Cochlear nuclei are the first CNS station of auditory pathways, and the sole target of primary auditory fibers from the cochlea, which terminate in a frequency-dependent (tonotopic) pattern. Cochlear nuclei include a ventral nucleus (VCN) involved in binaural comparisons and a dorsal nucleus (DCN) involved in the integration of auditory and nonauditory stimuli. Circuital responses to peripheral damage, such as noise trauma or cochlear destruction, are quite different between VCN and DCN, possibly related to different auditory pathologies (e.g. tinnitus and speech comprehension deficit in noise vs errors in sound localization in space). Microglial responses would be therefore expected to also display differences. However, most studies have so far concentrated on the VCN. We investigated the changes of DCN-related Iba1+ cells after 10 kHz noise trauma and unilateral cochlear destruction. A week after cochlear destruction, disorganized clusters of Iba1+ cells appeared at the ipsilateral DCN surface facing the 4th ventricle, especially at contact sites with the choroid plexus and cerebellum, whereas a rod microglia train was observed at the surface of the contralateral DCN. An increase in ring-shaped and dystrophic microglia was also observed in the ipsilateral DCN. In the choroid plexus, moreover, Iba1+ cells were significantly more numerous on both sides. Three days after noise trauma, Iba1+ cells increased in density and displayed activated morphology in the DCN region corresponding to noise trauma frequencies. At 12 days after trauma, activation had spread through the whole DCN, and superficial clusters of Iba1+ cells and choroid plexus Iba1+ cell increase was observed as for cochlear destruction. Morphological shifts were also observed in the microglial population, with an increase of ring-shaped and amoeboid (but not dystrophic) microglia. Minocycline bolished changes in Iba1+ cell density due to damage, although not morphological activation signs; stereotaxic (LPS) injections in the DCN induced instead a strong local amoeboid microgliosis. On the other hand, neither treatment affected choroid plexus macrophage density. These data suggest that the response of the Iba1+ population after peripheral trauma includes contribution from both local microglia and choroid plexus-derived factors. In order to differentiate Iba1+ populations and assess their relative importance, we labeled them selectively for CCR2 (for inflowing macrophages) and Tmem119 (for resident microglia). Moreover, we labeled other cell types (mast cells, neutrophils) at early stages after damage, counting them in choroid plexus and DCN parenchyma. The present work suggests that the DCN, in addition to integrating nonauditory context nerve signals with auditory stimuli, also integrates immune factors crossing its ventricular surface, possibly in order to differentiate physiological and pathological stimulation patterns.

Choroid plexus trafficking of immune cells towards the rat cochlear nuclei after noise trauma or cochlear destruction

PERIN, PAOLA;VENTURINO, ALESSANDRO;PIZZALA, ROBERTO
2017-01-01

Abstract

Cochlear nuclei are the first CNS station of auditory pathways, and the sole target of primary auditory fibers from the cochlea, which terminate in a frequency-dependent (tonotopic) pattern. Cochlear nuclei include a ventral nucleus (VCN) involved in binaural comparisons and a dorsal nucleus (DCN) involved in the integration of auditory and nonauditory stimuli. Circuital responses to peripheral damage, such as noise trauma or cochlear destruction, are quite different between VCN and DCN, possibly related to different auditory pathologies (e.g. tinnitus and speech comprehension deficit in noise vs errors in sound localization in space). Microglial responses would be therefore expected to also display differences. However, most studies have so far concentrated on the VCN. We investigated the changes of DCN-related Iba1+ cells after 10 kHz noise trauma and unilateral cochlear destruction. A week after cochlear destruction, disorganized clusters of Iba1+ cells appeared at the ipsilateral DCN surface facing the 4th ventricle, especially at contact sites with the choroid plexus and cerebellum, whereas a rod microglia train was observed at the surface of the contralateral DCN. An increase in ring-shaped and dystrophic microglia was also observed in the ipsilateral DCN. In the choroid plexus, moreover, Iba1+ cells were significantly more numerous on both sides. Three days after noise trauma, Iba1+ cells increased in density and displayed activated morphology in the DCN region corresponding to noise trauma frequencies. At 12 days after trauma, activation had spread through the whole DCN, and superficial clusters of Iba1+ cells and choroid plexus Iba1+ cell increase was observed as for cochlear destruction. Morphological shifts were also observed in the microglial population, with an increase of ring-shaped and amoeboid (but not dystrophic) microglia. Minocycline bolished changes in Iba1+ cell density due to damage, although not morphological activation signs; stereotaxic (LPS) injections in the DCN induced instead a strong local amoeboid microgliosis. On the other hand, neither treatment affected choroid plexus macrophage density. These data suggest that the response of the Iba1+ population after peripheral trauma includes contribution from both local microglia and choroid plexus-derived factors. In order to differentiate Iba1+ populations and assess their relative importance, we labeled them selectively for CCR2 (for inflowing macrophages) and Tmem119 (for resident microglia). Moreover, we labeled other cell types (mast cells, neutrophils) at early stages after damage, counting them in choroid plexus and DCN parenchyma. The present work suggests that the DCN, in addition to integrating nonauditory context nerve signals with auditory stimuli, also integrates immune factors crossing its ventricular surface, possibly in order to differentiate physiological and pathological stimulation patterns.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11571/1184776
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