About
171
Publications
31,540
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
9,939
Citations
Introduction
We study brain changes consequent to hearing loss. This task means that we first must study the basic features of brain organization with an emphasis on brain circuits of the auditory system. Only then can we identify those changes caused by hearing loss and deafness.
Skills and Expertise
Current institution
Additional affiliations
July 1978 - June 1987
July 1978 - June 1987
July 1976 - June 1978
Publications
Publications (171)
Auditory space has been conceptualized as a matrix of systematically arranged combinations of binaural disparity cues that arise in the superior olivary complex (SOC). The computational code for interaural time and intensity differences utilizes excitatory and inhibitory projections that converge in the inferior colliculus (IC). The challenge is to...
Mast Cells (MCs) have diverse roles in health and disease. These immune cells migrate in a tissue-specific manner to target sites where they can alert or amplify immune responses through exocytosis of their bioactive granules. Granule exocytosis can be triggered by both external immunological and non-immunological signals. Depending on the local mi...
Understanding the biology of hearing and hearing loss requires not only examination of the existing structure and function of the auditory system but also consideration of its evolutionary legacy. In this context, research in my group, in collaboration with others, utilizes a comparative approach to investigate hearing and hearing loss in various r...
The cochlear nucleus (CN) is often regarded as the gateway to the central auditory system because it initiates all ascending pathways. The CN consists of dorsal and ventral divisions (DCN and VCN, respectively), and whereas the DCN functions in the analysis of spectral cues, circuitry in VCN is part of the pathway focused on processing binaural inf...
[This corrects the article DOI: 10.3389/fncir.2022.1038500.].
Olfactory receptors (ORs) expressed by mature olfactory sensory neurons (mOSNs) in the olfactory neuroepithelium detect and distinguish volatile chemicals of diverse structure. Chemoreception begins when the odorant binds to the OR, initiating a signal transduction cascade involving olfactory G-protein (Golf), adenylyl cyclase 3 (AC3), and cyclic n...
The lateral superior olive (LSO) is a key structure in the central auditory system of mammals that exerts efferent control on cochlear sensitivity and is involved in the processing of binaural level differences for sound localization. Understanding how the LSO contributes to these processes requires knowledge about the resident cells and their conn...
In the post-natal mouse cochlea, type II spiral ganglion neurons (SGNs) innervating the electromotile outer hair cells (OHCs) of the ‘cochlear amplifier' selectively express the type III intermediate filament peripherin gene (Prph). Immunolabeling showed that Prph knockout (KO) mice exhibited disruption of this (outer spiral bundle) afferent innerv...
Idiopathic sudden sensorineural hearing loss (ISSNHL) is a condition affecting 5-30 per 100,000 individuals with the potential to significantly reduce one's quality of life. The true incidence of this condition is not known because it often goes undiagnosed and/or recovers within a few days. ISSNHL is defined as a ≥30 dB loss of hearing over 3 cons...
The medial olivocochlear (MOC) efferent feedback circuit projecting to the cochlear outer hair cells (OHCs) confers protection from noise-induced hearing loss and is generally thought to be driven by inner hair cell (IHC) - type I spiral ganglion afferent (SGN) input. Knockout of the Prph gene ( Prph KO) encoding the peripherin type III intermediat...
Diabetes (type 2) and sensorineural hearing loss are common health problems manifested with ageing. While both type 1 and type 2 diabetes have been associated with hearing loss, a causal link has been difficult to establish. Individuals with diabetes have twice the incidence of hearing loss compared to those without diabetes and those with prediabe...
Auditory efferents originate in the central auditory system and project to the cochlea. Although the specific anatomy of the olivocochlear (OC) efferents can vary between species, two types of auditory efferents have been identified based upon the general location of their cell bodies and their distinctly different axon terminations in the organ of...
