Christoph E. Schreiner - US grants

The long-term goal of the proposed experiments is to identify the fundamental processing principles and strategies that underlie the cortical receptive field transformations and representations of complex sounds. We will contrast the organization of two primary auditory fields, Al and AAF, in adult cat with specific reference to functional domains and laminar organization. A main premise is that Al and AAF receive largely independent thalamic and cortical inputs and have specific functional differences that may constitute task- specific processing streams. How do the inputs differ in source location and functional properties;what do the thalamic inputs contribute to the generation of receptive field (RF) diversity;and how are the functional characteristics at the cortical input level transformed in the output layers? The interrelations between heterogeneous spatial distributions of functional properties and the connection patterns of these primary fields will be studied in joint electrophysiological and neuroanatomical experiments. By relating the functional properties and cortical connectivity, global principles underlying the characteristics of cortical representations and transformations can be assessed for simple and complex sounds. . The first aim is to define layer-specific functional organizations of Al and AAF for simple and complex sounds. We think that single neurons in layers Illb/IV will show systematic differences in RF attributes from cells in other layers. RFs will be obtained with traditional stimuli as well as with a reverse-correlation method that creates binaural spectro-temporal receptive fields. We will also compare the lamina-specific changes in RF properties in Al and AAF of the anesthetized cat and in A! of the awake squirrel monkey to address comparative questions and RF organization in conscious animals. The second aim is to compare directly the RFs of thalamic sources and cortical targets by simultaneous recording of functionally connected neuron pairs in cat medial geniculate body and AI/AAF. It is hypothesized that thalamic input properties approximate some RF properties of their cortical targets but that construction of many cortical RFs is substantially shaped by corticocortical contributions. Finally, we will relate thalamic and intracortical connections to functional sub-regions of Al and AAF. How patchy thalamic and corticocortical projections are related to the patchy cortical organizations found for spectral, temporal and binaural properties is the main question. Labeling from retrograde tracers injected into physiologically defined functional zones in cat AI/AAF will be assessed relative to functional maps. These studies will establish a functional and structural framework of signal processing in primary cortical fields. Insight into these principles is crucial for understanding the flow of information in auditory cortex, the circuits for normal auditory processing and perceptual learning, and their contributions to auditory disorders.

The primary auditory cortex (AI) of mammals shows several superimposed functional organizations when explored with simple signals such as pure tones. Basic spatial organizations have been described now for stimulus frequency, bandwidth, spectral envelope, frequency modulations, and binaural interaction. The consequences of these organizations for the cortical representation of complex signals, in particular of elemental speech signals, is of special interest since similar principles may provide the basis for the perception and categorization of speech in humans. The representational principles will be explored with elemental speech signals in AI of naive cats and cats that have acquired high behavioral affinity to the signals. The behavioral relevance of the studied complex signals will be established by engaging the animals in a psychophysical task of signal discrimination and generalized classification. The task will be performed under varying stimulus and environmental conditions such as by using different stimulus intensities and different levels of background noise. These manipulations are designed to force the animal to utilize more generalized classification schemes that operate independent from signal level and bachground conditions, thus approaching human discrimination and classification abilities. Determining the cortical representation of elemental speech sounds with distinct phonetic features in naive and highly trained animals will illuminate basic attributes of complex signal representations as well as more refined attributes after learning to discriminate and classify the signals. The emergence of refined spatial-temporal patterns of cortical activity by learning-induced plasticity provides a basic model of speech representation. The proposed model can potentially be extended to developmental aspects of early cortical processes for speech sound representation and can be applied to the exploration of the basic auditory processes underlying the perception and categorization of distinct phonetic features.

DESCRIPTION: (Adapted from applicant's abstract): In these proposed Javits grant continuation studies, we focus directly on nine important, understudied aspects of cortical plasticity, in experiments that shall be conducted in primate and rodent models. First we shall define how the cortex creates-and expresses by the distributed responses of cortical neurons and by learning-based specialization of its processing machinery-sequence-dependent and context-dependent representation of complex acoustic and tactile inputs. Second, we shall further define how cortical plasticity is modulate separately and synergistically by cholinergic, dopaminergic, adrenegic and serotonergic control system that enable, and differentially amplify learning-induced cortical change. Third, we school further document, and compare and interrelate, behaviorally-driven vs. modulatroy -control-system/ acoustic-stimulation pairing-driven plasticity across the three dimension of cortical columns and minicolumns. Fourth, we shall define the spefic ways in which leaning-induced plasticity is modulated as a function of the predictability of inputs. Fifth, we shall further elaborate studies of "catastrophic' plasticity, specificity, specifically studying forms that appear to arise in human populations as one probable cause of severe behavioral impairments. Sixth, we shall reconstruct the ontogeny if development of the cortical processing of complex acoustic inputs. Seventh, we shall develop animal models designed to test the hypothesis that signal-to-noise conditions that apply for the young cortex underlie the quality and the extent of the progressive refinement of its complex-signal processing machinery, and thereby largely account for variations in complex signal processing abilities (speech and language development, reading ability, "intelligence") in human populations. Eighth, we shall define in detail, the ways in which plastic changes generated within "secondary" cortical fields are derived from, or are independent of, the evolution of processing refinements in "primary" sensory cortical areas. Ninth, these studies shall result in the development and elaboration of two new classes experimental models, designed to facilitate the study of molecular aspects of cortical plasticity mechanisms in mice, and the study of cellular and synaptic dynamics and plasticity in vitro experiments in rats. They experiments bare important implication for the further development of brain plasticity-based strategies for the remediation of neurological impairments, and for the amelioration of the symptoms of progressive neurological and psychiatric illness.

