Selective Deletion of Cochlear Hair Cells Causes Rapid Age-Dependent Changes in Spiral Ganglion and Cochlear Nucleus Neurons

Tong, Ling; Strong, Melissa K.; Kaur, Tejbeer; Juı́z, José M.; Oesterle, Elizabeth C.; Hume, Clifford R.; Warchol, Mark E.; Palmiter, Richard D.; Rubel, Edwin W.

doi:10.1523/jneurosci.2179-14.2015

Cited by 73 publications

(104 citation statements)

References 55 publications

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“…We used light microscopy to examine the stria vascularis in the same Pou4f3 DTR/ϩ mice following EP measurements and observed no obvious structural changes (data not shown). These data on C57BL/6J mice confirm and extend the data presented earlier by Tong et al (2015).…”

Section: Aјaљ) In Contrast Dt Treatment Of Pou4f3supporting

confidence: 92%

“…Our results, which are consistent with those of Tong et al (2015), indicate that SGNs can survive without hair cell targets for (at least) 56 d after DT treatment (Fig. 2F-J).…”

Section: Dt-induced Hair Cell Ablation Recruits Cochlear Macrophagessupporting

confidence: 91%

“…Similarly, a single DT treatment reduced the amplitude of DPOAEs so that they were indistinguishable from the "noise floor" of the measurement system (data not shown). Prior studies have shown that this functional deficit persists for at least 3 months (Mahrt et al, 2013;Tong et al, 2015). Finally, we measured the endocochlear potential (EP) from the basal cochlear turn in both Pou4f3 ϩ/ϩ and Pou4f3 DTR/ϩ mice at 3 d after DT injection.…”

Section: Aјaљ) In Contrast Dt Treatment Of Pou4f3mentioning

confidence: 95%

“…Identification of Pou4f3 DTR/ϩ and Pou4f3 ϩ/ϩ mice used methods similar to those described by Tong et al (2015). Briefly, tail biopsies were collected, and DNA was extracted using ethanol precipitation.…”

Section: Methodsmentioning

confidence: 99%

“…The secondary antibody solutions also contained DAPI (catalog #D9542, Sigma-Aldrich, 1 g/ml), to label cell nuclei. Proliferating (S-phase) cells were identified via BrdU immunohistochemistry (Warchol et al, 2012). Macrophages that were both BrdU-and GFP-labeled were considered to be undergoing proliferation.…”

Section: :Pou4f3mentioning

confidence: 99%

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Fractalkine Signaling Regulates Macrophage Recruitment into the Cochlea and Promotes the Survival of Spiral Ganglion Neurons after Selective Hair Cell Lesion

et al. 2015

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Macrophages are recruited into the cochlea in response to injury caused by acoustic trauma or ototoxicity, but the nature of the interaction between macrophages and the sensory structures of the inner ear remains unclear. The present study examined the role of fractalkine signaling in regulating the injury-evoked behavior of macrophages following the selective ablation of cochlear hair cells. We used a novel transgenic mouse model in which the human diphtheria toxin receptor (huDTR) is selectively expressed under the control of Pou4f3, a hair cell-specific transcription factor. Administration of diphtheria toxin (DT) to these mice resulted in nearly complete ablation of cochlear hair cells, with no evident pathology among supporting cells, spiral ganglion neurons, or cells of the cochlear lateral wall. Hair cell death led to an increase in macrophages associated with the sensory epithelium of the cochlea. Their numbers peaked at 14 days after DT and then declined at later survival times. Increased macrophages were also observed within the spiral ganglion, but their numbers remained elevated for (at least) 56 d after DT. To investigate the role of fractalkine signaling in macrophage recruitment, we crossed huDTR mice to a mouse line that lacks expression of the fractalkine receptor (CX 3 CR1). Disruption of fractalkine signaling reduced macrophage recruitment into both the sensory epithelium and spiral ganglion and also resulted in diminished survival of spiral ganglion neurons after hair cell death. Our results suggest a fractalkine-mediated interaction between macrophages and the neurons of the cochlea.