Expression of olfactory receptors (ORs) in non-olfactory tissues has been widely reported over the last 20 years. Olfactory marker protein (OMP) is highly expressed in mature olfactory sensory neurons (mOSNs) of the olfactory epithelium. It is involved in the olfactory signal transduction pathway, which is mediated by well-conserved components, inc...
Sensory input has profound effects on neuronal organization and sensory maps in the brain. The mechanisms regulating plasticity of the auditory pathway have been revealed by examining the consequences of altered auditory input during both developmental critical periods—when plasticity facilitates the optimization of neural circuits in concert with...
Deafness affects the expression and distribution of voltage-dependent potassium channels (Kvs) of central auditory neurons in the short-term, i.e., hours to days, but the consequences in the expression of Kvs after long-term deafness remain unknown. We tested expression and distribution of Kv1.1 and Kv3.1b, key for auditory processing, in the rat c...
The processing of sound by the brain requires tight coupling between acoustic events and brain activity. Auditory neurons must be capable of responding quickly and with high fidelity. Two pathways in the system rely on giant synaptic terminals to meet their functional demands. Endbulbs of Held and calyces of Held are large terminals that guarantee...
The archetypal T cell-dependent antigen is sheep red blood cells (SRBCs), which have defined much of what we know about humoral immunity. Early studies using solubilized or sonicated SRBCs argued that the intact structure of SRBCs was important for optimal antibody responses. However, the reason for the requirement of intact SRBCs for the response...
Ascending projections of the dorsal cochlear nucleus (DCN) primarily target the contralateral inferior colliculus (IC). In turn, the IC sends bilateral descending projections back to the DCN. We sought to determine the nature of these descending axons in order to infer circuit mechanisms of signal processing at one of the earliest stages of the cen...
Studies of congenital and early-onset deafness have demonstrated that an absence of peripheral sound-evoked activity in the auditory nerve causes pathological changes in central auditory structures. The aim of this study was to establish whether progressive acquired hearing loss could lead to similar brain changes that would degrade the precision o...
Neurons of the spiral ganglion exhibit a complex yet precise organization for delivering acoustic information from the mammalian inner ear to the brain. These neurons display a range of anatomical and physiological specializations for accurate encoding of sound features, and many of the characteristics observed in the periphery are reflected in the...
Perceptual performance in persons with hearing loss, especially those using devices to restore hearing, is not fully predicted by traditional audiometric measurements designed to evaluate the status of peripheral function. The integrity of auditory brainstem synapses may vary with different forms of hearing loss, and differential effects on the aud...
Data from our laboratory show that the auditory brain is highly malleable by experience. We establish a base of knowledge that describes the normal structure and workings at the initial stages of the central auditory system. This research is expanded to include the associated pathology in the auditory brain stem created by hearing loss. Utilizing t...
The Dominant White locus (W) in the domestic cat demonstrates pleiotropic effects exhibiting complete penetrance for absence of coat pigmentation and incomplete penetrance for deafness and iris hypopigmentation. We performed linkage analysis using a pedigree segregating White to identify KIT (Chr. B1), as the feline W locus. Segregation and sequenc...
The systematic and topographic representation of frequency is a first principle of organization throughout the auditory system. The dorsal cochlear nucleus (DCN) receives direct tonotopic projections from the auditory nerve (AN) as well as secondary and descending projections from other sources. Among the recipients of AN input in the DCN are verti...
The process of maturing as a scientist may be described as a process of discovery that simply occurs over and over. With each discovery, new insights are made and career trajectories are strengthened, altered, and sometimes split. I have tried to track my scientific path in the context of what was known at the time and what was hypothesized. Lurkin...
Spherical and globular bushy cells of the AVCN receive huge auditory nerve endings specialized for high fidelity neural transmission in response to acoustic events. Recent studies in mice and other rodent species suggest that the distinction between bushy cell subtypes is not always straightforward. We conducted a systematic investigation of mouse...
