms were constructed from period histograms in response to normal and reversed polarity stimuli. Discharge patterns were characterized by Fourier components of the histogram envelopes. The two stimulus frequencies constituted the principal harmonics in the histogram envelopes and their combination accounted for observed rate changes. Suppression of the test tone harmonic as a function of interfering tone intensity was always seen; rate suppression was not. The harmonic was typically suppressed by 20–30 dB compared to the value for the test tone alone and often reached the 40–60 dB resolution limit of the experiment. Suppression plots were nearly linear on a power scale with an average slope of-0.8. The onset of suppression occurred for an interfering tone 9 dB greater on average than the test tone intensity. Information transfer through the peripheral system was described by the ratio of the principal harmonic amplitudes versus the ratio of the intensities of the two stimulus tones. These plots were nearly linear on a power scale with an average slope of 0.9. Neither the onset of suppression nor the slopes of the harmonic plots displayed strong dependence on characteristic frequency or interfering tone frequency. These features of harmonic behavior, however, are closely related to system nonlinearity. Comparison of measured harmonics to the predictions of two phenomenological models suggest the presence of complex nonlinear transformations in the peripheral auditory system.     

海马脑片癫痫样放电时空特性的多电极记录研究

为了探索离体条件下癫痫样放电的时空特性,本研究采用多电极记录系统记录高钾人工脑脊液(artificial cerebrospinal fluid,ACSF)诱导的幼年大鼠海马脑片的自发放电活动。在成功诱导出癫痫样的簇样放电后,加入苯巴比妥钠以观察其对脑片各区域放电的压抑作用。结果显示:(1)高钾ACSF持续灌流脑片15min左右,多电极阵列上可记录到海马CA3(a~c)和CA1区反复出现同步节律的癫痫样簇样放电,与脑电信号中的发作间期痫性放电相似;定量分析结果提示,CA区各个亚区锥体细胞的活动特性无明显差异(P0.05),而齿状回(dentate gyrus,DG)颗粒细胞层没有出现簇样放电,仅有少量动作电位发放,发放频率远低于CA区(P0.05);(2)在持续高钾灌流下,稳定的簇样放电一旦建立即可至少持续40min;(3)簇样放电发放稳定后给予60μmol/L苯巴比妥钠,发现同步化放电的区域逐渐缩小,CA1和CA3c区的放电活动首先被压抑,而CA3a和b区的部分锥体细胞在加药10min后仍有较强的簇样放电。以上结果提示,多电极阵列能够有效地用于研究离体条件下癫痫样放电的时空特性,并可探索抗癫痫药对脑片不同区域癫痫样活动的作用。     

Types of thalamo-cortical relay neurons in the anteroventral nucleus of the cat

Summary Neurons displaying a thalamo-cortical projection were marked by means of the retrograde transport of horseradish peroxidase (HRP), and the labeled elements were compared with neurons impregnated by the Golgi technique. Injections of HRP into the posterior area of the limbic cortex resulted in its uptake by various anterior thalamic nuclei, especially the anteroventral nucleus. HRP-positive cells are characterized by their position, dendritic orientation, and the shape and size of their somata. On the basis of the combined HRP- and Golgi-analysis three different types of thalamo-cortical relay neurons can be distinguished.     

Neural organization and responses to complex stimuli in the dorsal cochlear nucleus.

The dorsal division of the cochlear nucleus (DCN) is the most complex of its subdivisions in terms of both anatomical organization and physiological response types. Hypotheses about the functional role of the DCN in hearing are as yet primitive, in part because the organizational complexity of the DCN has made development of a comprehensive and predictive model of its input-output processing difficult. The responses of DCN cells to complex stimuli, especially filtered noise, are interesting because they demonstrate properties that cannot be predicted, without further assumptions, from responses to narrow band stimuli, such as tones. In this paper, we discuss the functional organization of the DCN, i.e. the morphological organization of synaptic connections within the nucleus and the nature of synaptic interactions between its cells. We then discuss the responses of DCN principal cells to filtered noise stimuli that model the spectral sound localization cues produced by the pinna. These data imply that the DCN plays a role in interpreting sound localization cues; supporting evidence for such a role is discussed.     

Modelling the spatiotemporal dynamics of chemovirotherapy cancer treatment

Chemovirotherapy is a combination therapy with chemotherapy and oncolytic viruses. It is gaining more interest and attracting more attention in the clinical setting due to its effective therapy and potential synergistic interactions against cancer. In this paper, we develop and analyse a mathematical model in the form of parabolic non-linear partial differential equations to investigate the spatiotemporal dynamics of tumour cells under chemovirotherapy treatment. The proposed model consists of uninfected and infected tumour cells, a free virus, and a chemotherapeutic drug. The analysis of the model is carried out for both the temporal and spatiotemporal cases. Travelling wave solutions to the spatiotemporal model are used to determine the minimum wave speed of tumour invasion. A sensitivity analysis is performed on the model parameters to establish the key parameters that promote cancer remission during chemovirotherapy treatment. Model analysis of the temporal model suggests that virus burst size and virus infection rate determine the success of the virotherapy treatment, whereas travelling wave solutions to the spatiotemporal model show that tumour diffusivity and growth rate are critical during chemovirotherapy. Simulation results reveal that chemovirotherapy is more effective and a good alternative to either chemotherapy or virotherapy, which is in agreement with the recent experimental studies.     

