RESUMO
Novel stimulation methods are needed to overcome the limitations of contemporary cochlear implants. Optogenetics is a technique that confers light sensitivity to neurons via the genetic introduction of light-sensitive ion channels. By controlling neural activity with light, auditory neurons can be activated with higher spatial precision. Understanding the behaviour of opsins at high stimulation rates is an important step towards their translation. To elucidate this, we compared the temporal characteristics of auditory nerve and inferior colliculus responses to optogenetic, electrical, and combined optogenetic-electrical stimulation in virally transduced mice expressing one of two channelrhodopsins, ChR2-H134R or ChIEF, at stimulation rates up to 400 pulses per second (pps). At 100 pps, optogenetic responses in ChIEF mice demonstrated higher fidelity, less change in latency, and greater response stability compared to responses in ChR2-H134R mice, but not at higher rates. Combined stimulation improved the response characteristics in both cohorts at 400 pps, although there was no consistent facilitation of electrical responses. Despite these results, day-long stimulation (up to 13 h) led to severe and non-recoverable deterioration of the optogenetic responses. The results of this study have significant implications for the translation of optogenetic-only and combined stimulation techniques for hearing loss.
Assuntos
Vias Auditivas , Channelrhodopsins , Estimulação Elétrica , Optogenética , Animais , Optogenética/métodos , Camundongos , Vias Auditivas/fisiologia , Vias Auditivas/metabolismo , Channelrhodopsins/metabolismo , Channelrhodopsins/genética , Estimulação Elétrica/métodos , Colículos Inferiores/fisiologia , Colículos Inferiores/metabolismo , Nervo Coclear/fisiologia , Nervo Coclear/metabolismo , Cinética , Implantes CoclearesRESUMO
Several studies suggest that hearing loss results in changes in the balance between inhibition and excitation in the inferior colliculus (IC). The IC is an integral nucleus within the auditory brainstem. The majority of ascending pathways from the lateral lemniscus (LL), superior olivary complex (SOC), and cochlear nucleus (CN) synapse in the IC before projecting to the thalamus and cortex. Many of these ascending projections provide inhibitory innervation to neurons within the IC. However, the nature and the distribution of this inhibitory input have only been partially elucidated in the rat. The inhibitory neurotransmitter, gamma aminobutyric acid (GABA), from the ventral nucleus of the lateral lemniscus (VNLL), provides the primary inhibitory input to the IC of the rat with GABA from other lemniscal and SOC nuclei providing lesser, but prominent innervation. There is evidence that hearing related conditions can result in dysfunction of IC neurons. These changes may be mediated in part by changes in GABA inputs to IC neurons. We have previously used gene micro-arrays in a study of deafness-related changes in gene expression in the IC and found significant changes in GAD as well as the GABA transporters and GABA receptors (Holt 2005). This is consistent with reports of age and trauma related changes in GABA (Bledsoe et al., 1995; Mossop et al., 2000; Salvi et al., 2000). Ototoxic lesions of the cochlea produced a permanent threshold shift. The number, intensity, and density of GABA positive axon terminals in the IC were compared in normal hearing and deafened rats. While the number of GABA immunolabeled puncta was only minimally different between groups, the intensity of labeling was significantly reduced. The ultrastructural localization and distribution of labeling was also examined. In deafened animals, the number of immuno gold particles was reduced by 78 % in axodendritic and 82 % in axosomatic GABAergic puncta. The affected puncta were primarily associated with small IC neurons. These results suggest that reduced inhibition to IC neurons contribute to the increased neuronal excitability observed in the IC following noise or drug induced hearing loss. Whether these deafness diminished inhibitory inputs originate from intrinsic or extrinsic CNIC sources awaits further study.