Synaptic function and neuronal organization in the auditory system has been shown to be reactive and malleable to experience. In this regard, deafness has important implications for auditory processing. Although the general blueprint for auditory circuits appears to be established before the onset of hearing, reduced auditory stimulation during pos...
The relationship between structure and function is an invaluable context with which to explore biological mechanisms of normal and dysfunctional hearing. The systematic and topographic representation of frequency originates at the cochlea, and is retained throughout much of the central auditory system. The cochlear nucleus (CN), which initiates all...
Background
One of the main consequences of hearing loss is the impaired ability to understand speech in noisy environments. Medial olivocochlear (MOC) efferents are believed to be involved in this process due to their cholinergic damping effects on outer hair cell (OHC) function. Because deafness represents an extreme form of hearing loss, we exam...
Background:
A major consequence of hearing loss is the impaired ability to understand speech in noisy environments. Medial olivocochlear (MOC) efferents are thought to dampen background noise by their cholinergic effects on outer hair cells (OHCs), producing an “antimasking” effect. Because deafness represents an extreme form of hearing loss, we e...
Cats have among the best hearing of all mammals in that they are extremely sensitive to a broad range of frequencies. The ear is a highly complex structure that is delicately balanced in terms of its biochemistry, types of receptors, ion channels, mechanical properties, and cellular organization. Sensorineural deafness is caused by "flawed" genes t...
The medial superior olive (MSO) is a key auditory brainstem structure that receives binaural inputs and is implicated in processing interaural time disparities used for sound localization. The deaf white cat, a proven model of congenital deafness, was used to examine how deafness and cochlear implantation affected the synaptic organization at this...
It is well known that anesthesia alters neural response properties in various regions of the brain. In the auditory system, fundamental response properties of brainstem neurons including threshold, frequency specificity, and inhibitory sidebands are altered in significant ways under anesthesia. These observations prompted physiologists to seek ways...
Age-related synaptic change is associated with the functional decline of the nervous system. It is unknown whether this synaptic change is the cause or the consequence of neuronal cell loss. We have addressed this question by examining mice genetically engineered to over- or underexpress neuregulin-1 (NRG1), a direct modulator of synaptic transmiss...
In mammals, the initial bridge between the physical world of sound and perception of that sound is established by neurons of the spiral ganglion. The cell bodies of these neurons give rise to peripheral processes that contact acoustic receptors in the organ of Corti, and the central processes collect together to form the auditory nerve that project...
The auditory experience is crucial for the normal development and maturation of brain structure and the maintenance of the auditory pathways. The specific aims of this review are (i) to provide a brief background of the synaptic morphology of the endbulb of Held in hearing and deaf animals; (ii) to argue the importance of this large synaptic ending...
The biology of auditory and vestibular efferent systems encompasses a wide range of issues where exploration requires knowledge of basic anatomy, electrophysiology, and pharmacology of the inner ear. These topics lead into discussions of development and evolution of efferent systems. The functional significance of these systems is highlighted by an...
Descending pathways in the brain have been known, since the end of the nineteenth century (Held 1891) but their significance
was unappreciated due to the focus on ascending pathways and the unsuitability of the tract tracing methods then available
to reveal these projections. Renewed interest was triggered by the discovery of the olivocochlear bund...
It has long been observed that loss of auditory receptor cells is associated with the progressive degeneration of spiral ganglion cells. Chronic electrical stimulation via cochlear implantation has been used in an attempt to slow the rate of degeneration in cats neonatally deafened by ototoxic agents but with mixed results. The present study examin...
Organisms must learn what representations in the world are important – that is, which sights, smells, and sounds indicate
safety, food, or danger. Knowledge of what is and is not important is acquired by information arising from the sensory organs,
and this knowledge is then acted upon by the motor system, expressed by approach or avoidance behavio...
Congenital deafness results in synaptic abnormalities in auditory nerve endings. These abnormalities are most prominent in terminals called endbulbs of Held, which are large, axosomatic synaptic endings whose size and evolutionary conservation emphasize their importance. Transmission jitter, delay, or failures, which would corrupt the processing of...