Neural coding in the chick cochlear nucleus

Physiological recordings were made from single units in the two divisions of the chick cochlear nucleus-nucleus angularis (NA) and nucleus magnocellularis (NM). Sound evoked responses were obtained in an effort to quantify functional differences between the two nuclei. In particular, it was of interest to determine if nucleus angularis and magnocellularis code for separate features of sound stimuli, such as temporal and intensity information. The principal findings are: 1. Spontaneous activity patterns in the two nuclei are very different. Neurons in nucleus angularis tend to have low spontaneous discharge rates while magnocellular units have high levels of spontaneous firing. 2. Frequency tuning curves recorded in both nuclei are similar in form, although the best thresholds of NA units are about 10 dB more sensitive than their NM counterparts across the entire frequency range. A wide spread of neural thresholds is evident in both NA and NM. 3. Large driven increases in discharge rate are seen in both NA and NM. Rate intensity functions from NM units are all monotonic, while a substantial percentage (22%) of NA units respond to increased sound level in a nonmonotonic fashion. 4. Most NA units with characteristic frequencies (CF) above 1000 Hz respond to sound stimuli at CF as 'choppers', while units with CF's below 1000 Hz are 'primary-like'. Several 'onset' units are also seen in NA. In contrast, all NM units show 'primary-like' response. 5. Units in both nuclei with CF's below 1000 Hz show strong neural phase-locking to stimuli at their CF. Above 1000 Hz, few NA units are phase-locked, while phase-locking in NM extends to 2000 Hz. 6. These results are discussed with reference to the hypothesis that NM initiates a neural pathway which codes temporal information while NA is involved primarily with intensity coding, similar in principle to the segregation of function seen in the cochlear nucleus of the barn owl (Sullivan and Konishi 1984).     

Oscillating neurons in the cochlear nucleus: II. Simulation results

A computer model of sustained chopper neurons in the ventral cochlear nucleus is presented and investigated. In the companion paper, the underlying neurophysiological and neuroanatomical data are demonstrated. To explain the preference of chopper neurons for oscillations with periods which are multiples of a 0.4 ms synaptic delay, we suggest a model of circularly connected chopper neurons. In order to simulate chopper neurons within a physiological dynamic range for periodicity encoding, it is necessary to assume that they receive an input from onset neurons. Our computer analysis of the resulting simple neuronal network shows that it can produce stable oscillations. The chopping can be triggered by an amplitude-modulated signal (AM). The dynamic range and the synchronous response of the simulated chopper neurons to AM are enhanced significantly by an additional input from onset neurons. Physiological properties of chopper neurons in the cat, such as mean, standard deviation, and coefficient of variation of the interspike interval are matched precisely by our simulations.     

Neural response to very low-frequency sound in the avian cochlear nucleus

Recordings were made in the chick cochlear nucleus from neurons that are sensitive to very low frequency sound. The tuning, discharge rate response and phase-locking properties of these units are described in detail. The principal conclusions are: 1. Low frequency (LF) units respond to sound frequencies between 10-800 Hz. Best thresholds average 60 dB SPL, and are occasionally as low as 40 dB SPL. While behavioral thresholds in this frequency range are not available for the domestic chick, these values are in good agreement with the pigeon behavioral audiogram (Kreithen and Quine 1979). 2. About 60% of the unit population displays tuning curves resembling low-pass filter functions with corner frequencies between 50-250 Hz. The remaining units have broad band-pass tuning curves. Best frequencies range from 50-300 Hz. 3. Spontaneous discharge rate was analyzed quantitatively for LF units recorded from nucleus angularis. The distribution of spontaneous rates for LF units is similar to that seen from higher CF units (300-5000 Hz) found in the same nucleus. However, the spontaneous firing of LF units is considerably more regular than that of their higher CF counterparts. 4. Low frequency units with low spontaneous rates (SR's less than 40 spikes/s) show large driven rate increases and usually saturate by discharging once or twice per stimulus cycle. Higher SR units often show no driven rate increases. 5. All LF units show strong phase-locking at all excitatory stimulus frequencies. Vector strengths as high as 0.98 have been observed at moderate sound levels. 6. The preferred phase of discharge (relative to the sound stimulus) increases with stimulus frequency in a nearly linear manner. This is consistent with the LF units being stimulated by a traveling wave. The slope of these phase-frequency relationships provides an estimate of traveling wave delay. These delays average 7.2 ms, longer than those seen for higher CF auditory brainstem units. These observations suggest that the peripheral site of low frequency sensitivity is the very distal region of the basilar papilla, an area whose morphology differs significantly from the rest of the chick basilar papilla. 7. LF units are described whose response to sound is inhibitory at frequencies above 50 Hz.     

