2023-24 Sensory Neuroscience & Engineering Seminar Series
Sensory hair cell regeneration in the zebrafish – how to turn the lateral line into an ear
Tatjana Piotrowski, PhD, Stowers Institute for Medical Research
Hearing loss in mammals is due to the lack of regeneration in the cochlea after the death of mechanosensory hair cells. Regenerating hair cells is a central strategy for restoring hearing, but triggering proliferative regeneration and maturation of hair cells remains elusive. Zebrafish have an array of mechanosensory hair cell-containing neuromasts along the trunk, called the lateral line. Zebrafish hair cells share genetic, functional, and structural similarity with mammalian inner ear hair cells, but zebrafish hair cells readily and rapidly regenerate following death to restore full function. We have characterized the transcriptional changes during regeneration in the lateral line in a fine time scale using scRNA-seq. We identified three subsequently activated gene modules that serve as a blueprint to trigger regeneration in mammals. The transcription factor prdm1a is upregulated in the third module and expressed in hair cells of the lateral line, but not in hair cells of the zebrafish or mammalian inner ear. Previously, prdm1 has been shown to control a fate switch in various cell types, including B lymphocytes and photoreceptors in the retina. We mutated prdm1a in zebrafish and found a cell type fate switch between lateral line and inner ear hair cells, with many specific inner ear hair cell genes ectopically expressed in lateral line hair cells of the mutants. We performed ATAC-seq and ChIP-seq to characterize enhancers and binding motifs that allowed us to build a gene regulatory network that resembles inner versus outer hair cell fate decisions in the mouse. Prdm1a plays an important role in hair cell evolution but might also have implications for triggering hair cell regeneration in the mouse.
Towards Hearing Restoration: Investigating the Genetic Restrictions on Hair Cell Regeneration in the Mature Inner Ear
Melissa McGovern, PhD, University of Pittsburgh
One significant cause of hearing loss is the loss of sensory cells in the inner ear called hair cells. These cells detect sound from the environment and send signals to the brain. These hair cells are susceptible to numerous insults including loud noises (think rock concerts, military activities, industrial noise exposure), ototoxic medications (for example aminoglycoside antibiotics and platinum-based chemotherapeutics), and the natural aging process.
Melissa investigates the ability of the mature mouse ear to respond to genetic reprogramming of non-sensory cells. She has found that cells directly adjacent to the sensory hair cells (called supporting cells) are responsive to reprogramming following hair cell loss. These cells convert into hair cells and attract innervation; however, they do not yet transmit sound signals to the brain. In addition, Melissa has found that other cells within the hearing organ can robustly respond to genetic reprogramming and be converted into hair cells. While these cells are not in the correct location for hearing recovery, these are thought to be the cells that form a scar in the ear following severe cochlear damage. This makes them an important target for hearing restoration therapeutics.
Physics of the Auditory System
Dolores Bozovic, PhD, University of California Los Angeles
Hair cells of the auditory system constitute a remarkable biological sensor that exhibits nanometer-scale sensitivity of mechanical detection. Our experiments explore the active nonlinear processes behind the detection of very weak signals. We demonstrate the presence of chaos in the innate motility of active bundles, and explore both theoretically and experimentally its role in enhancing the sensitivity of detection. We further show that these cells utilize weakly chaotic dynamics to combine sensitive response with high temporal resolution. The presence of chaos in individual hair bundles also aids in the synchronization between coupled hair cells, and gives rise to new dynamical states. Finally, we explore the neural mechanisms that reduce and control the responsiveness of the cell. Specifically, we show that the efferent neurons serve as a gain control system, which can strongly affect the very compliance of the mechanosensory cells.
Mechanisms of Hair Cell Mechanotransduction Sensitivity Control
Anthony Peng, PhD, University of Colorado Denver
Our sense of hearing relies on converting sound vibrations into electrical signals in sensory hair cells. The apically located stereocilia hair bundle is responsible for this conversion of energy through the mechanotransduction process. The regulation of the sensitivity of the mechanotransduction process likely contributes to maximizing the dynamic range of hearing and contributes to the function of the cochlear amplifier. At least two mechanisms can regulate the sensitivity of mechanotransduction. cAMP has been shown to reduced sensitivity of the channel, and we recently described the mechanical changes in the hair bundle leading to the reduction in sensitivity. A second mechanism for sensitivity control is slow adaptation. We recently challenged the prevailing model of slow adaptation and proposed a new model of how slow adaptation functions.
Biophysical diversity amongst inner ear bipolar neurons
Radha Kalluri, PhD, University of Southern California
The cell bodies of vestibular and auditory ganglion neurons express a diverse range of ion channels and neurotransmitter receptors. This diversity provides a rich biophysical substrate for shaping the excitability of neurons and expands the populations’ repertoire for sensory signaling. In the vestibular nerve, the temporal precision needed to code rapid head movements is determined by neurons firing at irregular intervals whereas the ability to sensitively detect slow head movements is determined by neurons firing at regular intervals. I will describe recent work from my laboratory testing the idea that ion channels resident in the membranes of vestibular neurons are responsible for producing this diversity in spike-timing regularity. Our results suggest that definitive relationships between ion channel composition and neuronal function cannot be established without also considering the impact that efferent modulation has on individual ion channels. I’ll show that the role played by an ion channel can be context dependent; varying based on its density, and activation state, as well as on its interactions with other channels. I will end the talk by describing our recent work linking the ion channel properties of spiral ganglion neurons to sub-groups of Type I auditory afferents.