Human bilateral cochlear implant users do poorly on tasks involving interaural time differences (ITD), a cue that provides important benefits to the normal hearing, especially in challenging acoustic environments, yet the precision of neural ITD coding in acutely deafened, bilaterally implanted cats is essentially normal (Smith and Delgutte, 2007a)...
Congenital deafness results in synaptic abnormalities in auditory nerve endings. These abnormalities are most prominent in terminals called endbulbs of Held, which are large, axosomatic synaptic endings whose size and evolutionary conservation emphasize their importance. Transmission jitter, delay, or failures, which would corrupt the processing of...
The endbulbs of Held are formed by the ascending branches of myelinated auditory nerve fibers and represent one of the largest synaptic endings in the brain. Normally, these endings are highly branched and each can form up to 1000 dome-shaped synapses. The deaf white cat is a model of congenital deafness involving a type of cochleosaccular degenera...
The effects of deafness on brain structure and function have been studied using animal models of congenital deafness that include surgical ablation of the organ of Corti, acoustic trauma, ototoxic drugs, and hereditary deafness. This report describes the morphologic plasticity of auditory nerve synapses in response to ototoxic deafening and chronic...
The processing of sound by the brain requires tight coupling between acoustic events and brain activity. Auditory neurons must be capable of responding quickly and with high fidelity. Two pathways in the system rely on giant synaptic terminals to meet their functional demands. Endbulbs of Held and calyces of Held are large terminals that guarantee...
Stem cell grafts have been advocated as experimental treatments for neurological diseases by virtue of their ability to offer trophic support for injured neurons and, theoretically, to replace dead neurons. Human embryonic stem cells (HESCs) are a rich source of neural precursors (NPs) for grafting, but have been questioned for their tendency to fo...
Stem-cell grafts have been advocated as experimental treatments for neurological diseases by virtue of their ability to offer trophic support for injured neurons and, theoretically, to replace dead neurons. Human embryonic stem cells (HESCs) are a rich source of neural precursors (NPs) for grafting, but have been questioned for their tendency to fo...
Cell replacement strategies for degenerative and traumatic diseases of the nervous system depend on the functional integration of grafted cells into host neural circuitry, a condition necessary for the propagation of physiological signals and, perhaps, targeting of trophic support to injured neurons. We have recently shown that human neural stem ce...
In nonprimate mammals, the dorsal cochlear nucleus (DCN) is thought to play a role in the orientation of the head toward sounds of interest by integrating acoustic and somatosensory information. Humans and higher primates might not use this system because of reported phylogenetic changes in DCN cytoarchitecture [Moskowitz N (1969) Comparative aspec...
The marginal shell of the anteroventral cochlear nucleus houses small cells that are distinct from the overlying microneurons of the granule cell domain and the underlying projection neurons of the magnocellular core. This thin shell of small cells and associated neuropil receives auditory nerve input from only the low (<18 spikes/s) spontaneous ra...
The lateral reticular nucleus (LRN) resides in the rostral medulla and caudal pons, is implicated in cardiovascular regulation and cranial nerve reflexes, and gives rise to mossy fibers in the cerebellum. Retrograde tracing data revealed that medium-sized multipolar cells from the magnocellular part of the LRN project to the cochlear nucleus (CN)....
Considerable progress has been made over the past decade identifying many genes associated with deafness. With the identification of these hereditary deafness genes and the proteins they encode, molecular elements of basic hearing mechanisms emerge. As functional studies of these molecular elements become available, we can put together the pieces o...
Hearing deficits have often been associated with loss of or damage to receptor hair cells and/or degeneration of spiral ganglion cells. There are, however, some physiological abnormalities that are not reliably attributed to loss of these cells. The afferent synapse between radial fibers of spiral ganglion neurons and inner hair cells (IHCs) emerge...
