Eric D. Young - US grants

The overall goal of this project is to understand the response characteristics of neurons in the cochlear nuclei (CN) in terms of their roles in auditory information processing. There are two aspects to the approach to this general goal. In one, the means by which inputs from the auditory nerve (AN) are integrated in CN cells are studied. The focus here is on the cellular mechanisms by which AN spike trains are converted to CN spike trains. The integrative relationships are considered with respect to models of CN cells. In the other aspect, the response properties of CN cells are studied for complex stimuli; this input/output analysis of the CN allows description of information processing activities in terms of preservation and sharpening of information-bearing features of the acoustic stimulus. Three aims are included. 1. Cross-correlation analysis of connected pairs consisting of an AN fiber and a simultaneously-isolated CN cell. This analysis provides information on the organization of inputs to CN cells and on the contribution of individual fibers' spike trains to the responses of the CN cell. 2. Characterization of the spike trains of AN fibers and CN cells in terms of their regulatory of discharge and latency of response. These studies allow development and testing of models of synaptic interaction in the cochlea and CN. 3. Study of the representation of the monaural spectral cues and binaural interaural-level-difference cues for sound localization in the AN and CN. This study will focus on cues produced by directional filtering of the pinna. Hypothesis about specific CN mechanisms for detection, representation and sharpening of sound localization cues will be tested.

The dorsal cochlear nucleus (DCN) is a laminar structure with intricate internal organization based on isofrequency sheets generated by auditory nerve (AN) projections to the DCN. A second organization is provided by axons of cochlear nucleus granule cells, which run orthogonal to the isofrequency sheets. The DCN contains several types of inhibitory interneurons which play an important role in the responses to sound of its principal cells. The goals of this project are to provide new information about the functional organization of the DCN, to develop new methods for characterizing neurons with complex responses to sound like those of DCN, and to pursue a hypothesis about the functional role of the DCN in hearing. The first and second aims are designed to characterize the effects of excitatory and inhibitory inputs to DCN principal cells in shaping their response properties. In addition to AN fibers, the DCN receives tonotopically organized excitatory and inhibitory inputs from the posteroventral cochlear nucleus (PVCN). In the first aim, excitotoxic lesions of the PVCN will be made using kainic acid or ibotenic acid to eliminate the PVCN cellular input to DCN, while sparing the AN inputs; the effects of the PVCN inputs will be inferred by studying the DCN before and after such lesions. The second aim will use cross-correlation of spike trains recorded simultaneously from pairs of units to search for as-yet-unrecognized inhibitory inputs to DCN principal cells. The presence of such inputs is suggested by experiments currently underway. The third aim will apply a new non-linear characterization method to the problem of describing the input/output relationships of DCN cells. Current methods for characterizing auditory neurons fail to predict the responses of complex neurons, such as DCN principal cells, to biologically important stimuli. Success in this aim could have wide application to the study of other parts of the central auditory system. The fourth aim will study the representation, in DCN and lateral superior olive (LSO), of spectrally-encoded sound localization cues produced by the pinna. Current experiments suggest that the DCN is specialized to extract and encode the information-bearing features of such stimuli; the LSO is another part of the central auditory system that is likely to be important in analysis of these features. A goal of this portion of the project is to compare the representation of spectral sound localization features in DCN and LSO, which are parallel pathways in the brainstem auditory system, so that hypotheses about the processing of these features can be refined. The DCN is a valuable model for neuroscience research because it is a complex neural machine which shares some features with cerebellar and cerebral cortex, but is still close enough to the periphery that its inputs are easy to characterize and manipulate. It is interesting to clinical otolaryngology because it is the most likely site, for technical reasons, for a human cochlear nucleus prosthesis.

balance; training; postgraduate education; hearing disorders;

This is a proposal to study somatosensory inputs to the dorsal cochlear nucleus (DCN); these inputs originate in the dorsal column and spinal trigeminal nuclei and project to the granule cell domains of the cochlear nucleus. Somatosensory effects produce rate changes in DCN principal cells which are comparable in magnitude to those produced by sound; current data suggest that the somatosensory input carries information primarily about movement of the pinna. Four projects are proposed to investigate hypotheses suggested by these results. Experiments are conducted in unanesthetized, decerebrate cats or in an awake chronic cat preparation. Methods include recording single unit responses to sound, to electrical stimulation in somatosensory nuclei, and to natural somatosensory stimuli. The first goal is to test the hypothesis that pinna movement is the most potent somatosensory stimulus. We will use a new surgical preparation which keeps the skin and musculature on the ipsilateral side of the head intact. These experiments will differentiate between motion of the pinna, displacement of the pinna, and other somatosensory stimuli to the pinna or the body. Second, the distribution of somatosensory effects within an isofrequency sheet in DCN will be determined. Comparison of somatosensory effects on principal cells in superficial and deep DCN will be done to identify differences expected from the differences in innervation of fusiform and giant cells. Properties of three likely inhibitory interneurons will be studied in order to develop a model of the functional effects of somatosensory inputs in DCN. Interactions of acoustic and somatosensory stimuli will be studied. Third, the properties of the somatosensory projection neurons will be studied by recording from neurons in the dorsal column nuclei that can be antidromically activated from DCN. Their somatosensory responses will be compared to the properties of somatosensory effects in DCN in order to determine what processing is done in the granule cell system of DCN. Fourth, DCN neurons will be recorded in awake animals trained to perform pinna movements in response to external cues (shifting of a sound from one loudspeaker to another). The responses in this preparation will be compared with responses to passive pinna movement in decerebrate preparations to see whether other inputs, possibly correlated with motor commands to the pinna, are also active. Pinna movement will be coupled with sound stimulation in order to search for adaptive plasticity in the responses to either sound or pinna movement; such plasticity is expected from the molecular anatomy of the DCN.