stimulus /response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We wish to utilize the computing facilities to analyze the responses of neurons in the central auditory system. Specifically, we wish to compute the response functions of auditory neurons using a novel computational methodology. Under a previous collaboration with Tatyana Sharpee, formerly of UCSF and now at the Salk Institute, the supercomputer facilities were utilized to perform a similar analysis, though now we would like to continue the methodology but on a different set of data from subcortical and cortical stations. The computational methodology we will implement has been previously published (Atencio et al., 2008). We will compute the receptive fields of auditory neurons. The receptive field describes the relationship between the stimulus and the response of a neuron. The receptive field can be approximated as a set of linear filters, each of which may be calculated by maximizing the information between the stimulus and the neural spiking response. Thus, each filter is termed a maximally informative dimension (MID). Briefly, the first MID is the direction, or dimension, in stimulus space that accounts for the most mutual information between the stimulus and the response. We obtain the first MID through an iterative procedure, where the relevance of any "candidate" dimension V is quantified by computing the mutual information between the occurrence of single spikes and projections of the stimulus onto V. We search through different directions in the stimulus space until convergence. Upon finding the first MID, we then estimate a second MID. The second MID is the dimension in the stimulus space that, together with the first MID, further maximizes the information. The stimulus is approximately 15,000 different stimulus spectrograms, each having 500 pixels. A direction in stimulus space is a spectrogram, where the pixels in the spectrogram may take on any value. The computational algorithm searches through the stimulus spectrograms till it converges to a single direction, or image, which is the MID. Since each pixel in a spectrogram may take on multiple values, searching and converging to the appropriate pixel values over this data set is computationally intensive, and thus ideally suited for implementation on the supercomputer facilities. From previous work with Dr. Sharpee, where she used the supercomputer facilities, we know that to calculate two MIDs for one neuron takes approximately 160 hours. Thus, given our data set size, we wish to request 75,000 hours of facility service units, as well as 2 terabyte of disk space. The work from our collaboration with Dr. Sharpee has already led to publication in an high impact journal, and we anticipate that these further computations will be similarly fruitful. Atencio CA, Sharpee T, Schreiner CE (2008) Cooperative nonlinearities in auditory cortical neurons. Neuron 58:956-966.

PROJECT SUMMARY The proposed experiments aim to determine how the consequences of asymmetric hearing loss (AHL) in auditory cortex affect the neural processes that allow listeners to parse and decode foreground sounds in background noise. AHL is one of the most common forms of hearing impairment, and it profoundly disrupts spatial hearing and the ability to process signals in noise (SIN). Disabilities across hearing domains are generally more severe in AHL patients than in equivalent cases of symmetric sensorineural hearing loss (SNHL). Thus, AHL has broad implications for health, including tinnitus, cognitive impairment, and reduced quality of life. We recently discovered that the cortical hemispheres ipsilateral and contralateral to the hearing loss recover differently after asymmetric acoustic trauma. Specifically, spectral preferences for sounds emanating from the two ears realign in the contralateral hemisphere within ~6 months after AHL but remain misaligned in the ipsilateral hemisphere. Neither the dynamics nor the functional consequences of these hemispheric differences on SIN processing or crucial auditory functions such as central gain adaptation are known. Furthermore, we recently discovered that neurons in normal auditory cortex are considerably diverse in how well they tolerate background noise. Some neurons actually improving their processing in the presence of noise. This diversity creates an opportunity to identify the factors that determine the noise tolerance of cortical neurons and the consequences of AHL. We propose to conduct a multifaceted, longitudinal analysis of bilateral cortical reorganization following AHL. The role of inhibitory interneurons is of special interest because inhibitory dysregulation has been implicated as both a cause and consequence of hearing loss. Our Aims will determine (1) how AHL affects the sensitivity to background sounds in the cortical circuits, (2) how AHL affects the ability of cortical neurons to adapt to changes in stimulus level and contrast, and (3) how functional changes in AHL relate to the structural and functional expression of inhibition in cortical networks. We will estimate spectral and temporal tuning properties, excitatory-inhibitory balance, and temporal context capabilities, which are all critical for optimal speech perception. We will provide the first examination of disrupted cortical SIN processing in AHL by studying monaural and binaural signal decoding abilities over a range of competing background noise levels. We will relate the degree and time course of AHL-induced functional processing changes to neuroanatomically determined alterations in the interneuron density across core cortical fields in the two hemispheres. The wealth of new insights generated by this approach will resolve numerous outstanding questions regarding central reorganization in AHL and its dynamic time course, equip clinical researchers with new and better-defined central biomarkers of AHL, facilitate the development of improved rehabilitation strategies, and provide a new way to understand how the brain extracts signals from noise in normal and impaired hearing.