Glycoconjugates in the mammalian auditory system

Cell-surface glycoconjugates, such as proteoglycans, glycoproteins, and glycosphingolipids have been suggested to serve important functions in hearing because of their variety and their specific expression patterns during the development and maturation of cochlea. However, there has been no definitive proof regarding their involvement in auditory functions. In this study, we provide an overview of the expression of glycoconjugates in auditory systems and consider their possible involvement in hearing functions. We include our recent findings regarding deafness in ganglioside (sialic acid containing glycosphingolipids)-deficient mice, and address the importance of functional glycobiology in auditory systems.     

A model of the peripheral auditory system

Summary Recent electrophysiological data obtained from auditory nerve fibers of cats have made possible the formulation of a model of the peripheral auditory system that relates the all-or-none activity of these fibers to acoustic stimulation. The components of the model are intended to represent the major functional components of the peripheral system. These components are: (i) a linear mechanical system intended to represent the outer, middle, and mechanical parts of the inner ear; (ii) a transducer intended to represent the action of the sensory cells; and (iii) a model neuron whose properties are intended to represent the nerve excitation process. A general-purpose digital computer has been used to determine the response of the model to a variety of acoustic stimuli. These results have been compared with data obtained from auditory nerve fibers.This work was supported in part by the Joint Services Electronics Program (Contract DA 36-039-AMC-03200(E); and in part by the National Science Foundation (Grant GP-2495), the National Institutes of Health (Grant MH-04737-05), the National Aeronautics and Space Administration (Grant NsG-496); and by Research Grant NB-01344, National Institute of Neurological Diseases and Blindness of the National Institutes of Health, Public Health Service.     

A computational model of rapid task-related plasticity of auditory cortical receptive fields

Receptive field properties of neurons in A1 can rapidly adapt their shapes during task performance in accord with specific task demands and salient sensory cues (Fritz et al., Hearing Research, 206:159–176, 2005a, Nature Neuroscience, 6: 1216–1223, 2003). Such modulatory changes selectively enhance overall cortical responsiveness to target (foreground) sounds and thus increase the likelihood of detection against the background of reference sounds. In this study, we develop a mathematical model to describe how enhancing discrimination between two arbitrary classes of sounds can lead to the observed receptive field changes in a variety of spectral and temporal discrimination tasks. Cortical receptive fields are modeled as filters that change their spectro-temporal tuning properties so as to respond best to the discriminatory acoustic features between foreground and background stimuli. We also illustrate how biologically plausible constraints on the spectro-temporal tuning of the receptive fields can be used to optimize the plasticity. Results of the model simulations are compared to published data from a variety of experimental paradigms.     

Gain adjustment of inhibitory synapses in the auditory system

A group of central auditory neurons residing in the lateral superior olivary nucleus (LSO) responds selectively to interaural level differences and may contribute to sound localization. In this simple circuit, ipsilateral sound increases firing of LSO neurons, whereas contralateral sound inhibits the firing rate via activation of the medial nucleus of the trapezoid body (MNTB). During development, individual MNTB fibers arborize within the LSO, but they undergo a restriction of their boutons that ultimately leads to mature topography. A critical issue is whether a distinct form of inhibitory synaptic plasticity contributes to MNTB synapse elimination within LSO. Whole-cell recording from LSO neurons in brain slices from developing gerbils show robust long-term depression (LTD) of the MNTB-evoked IPSP/Cs when the MNTB was activated at a low frequency (1 Hz). These inhibitory synapses also display mixed GABA/glycinergic transmission during development, as assessed physiologically and immunohistochemically (Kotak et al. 1998). While either glycine or GABA_A receptors could independently display inhibitory LTD, focal delivery of GABA, but not glycine, at the postsynaptic-locus induces depression. Furthermore, the GABA_B receptor antagonist, SCH-50911, prevents GABA or synaptically induced depression. Preliminary evidence also indicated strengthening of inhibitory transmission (LTP) by a distinct pattern of inhibitory activity. These data support the idea that GABA is crucial for the expression inhibitory LTD and that this plasticity may underlie the early refinement of inhibitory synaptic connections in the LSO.     

A new model of developmental constraints as applied to the Drosophila system

Von Baer's laws of development observe that an embryo, in the course of its ontogeny, progresses through a series of forms which diverge increasingly from the embryonic forms of related species, and in an evolutionary interpretation, from those of its phylogenetic ancestors. This observation on the relation of phylogeny to ontogeny is explained by Wimsatt's (1986) "Developmental Lock" model of complex generative systems, which proposes that evolution is constrained to alter developmental programs in a manner that usually modifies or adds new complexity to pre-existent developmental functions at positions relatively "downstream" in the causal structure. If the Developmental Lock model is correct, (1) evolution should have resulted in hierarchically ordered developmental programs, and (2) the most important developmental functions in the hierarchy should be ancient. Wimsatt also suggests that developmental functions be analyzed according to a degree property called "generative entrenchment", which replaces the temporal analysis in the traditional formulation of von Baer's laws. Herein, a substantial body of data on Drosophila ontogeny is analyzed according to generative entrenchment, in order to try the effectiveness of this form of analysis, and also to empirically test these two main predictions of the Developmental Lock model. The novel analytic approach proves to be fruitful, both in generating experimental hypotheses and in ordering existing data. Moreover, data concerning the developmental functions discussed here indicate that the order of the Drosophila developmental program conforms to the predictions of Wimsatt's model with few deviations. Explanations of the anomalies are offered, along with proposals for experiments to test some of those explanations.     

