Alfred L. Nuttall, PhD OHRC Lab

Fred Nuttall

NUTTALL LABORATORY

Dr. Nuttall's research specialization is in cochlear physiology with a dual focus on cochlear mechanics and cochlear blood flow (CoBF). In the study of cochlear mechanics, his laboratory currently works on determining the micromechanical motions, forces, and electrochemical signals needed for the "cochlear amplifier." The biological amplifier powers the extraordinary sensitivity of the ear for detection of sound. For the area of cochlear blood flow, his laboratory studies the cellular mechanisms of noise-induced hearing loss in the vascular tissue and in the sensory cells of the organ of Corti. This damage includes a form of stress induced inflammation. The goal of the laboratory is to understand the molecular mechanisms of the damage from exposure to loud sound. An additional goal is to develop imaging technology for the clinical assessment of altered blood flow in the human ear and for the diagnosis of Ménière's disease. 

Cochlear Mechanics:
The broad goal is to understand the electro-mechanical processing of acoustic energy by the cells of the organ of Corti. This process consists of the transduction of the sound stimulated vibration of the organ through movement of stereocilia of hair cells. This movement gates a mechano-sensitive channel. One type of hair cell, the outer hair cell, has a voltage-sensitive motor capable of changing cell mechanical properties at great speed. These properties of hair cells set the stage for what is thought to be a feedback amplifier of the acoustic stimulus.  The pathophysiology of sound is studied by measurements of the dynamic changes in the electrical and mechanical properties of the organ. Pharmacological and genetic approaches are used to manipulate hair cells in combination with sound.

Current projects: 
Developing non-invasive techniques to perform structural and vibrational imaging of the microstructure of the hearing organ (organ of Corti).  Laser Doppler vibrometry (LDV) is a non-invasive tool for the study of cochlear mechanics. There has been a growing interest in the field of hearing research to adopt optical coherence tomography (OCT) as a tool for the studies of cochlear mechanics. We developed recently, a Fourier domain OCT (PSFDOCT) for vibration of tissue at a sub-nanometer scale with dual angle delay encoded small beam capable of measuring both radial and transverse motion.

Investigating the mechanisms underlying speech-frequency hearing. To understand how the cochlea encodes speech, we need to examine regions that actually represent speech, since several studies indicate that mechanisms Nuttall Lab imageof low frequency hearing differ substantially from those in the extensively studied cochlear base, which mediates high-frequency hearing. Sound entering the outer ear vibrates the stapes and stimulates the cochlea via the launch of a fluid-structure traveling wave along the structures in the inner ear. The constituent sound frequencies are separated along the length of the cochlea with high frequencies near the stapes, which inputs sound energy and low frequencies near the cochlear apex. The sound-induced vibrations inside the cochlea are highly complex in a living mammal and are vulnerable to damage. These vibrations could, therefore, provide important information on the mechanisms of normal and impaired hearing. Recent developments, pioneered largely by our group have made it feasi¬ble to study the previously inaccessible low-frequency parts of the cochlea in vivo, without creating an artificial opening in the bony capsule. These advances remove concerns about artifacts that plagued research on low-frequency hearing mechanisms for decades and we are now entering a new era of minimally invasive in vivo studies. These studies will help us understand how the cochlea encodes speech, and may allow optimized stimulation paradigms to be designed for cochlear implants.

Cochlear Blood Flow:
The overarching goal of these studies is to learn the role of inner ear blood flow in normal cochlear function (homeostasis) and pathological conditions such as loud sound induced damage. The blood flow to the inner ear is supplied by a single end artery, the spiral modiolar artery. This small artery has various mechanisms of vasoconstriction and dilation.  The capillary-based control of flow and vascular permeability of the capillaries are being studied as a pathological mechanisms of age and noise induced hearing loss.  Current projects: In collaboration with Drs. Ricky Wang and Timothy Hullar, we are currently developing an outpatient optical coherence tomography/optical microangiography (OCT/OMAG) instrument capable of taking 3D images of the cochlea. The goal of this translational research is to use OMAG in clinical settings for quantitatively measuring CoBF and imaging Reissner’s membrane in order to aid in the diagnosis of SSHL and Meniere’s disease. With this instrument, we will be able to measure CoBF and, ultimately, to categorize the flow level as normal or abnormal and to identify the position of the Reissner’s membrane. This information can reveal whether cochlea hydrops is present and, in turn, can assist in the diagnosis of Meniere’s disease. Our instrument will also provide data that will be useful in determining metrics for a diagnosis of ‘vascular’ sudden sensorineural hearing loss (SSHL) and in developing a rational treatment for SSHL, involving vasoactive and anti-inflammatory agents.

Nuttall Lab illustration 

Sound induced signal transduction mechanisms leading to cellular pathology:
Current projects focus on the signal transduction mechanisms by which loud sound alters blood flow, vascular permeability and cellular damage in multiple cells types in the cochlea including outer hair cells, fibrocytes and endothelial cells. We have found that the JAK2/STAT3 plays a key role in the generation of reactive oxygen species in outer hair cells. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor, activated by phosphorylation in response to cytokines, hormones, growth factors and vasoactive agents.  Transcriptional targets of STAT3 include vascular endothelial growth factor, manganese superoxide dismutase and survivin. Inhibiting the JAK2/STAT3 pathway (with JSI-124) reduces loud sound-induced  reactive oxygen species in outer hair cells as shown by fluorescent intensity (CellROX Green, 488) at 2 h following noise exposure (NE) shown below.  Further studies reveal that STAT3 inhibition increase outer hair cell survival within the basal region of the cochlea improves auditory brainstem responses. 

Nuttall Lab fig3

We are also investigating the mechanisms by which loud sound induced temporary hearing loss induced hypoxia/ischemia can result in dynamic changes in endothelial cell cytoskeletal organization, a hallmark of vascular permeability change and loss of barrier function in the stria vascularis.  VE-Cadherin is required for maintaining a restrictive endothelial barrier.  We have been able to image endothelial cells of intact isolated capillaries in the stria vascularis with super resolution microscopy, and are investigating upstream signaling cascades leading to the alterations in VE-cadherin location and endothelial cell function.

Nuttall Lab illustration