DESCRIPTION (provided by applicant): The goal of the Engineering Core is to provide for the development of new equipment and computer programs to take advantage of the rapid developments in theoretical and computational neuroscience. A set of computer programs will be developed that will allow experimenters to construct special purpose data acquisition functions using software tools like Matlab. The system will be designed for a standardized set of hardware, commonly available in our laboratories, and will facilitate performing new and creative experiments by reducing the instrumentation-development time and cost. Core staff will also assist users in writing software to perform sophisticated analyses of spike-train data, making the latest developments in the theory of information representation by spike trains available to investigators. Finally, the core will provide routine support for design and construction of small electronic items and installation and maintenance of computer systems and networks.

DESCRIPTION (provided by applicant): Although the lesion in sensorineural hearing loss (SNHL) is almost always in the cochlea, the abnormal activity patterns of auditory nerve fibers in a damaged ear cause adaptive changes in the central nervous system as well. The work proposed here will study two aspects of the central neural representation of auditory stimuli. The goal is to answer questions about perceptual deficits observed in persons with SNHL. The first aim is to study deficits in intensity perception. In persons with SNHL, loudness grows more steeply over some part of the range of sound levels, called recruitment. Although recruitment is consistent with changes occurring in the cochlea, our studies of auditory nerve fibers do not show a corresponding steepening of their response growth. Thus it is not clear how the cochlear effects are communicated to the brain. This aim is motivated by the hypothesis, supported by some existing evidence, that the central auditory system has an abnormally steep intensity sensitivity in cases of SNHL, accounting for some aspects of loudness recruitment. Neurons in the cochlear nucleus of cats with noise-induced SNHL will be characterized with a variety of measures of intensity sensitivity. A second problem accompanying SNHL is loss of frequency selectivity. Frequency selectivity of central auditory neurons is governed by both the peripheral sensitivity of the cochlea and the degree of spread of anatomical connections along the frequency axis in central circuits. We will analyze the receptive fields of neurons in the cochlear nucleus and inferior colliculus to characterize deficits of frequency analysis that go beyond peripheral tuning changes. We will also use a new method for characterizing connectivity in auditory circuitry to look for deficits in wiring specificity of the cochlear nucleus. Finally, cats are used as the animal model for this research, but the degree to which the preparation that we use suffer from loudness recruitment is unknown. Behavioral determination of response latency as a function of stimulus intensity will be used to characterize the growth of perceptual stimulus intensity in normal cats and cats with noise-induced SNHL. These data will be used to connect human perceptual data with data on cat auditory neurophysiology.

Many neurons in the auditory system respond to sounds nonlinearly; that is, its response to two sounds played simultaneously differs from the sum of its responses to each sound played alone. Nonlinearities are necessary for many computational functions, but unlike nonlinear models that allow closed-form solutions, nonlinear models are often too hard to characterize in practice. To make nonlinear models tractable, this project will combine single-unit recording in awake marmoset monkey with automated online stimulus design by parallel computing. The goal of this stimulus design is not to maximize the firing rate of a neuron, but to extract the most information about the global stimulus-response relationship. Optimal sounds will be designed "on the fly" according to a neuron's response history, with the help of a fast parallel computer whose running time is compatible with the single-unit recording experiment. The proposed research is expected to produce practical and widely applicable methods for characterizing nonlinear sensory neurons. The auditory system is an ideal system for this type of online experiment because sound space is of lower dimensions and allows faster computations. The methods developed here are expected to generalize to nonlinear problems in other sensory modalities.

Theory and algorithm development will focus on generating sound stimuli which can either most accurately estimate a given model, or maximally distinguish competing models. Nonlinear models with various degrees of complexity, including neural network models, will be used simultaneously, and contrasted against one another in the automated experiment. The model-based sound design method will be used to characterize complex response properties of neurons in auditory cortex and inferior colliculus of awake marmoset monkey, a vocal primate. This project focuses on the auditory cortex because studies of its pronounced nonlinearities may potentially benefit most from the new method. For comparison the same method will also be applied to the inferior colliculus, the inputs to which are better known, allowing more realistic hierarchical models to be developed. The models obtained from this method should provide a concise summary of the global stimulus-response relationship of a neuron that generalizes across all types of stimuli. Neural network models may also help extract additional information about the connectivity between different neuronal types, thus providing a link between the stimulus-response function and the structure of the underlying neural circuits.

DESCRIPTION (provided by applicant): The proposed work investigates the representation of information about sound in the central nucleus of the inferior colliculus (CNIC). This structure receives a complex array of inputs containing different kinds of information about the sounds coming into the ears. As many as 20-30 separate processing centers in the brainstem contribute inputs to the CNIC. These include information about what the sound is, who or what produced it, and where the source is located. All of this information must pass through the CNIC on the way to the cortex, so the way in which the neurons of the CNIC assemble these diverse representations is essential to understanding auditory processing. Three investigations are proposed. First, a new statistical method will be applied to construct generic models of the receptive fields of neurons in CNIC. These models will allow understanding of the way the identity of sounds and their information content is represented. Second, the way in which the three cues for sound localization are combined in neurons of the CNIC will be studied. This will provide insights into the way in which neurons encode multiple aspects of stimuli, a common problem in all parts of the brain. Third, the circuits that amplify dynamic features of sound will be studied. These elements allow us to deal with complex acoustic environments with multiple sound sources, especially with the problem of separating sources that produce overlapping sounds.