A network model for activity-dependent sleep regulation

We develop and characterize a dynamical network model for activity-dependent sleep regulation. Specifically, in accordance with the activity-dependent theory for sleep, we view organism sleep as emerging from the local sleep states of functional units known as cortical columns; these local sleep states evolve through integration of local activity inputs, loose couplings with neighboring cortical columns, and global regulation (e.g. by the circadian clock). We model these cortical columns as coupled or networked activity-integrators that transition between sleep and waking states based on thresholds on the total activity. The model dynamics for three canonical experiments (which we have studied both through simulation and system-theoretic analysis) match with experimentally observed characteristics of the cortical-column network. Most notably, assuming connectedness of the network graph, our model predicts the recovery of the columns to a synchronized state upon temporary overstimulation of a single column and/or randomization of the initial sleep and activity-integration states. In analogy with other models for networked oscillators, our model also predicts the possibility for such phenomena as mode-locking.     

A model of activity-dependent formation of cerebellar microzones

According to modern views of the cerebellum in motor control, each cerebellar functional unit, or microzone, learns how to execute predictive and coordinative control, based on long-term depression of the granule cell-Purkinje cell synapses. In the present paper, in light of recent experimental and theoretical studies on synaptic elimination and cerebellar motor learning, a model of the formation of cerebellar microzones by climbing fiber synaptic elimination is proposed. It is shown that competition for an activity-dependent supply of neurotrophic factor can reproduce the spatio-temporal characteristics of climbing fiber synaptic elimination. It is further shown that when this elimination is accurate, motor coordination can be acquired in an arm reaching task. In view of the results of the present study, several predictions are proposed. Received: 19 January 1998 / Accepted in revised form: 22 April 1998     

A comparative anatomical study of the mammalian uterotubal junction

Among eight species of mammals in this study (cattle, sheep, pig-tail and rhesus monkeys, rabbit, pig, rat, and dog) four basic patterns of anatomical structure at the uterotubal junction are described. The classification of types is based upon the presence or absence of an intramural portion of the oviduct and of isthmal folds or plicae projecting into the lumen of the uterine cornu. Histological variations are reported for three tissues: epithelial and connective of the mucosa and smooth muscle of the tunica muscularis. In the epithelium during the estrous cycle the differences recorded include: (a) absence of ciliated cells in the distal end of the oviduct in rat and dog; (b) variations in ciliated and nonciliated cells in (1) cell height, (2) location, shape and stainability of the nucleus, and (3) in amount and stainability of apical cytoplasm; (c) presence of lymphoblast-like cells which appear to migrate through the epithelium from the lamina propria. The connective tissue of the mucosa, as a circular layer and as cores for the mucosal folds, shows variations in thickness and in relative density of cells and fibers of the matrix. Emphasis is given to the presence of an inner longitudinal layer of smooth muscle in the tunica muscularis of the distal oviduct in six of the eight species.     

Mechanisms involved in activity-dependent synapse formation in mammalian central nervous system cell cultures

Differences in neuronal activity produced by electrical stimulation lead to competition between synapses from sensory afferents converging on a common spinal cord neuron. Studies were performed on neurons dissociated from the mouse spinal cord and grown in culture dishes with three compartments. Synaptic efficacy from stimulated afferents was increased compared with unstimulated convergents, and the number of functional connections was increased by stimulation compared with control cultures. Blocking NMDA channel activation with 100 microM APV in medium containing 1.8 mM calcium inhibited this synaptic plasticity, but plasticity was not blocked by APV in medium in which the calcium concentration was elevated to 3 mM. These experiments support the view that electrical activity differentially influences processes that cause a persistent decrease in synaptic efficacy or lead to synapse elimination and those that increase synaptic strength or lead to synapse augmentation. We interpret our results in terms of a model in which these antagonistic mechanisms are both regulated via changes in calcium levels and second messengers that are modulated by electrical activity. A significant portion of the activity-related calcium influx relevant to synaptic plasticity passes through the NMDA channel, but other sources of calcium are involved. In particular, competitive elimination of synapses appears to occur during blockade of NMDA channels if the extracellular concentration of calcium is elevated moderately. The outcome of competition between the two calcium-dependent but antagonistic processes may depend either on their differential sensitivity to intracellular calcium concentration or separate specificities to NMDA and non-NMDA receptor-linked mechanisms.     