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Section: Aјaљ) In Contrast Dt Treatment Of Pou4f3supporting

confidence: 92%

“…Our results, which are consistent with those of Tong et al (2015), indicate that SGNs can survive without hair cell targets for (at least) 56 d after DT treatment (Fig. 2F-J).…”

Section: Dt-induced Hair Cell Ablation Recruits Cochlear Macrophagessupporting

confidence: 91%

Section: Aјaљ) In Contrast Dt Treatment Of Pou4f3mentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

Section: :Pou4f3mentioning

confidence: 99%

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Fractalkine Signaling Regulates Macrophage Recruitment into the Cochlea and Promotes the Survival of Spiral Ganglion Neurons after Selective Hair Cell Lesion

et al. 2015

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Cellular distribution of the fragile X mental retardation protein in the mouse brain

Zorio

Jackson

Liu

et al. 2016

J of Comparative Neurology

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The fragile X mental retardation protein (FMRP) plays an important role in normal brain development. Absence of FMRP, caused by transcriptional silencing of FMR1 gene, results in abnormal neuronal morphologies in a selected manner throughout the brain and leads to intellectual deficits and sensory dysfunction in the fragile X syndrome (FXS). Despite the paramount importance of FMRP for proper brain function, its overall expression pattern in the mammalian brain at the resolution of individual neuronal cell groups is not known. In this study, we used FMR1 knockout and their isogenic wild type mice to systematically map the distribution of FMRP expression in the entire mouse brain. Using immunocytochemistry and cellular quantification analyses, we identified a large number of prominent cell groups expressing high levels of FMRP at the subcortical levels, in particular sensory and motor neurons in the brainstem and thalamus. In contrast, many cell groups in the midbrain and hypothalamus exhibit low FMRP levels. More importantly, we describe differential patterns of FMRP distribution in both cortical and subcortical brain regions. Almost all major brain areas contain high and low levels of FMRP cell groups adjacent to each other or between layers of the same cortical areas. These differential patterns indicate that FMRP expression is specific to individual neuronal cell groups, instead of associated with brain regions as previously considered. Taken together, these findings support the notion that FMRP mechanisms of neuronal regulation are cell-type specific and strongly implicate the contribution of fundamental sensory and motor processing at subcortical levels to FXS pathology.

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Genetic disruption of fractalkine signaling leads to enhanced loss of cochlear afferents following ototoxic or acoustic injury

Kaur

Ohlemiller

Warchol

2017

J of Comparative Neurology

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Cochlear hair cells are vulnerable to a variety of insults like acoustic trauma and ototoxic drugs. Such injury can also lead to degeneration of spiral ganglion neurons (SGNs), but this occurs over a period of months to years. Neuronal survival is necessary for the proper function of cochlear prosthetics, therefore, it is of great interest to understand the mechanisms that regulate neuronal survival in deaf ears. We have recently demonstrated that selective hair cell ablation is sufficient to attract leukocytes into the spiral ganglion, and that fractalkine signaling plays a role in macrophage recruitment and in the survival of auditory neurons. Fractalkine (CX CL1), a chemokine that regulates adhesion and migration of leukocytes is expressed by SGNs and signals to leukocytes via its receptor CX CR1. The present study has extended the previous findings to more clinically relevant conditions of sensorineural hearing loss by examining the role of fractalkine signaling after aminoglycoside ototoxicity or acoustic trauma. Both aminoglycoside treatment and acoustic overstimulation led to the loss of hair cells as well as prolonged increase in the numbers of cochlear leukocytes. Lack of CX CR1 did not affect macrophage recruitment after injury, but resulted in increased loss of SGNs and enhanced expression of the inflammatory cytokine interleukin-1β, when compared to mice with intact CX CR1. These data indicate that the dysregulation of macrophage response caused by the absence of CX CR1 may contribute to inflammation-mediated neuronal loss in the deafened ear, suggesting a key role for inflammation in the long-term survival of target-deprived afferent neurons.

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Selective Deletion of Cochlear Hair Cells Causes Rapid Age-Dependent Changes in Spiral Ganglion and Cochlear Nucleus Neurons

Abstract: During nervous system development, critical periods are usually defined as early periods during which manipulations dramatically change neuronal structure or function, whereas the same manipulations in mature animals have little or no effect on the same property.

Cited by 73 publications

References 55 publications

Fractalkine Signaling Regulates Macrophage Recruitment into the Cochlea and Promotes the Survival of Spiral Ganglion Neurons after Selective Hair Cell Lesion

Fractalkine Signaling Regulates Macrophage Recruitment into the Cochlea and Promotes the Survival of Spiral Ganglion Neurons after Selective Hair Cell Lesion

Cellular distribution of the fragile X mental retardation protein in the mouse brain

Genetic disruption of fractalkine signaling leads to enhanced loss of cochlear afferents following ototoxic or acoustic injury

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