The endbulbs of Held are formed by the ascending branches of myelinated auditory nerve fibers and represent one of the largest synaptic endings in the brain. Most of the developmental changes in structure occur during the first 30 postnatal days of age. The neonatal endbulb begins as a flattened expansion with many filopodia, resembling a growth co...
Physiological, anatomical, and clinical data have demonstrated interactions between somatosensory and auditory brainstem structures. Spinal nerve projections influence auditory responses, although the nature of the pathway(s) is not known. To address this issue, we injected biotinylated dextran amine into the cochlear nucleus or dorsal root ganglio...
Multipolar cells in the ventral cochlear nucleus (VCN) are a structurally and functionally diverse group of projection neurons. Understanding their role in the ascending pathway involves partitioning multipolar cells into distinct populations and determining where in the brain each sends its coded messages. In this study, we used retrograde labelin...
Mammalian hearing is a complex special sense that involves detection, localization, and identification of the auditory stimulus. The cerebral cortex may subserve higher auditory processes by providing direct modulatory cortical projections to the auditory brainstem. To support the hypothesis that corticofugal projections are a conserved feature in...
The afferent synapse between the auditory nerve fiber and the inner hair cell (IHC) represents a critical junction for hearing. Elucidation of the structure at this site will help establish the substrate for normal sound encoding as well as pathologic processes associated with hearing dysfunction. Previous applications of unbiased (design-based) st...
The Golgi silver-impregnation method established itself as an important technique for distinguishing morphology at the individual neuron level. This technique has been especially useful for studying human neuroanatomy because it works on postmortem tissue but it is also unreliable and capricious. In this report, we describe a simple technique that...
Sensorineural hearing loss is the most common form of deafness in humans. In patients with a severe-profound sensorineural hearing loss therapeutic intervention can only be achieved by direct electrical stimulation of the auditory nerve via a cochlear implant, or – in cases where a cochlear implant is not a surgical option – neurons within the cent...
Congenital deafness results in abnormal synaptic structure in endings of the auditory nerve. If these abnormalities persist after restoration of auditory nerve activity by a cochlear implant, the processing of time-varying signals such as speech would likely be impaired. We stimulated congenitally deaf cats for 3 months with a six-channel cochlear...
The integration of information across sensory modalities enables sound to be processed in the context of position, movement, and object identity. Inputs to the granule cell domain (GCD) of the cochlear nucleus have been shown to arise from somatosensory brain stem structures, but the nature of the projection from the spinal trigeminal nucleus is un...
Previously, we identified PHR1 as an abundantly expressed gene in photoreceptors and showed that it encodes four isoforms, each with N-terminal pleckstrin
homology (PH) and C-terminal transmembrane domains. To better understand PHR1 function and expression, we made a Phr1 null mouse by inserting a β-galactosidase/neor cassette into exon 3. In addit...
Afferent synapses on inner hair cells (IHC) transfer auditory information to the central nervous system (CNS). Despite the importance of these synapses for normal hearing, their response to cochlear disease and dysfunction is not well understood. The C57BL/6J mouse is a model for presbycusis and noise-induced hearing loss because of its age-related...
To test the feasibility of using the deaf white cat model of early-onset deafness. We studied the neuronal effects of prosthetic intervention with a clinical, "off-the-shelf" multichannel cochlear implant.
We placed cochlear implants in 5 deaf white kittens at age 12 and 24 weeks. The devices were activated and stimulated in the laboratory using a...
Using the in vitro isolated whole brain preparation of the guinea pig maintained at 29 degrees C, we intracellularly recorded and stained cochlear nucleus (CN) neurons and auditory nerve (AN) fibers. Discharge properties of CN cells and AN axons were tested in response to 50-ms trains of electrical pulses delivered to the AN at rates ranging from 1...