Hair cell physiology and the feature extraction in the cochlear nucleus.

The author examines hair cell physiology and mechanisms of signal transduction in the cochlear nucleus. He reports studies of avian auditory nerve fiber firing frequency and firing patterns.     

The kinetics of the response to glutamate and kainate in neurons of the avian cochlear nucleus.

Neurons in the nucleus magnocellularis (nMAG) of the chicken precisely transmit auditory nerve activity via glutamatergic synapses. Using techniques for rapid application of solutions, we have explored the properties of CNQX-sensitive glutamate receptors in whole cells and outside-out patches from the nMAG. Glutamate-evoked current in patches desensitized biphasically to less than 1% of the peak current, with a fast time constant of 960 microseconds at 22 degrees C, decreasing to 570 microseconds at 33 degrees C. Dose-response studies using kainate indicated that at least two agonist molecules bind to gate the channel. We propose a kinetic model that quantitatively describes our experimental observations. The rapid kinetics of this receptor are well suited to allow phase locking of synaptic signals to auditory stimuli.     

Isolation and characterization of neural stem cells from the neonatal rat cochlear nucleus

Neural stem cells have been identified in multiple parts of the postnatal mammalian brain, as well as in the inner ear. No investigation of potential neural stem cells in the cochlear nucleus has yet been performed. The aim of this study was to investigate potential neural stem cells from the cochlear nucleus by neurosphere assay and in histological sections to prove their capacity for self-renewal and for differentiation into progenitor cells and cells of the neuronal lineage. For this purpose, cells of the cochlear nucleus of postnatal day 6 rats were isolated and cultured for generation of primary neurospheres. Spheres were dissociated and cells analyzed for capacity for mitosis and differentiation. Cell division was detected by cell-counting assay and BrdU incorporation. Differentiated neural progenitor cells showed distinct labeling for Nestin and for Atoh1. Positive staining of ß-III Tubulin, glial fibrillary acid protein (GFAP) and myelin basic protein (MBP) showed differentiation into neurons, astrocytes and oligodendrocytes. Furthermore, Nestin- and BrdU-labeled cells could also be detected in histological sections. In conclusion, the isolated cells from the cochlear nucleus presented all the features of neural stem cells: cell division, presence of progenitor cells and differentiation into different cells of the neuronal lineage. The existence of neural stem cells may add to the understanding of developmental features in the cochlear nucleus.     

Thresholds of cat cochlear nucleus neurons to microwave pulses

Action potentials of neurons in cat dorsal and posteroventral cochlear nuclei were recorded extracellularly with glass microelectrodes while the head of the cat was exposed to microwave pulses at 915 MHz using a diathermy applicator. Response thresholds to acoustic tones, acoustic clicks, and microwave pulses were determined for auditory units with characteristic frequencies (CFs) from 278 Hz to 39.2 kHz. Tests with pulsatile stimuli were performed for durations of 20-700 mus, principally 20, 70, and 200 mus. Brainstem midline specific absorption rate (SAR) threshold was as small as 11.1 mW/g per pulse, and specific absorption (SA) threshold was a small as 0.6 muJ/g per pulse. Microwave thresholds were generally lower for CF less than 9 kHz, as were most acoustic thresholds. However, microwave threshold was only weakly related to click threshold and CF-tone threshold of each unit.     

Expression of estrogen receptor {alpha} in the anteroventral periventricular nucleus of hypogonadal mice

Gonadotropin-releasing hormone-1 (GnRH-1) neurons play critical roles in the development and maintenance of reproductive function in all vertebrates. Due to a truncation in the GnRH-1 gene, hypogonadal (hpg) mice are unable to synthesize GnRH-1 and are infertile. These animals develop in the complete absence of exposure to gonadal steroid hormones, making them an interesting model for understanding brain sexual differentiation and dimorphism. We studied expression of the estrogen receptors (ERs) alpha and beta in the medial anteroventral periventricular nucleus (mAVPV), an important reproductive neuroendocrine brain region, in wild-type and hpg mice of both sexes. Adult wild-type and hpg mice of the same genetic background were used to quantify numbers of ERalpha and ERbeta immunoreactive cells in the mAVPV using a stereologic approach. Quantitative analyses showed that ERalpha cell numbers were significantly higher in hpg than wild-type mice, irrespective of sex. Qualitatively, ERalpha-immunoreactive cells were concentrated more densely along the ventricular zone of the AVPV of wild-type female mice compared with wild-type male mice or hpg male and female mice. No ERbeta-immunoreactive cells were detected in the mAVPV of any mice, a result that was surprising because ERbeta expression is abundant in the mAVPV of rats. These results on ERalpha provide additional evidence that the female brain is not the "default" organizational pattern, because neither ERalpha cell number nor its distribution in hpg mice, which develops with a deficiency of reproductive hormones, resembles that of the wild-type female mouse. Differences in ERalpha expression may be due in part to the absence of gonadal steroid hormones, although they more likely to also involve other factors, potentially GnRH itself.