Fast homeostatic plasticity of inhibition via activity-dependent vesicular filling

Synaptic activity in the central nervous system undergoes rapid state-dependent changes, requiring constant adaptation of the homeostasis between excitation and inhibition. The underlying mechanisms are, however, largely unclear. Chronic changes in network activity result in enhanced production of the inhibitory transmitter GABA, indicating that presynaptic GABA content is a variable parameter for homeostatic plasticity. Here we tested whether such changes in inhibitory transmitter content do also occur at the fast time scale required to ensure inhibition-excitation-homeostasis in dynamic cortical networks. We found that intense stimulation of afferent fibers in the CA1 region of mouse hippocampal slices yielded a rapid and lasting increase in quantal size of miniature inhibitory postsynaptic currents. This potentiation was mediated by the uptake of GABA and glutamate into presynaptic endings of inhibitory interneurons (the latter serving as precursor for the synthesis of GABA). Thus, enhanced release of inhibitory and excitatory transmitters from active networks leads to enhanced presynaptic GABA content. Thereby, inhibitory efficacy follows local neuronal activity, constituting a negative feedback loop and providing a mechanism for rapid homeostatic scaling in cortical circuits.     

Proteomic analysis of activity-dependent synaptic plasticity in hippocampal neurons

Following long-term treatment with bicuculline and tetrodotoxin (TTX) aimed at modifying synaptic activity in cultured neurons, we used a proteomic approach to identify the associated changes in protein expression. The neurons were left untreated, or treated with bicuculline or TTX, and fractionated by means of differential detergent extraction, after which the proteins in each fraction were separated by means of two-dimensional (2D) gel electrophoresis, and 57 proteins of interest were identified by mass spectrometry. The proteins that showed altered expression and/or post-translational modifications include proteins or enzymes involved in regulating cell and protein metabolism, the cytoskeleton, or mitochondrial activity. These results suggest that extensive alterations in neuronal protein expression take place as a result of increased or decreased synaptic activity.     

Activity-dependent organization of inhibitory circuits: lessons from the auditory system

In contrast to our detailed knowledge about the development and plasticity of excitatory neuronal circuits, little is known about the development of inhibitory circuits. Recent studies from the developing mammalian auditory system have revealed the presence of substantial activity-dependent synaptic reorganization in several inhibitory pathways. These studies importantly shed some new light on the general rules and cellular mechanisms that manage the organization of precise inhibitory circuits in the developing brain.     

Bayesian phylogenetics using an RNA substitution model applied to early mammalian evolution

We study the phylogeny of the placental mammals using molecular data from all mitochondrial tRNAs and rRNAs of 54 species. We use probabilistic substitution models specific to evolution in base paired regions of RNA. A number of these models have been implemented in a new phylogenetic inference software package for carrying out maximum likelihood and Bayesian phylogenetic inferences. We describe our Bayesian phylogenetic method which uses a Markov chain Monte Carlo algorithm to provide samples from the posterior distribution of tree topologies. Our results show support for four primary mammalian clades, in agreement with recent studies of much larger data sets mainly comprising nuclear DNA. We discuss some issues arising when using Bayesian techniques on RNA sequence data.     

An activity-dependent determinant of synapse elimination in the mammalian brain

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Carrier frequency-sensitive primary auditory neurons in crickets and their anatomical projection to the central nervous system

The tympanal organ of the cricket Scapsipedus marginatus contains receptor neurons that are tuned to the dominant frequency of the species-specific calling song (F₁ units), as demonstrated by single unit recordings. F₁ units have simple threshold curves with just one characteristic frequency, and they can be characterized by their latency and adaptation rate. The pattern with which these units respond to song indicates that they are a principal source of peripheral input to the CNS for song reception. The tympanal nerve sends its sensory arborizations to the ventromedial neuropile of the prothoracic ganglion. Fibers of the tympanal nerve do not cross the midline; nor do they project to other ganglia, insofar as can be demonstrated with cobalt chloride iontophoresis.     

Classification of inhibitory amino acid receptors in the mammalian nervous system

Electrophysiological and pharmacological evidence is summarized for the existence of an inhibitory receptor system operated by glycine and another two separate systems operated by gamma-aminobutyric acid (GABA) through GABA-A and GABA-B receptors, respectively. Claims for subclasses of GABA-A receptor are critically reviewed and found not-proven. A quantitative pharmacological profile of the GABA-A receptor and associated regulatory sites for picrotoxin, barbiturates and benzodiazepines on the dorsal funiculus of the rat cuneate nucleus is described. When compared with this profile and the pharmacological properties of the glycine receptor complex, the effects of taurine cannot be entirely explained by actions on these two receptor systems.     

A neural circuit model forming semantic network with exception using spike-timing-dependent plasticity of inhibitory synapses

We propose a neural circuit model forming a semantic network with exceptions using the spike-timing-dependent plasticity (STDP) of inhibitory synapses. To evaluate the proposed model, we conducted nine types of computer simulation by combining the three STDP rules for inhibitory synapses and the three spike pairing rules. The simulation results obtained with the STDP rule for inhibitory synapses by Haas et al. [Haas, J.S., Nowotny, T., Abarbanel, H.D.I., 2006, Spike-timing-dependent plasticity of inhibitory synapses in the entorhinal cortex. J. Neurophysiol. 96, 3305–3313] are successful, whereas, the other results are unsuccessful. The results and examinations suggested that the inhibitory connection from the concept linked with an exceptional feature to the general feature is necessary for forming a semantic network with an exception.