Cortical area Te1 in the rat commonly is associated with primary auditory cortex. It is the source of direct projections to the inferior colliculus (IC), superior olivary complex (SOC), and the cochlear nucleus (CN). A question that arises is whether these descending pathways derive from a common source or separate populations of cortical neurons....
There is growing evidence that hearing involves the integration of many brain functions, including vision, balance, somatic sensation, learning and memory, and emotional state. Some of these integrative processes begin at the earliest stages of the central auditory system. In this review, we will discuss evidence that reveals multimodal projections...
This report relates patterns of age-related outer hair cell (OHC) loss to auditory behavioral deficits in C57BL/6J mice. Hair cell counts were made from serial sections of the cochlear partition in three subject groups representing young (2-3 months), middle (8-9 months), and old ages (12-13 months). The cochlear location of OHC counts was determin...
Congenital deafness due to cochlear pathology can have an immediate or progressive onset. The timing of this onset could have a significant impact on the development of structures in the central auditory system, depending on the animal's hearing status during its critical period. In order to determine whether cats in our deaf white cat colony suffe...
The lateral superior olive (LSO) contains cells that are sensitive to intensity differences between the two ears, a feature used by the brain to localize sounds in space. This report describes a source of input to the LSO that complements bushy cell projections from the ventral cochlear nucleus (VCN). Injections of biotinylated dextran amine (BDA)...
The auditory nerve of birds and mammals exhibits differences and similarities, but given the millions of years since the two classes diverged from a common ancestor, the similarities are much more impressive than the differences. The avian nerve is simpler than that of mammals, but share many fundamental features including principles of development...
Ventrotubercular cells are multipolar cells in the ventral cochlear nucleus (VCN) that project a collateral axon to the ipsilateral dorsal cochlear nucleus (DCN). These cells are thought to be involved in sensitizing DCN output neurons to spectral shapes that represent the location of a sound source in space. The present report focused on the neuro...
It is well established that manipulation of the sensory environment can significantly alter central auditory system development. For example, congenitally deaf white cats exhibit synaptic alterations in the cochlear nucleus distinct from age-matched, normal hearing controls. The large, axosomatic endings of auditory nerve fibers, called endbulbs of...
Sensory deprivation has been shown to exert detrimental effects on the structure and function of central sensory systems. Congenital deafness represents an extreme form of auditory deprivation, and in the adult white cat, synapses between auditory nerve endings and resident cells of the anteroventral cochlear nucleus exhibited abnormal structure. E...
The cochlea of the mammalian inner ear contains three rows of outer hair cells and a single row of inner hair cells. These hair cell receptors reside in the organ of Corti and function to transduce mechanical stimuli into electrical signals that mediate hearing. To date, the molecular mechanisms underlying the maintenance of these delicate sensory...
The cochlea of the mammalian inner ear contains three rows of outer hair cells and a single row of inner hair cells. These hair cell receptors reside in the organ of Corti and function to transduce mechanical stimuli into electrical signals that mediate hearing. To date, the molecular mechanisms underlying the maintenance of these delicate sensory...
Synaptic inputs from one cochlear nucleus (CN) to the other can play an important role in modulating the activity of CN neurons. Using the isolated whole brain preparation of the guinea pig, we tested the effects of electrical stimulation of the contralateral auditory nerve (AN) on intracellularly recorded and stained neurons of the anteroventral c...
Corticofugal pathways originating in auditory cortex innervate most subcortical auditory nuclei in the ascending pathway [Auditory Neurosci. 1 (1995) 287-308; J. Comp. Neurol. 371 (1996) 15-40]. Our goal is to determine if these projections arise from the same neurons or if different neurons project to each of the separate structures. We also seek...
In the cochlear nucleus, there is a magnocellular core of neurons whose axons form the ascending auditory pathways. Surrounding this core is a thin shell of microneurons called the granule cell domain (GCD). The GCD receives auditory and nonauditory inputs and projects in turn to the dorsal cochlear nucleus, thus appearing to serve as a central loc...