Assuntos
Colículos Inferiores , Ratos Sprague-Dawley , Ácido gama-Aminobutírico , Animais , Colículos Inferiores/metabolismo , Colículos Inferiores/patologia , Ácido gama-Aminobutírico/metabolismo , Perda Auditiva Provocada por Ruído/metabolismo , Perda Auditiva Provocada por Ruído/fisiopatologia , Perda Auditiva Provocada por Ruído/patologia , Ototoxicidade/metabolismo , Ototoxicidade/etiologia , Masculino , Vias Auditivas/metabolismo , Vias Auditivas/patologia , Vias Auditivas/fisiopatologia , Modelos Animais de Doenças , Imuno-Histoquímica , Ratos , Glutamato Descarboxilase/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Inibição NeuralRESUMO
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 determine the neural circuits underlying this convergence and to model how the binaural cues encode location. It has been shown that midbrain neurons are largely excited by sound from the contralateral ear and inhibited by sound leading at the ipsilateral ear. In this context, ascending projections from the lateral superior olive (LSO) to the IC have been reported to be ipsilaterally glycinergic and contralaterally glutamatergic. This study used CBA/CaH mice (3-6 months old) and applied unilateral retrograde tracing techniques into the IC in conjunction with immunocytochemical methods with glycine and glutamate transporters (GlyT2 and vGLUT2, respectively) to analyze the projection patterns from the LSO to the IC. Glycinergic and glutamatergic neurons were spatially intermixed within the LSO, and both types projected to the IC. For GlyT2 and vGLUT2 neurons, the average percentage of ipsilaterally and contralaterally projecting cells was similar (ANOVA, p = 0.48). A roughly equal number of GlyT2 and vGLUT2 neurons did not project to the IC. The somatic size and shape of these neurons match the descriptions of LSO principal cells. A minor but distinct population of small (< 40 µm2) neurons that labeled for GlyT2 did not project to the IC; these cells emerge as candidates for inhibitory local circuit neurons. Our findings indicate a symmetric and bilateral projection of glycine and glutamate neurons from the LSO to the IC. The differences between our results and those from previous studies suggest that species and habitat differences have a significant role in mechanisms of binaural processing and highlight the importance of research methods and comparative neuroscience. These data will be important for modeling how excitatory and inhibitory systems converge to create auditory space in the CBA/CaH mouse.
Assuntos
Vias Auditivas , Ácido Glutâmico , Proteínas da Membrana Plasmática de Transporte de Glicina , Glicina , Colículos Inferiores , Camundongos Endogâmicos CBA , Complexo Olivar Superior , Animais , Glicina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Camundongos , Colículos Inferiores/fisiologia , Colículos Inferiores/metabolismo , Colículos Inferiores/citologia , Vias Auditivas/fisiologia , Vias Auditivas/metabolismo , Ácido Glutâmico/metabolismo , Complexo Olivar Superior/fisiologia , Complexo Olivar Superior/metabolismo , Masculino , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo , Neurônios/metabolismo , Neurônios/fisiologiaRESUMO
Cholinergic signaling is essential to mediate the auditory prepulse inhibition (PPI), an operational measure of sensorimotor gating, that refers to the reduction of the acoustic startle reflex (ASR) when a low-intensity, non-startling acoustic stimulus (the prepulse) is presented just before the onset of the acoustic startle stimulus. The cochlear root neurons (CRNs) are the first cells of the ASR circuit to receive cholinergic inputs from non-olivocochlear neurons of the ventral nucleus of the trapezoid body (VNTB) and subsequently decrease their neuronal activity in response to auditory prepulses. Yet, the contribution of the VNTB-CRNs pathway to the mediation of PPI has not been fully elucidated. In this study, we used the immunotoxin anti-choline acetyltransferase (ChAT)-saporin as well as electrolytic lesions of the medial olivocochlear bundle to selectively eliminate cholinergic VNTB neurons, and then assessed the ASR and PPI paradigms. Retrograde track-tracing experiments were conducted to precisely determine the site of lesioning VNTB neurons projecting to the CRNs. Additionally, the effects of VNTB lesions and the integrity of the auditory pathway were evaluated via auditory brain responses tests, ChAT- and FOS-immunohistochemistry. Consequently, we established three experimental groups: 1) intact control rats (non-lesioned), 2) rats with bilateral lesions of the olivocochlear bundle (OCB-lesioned), and 3) rats with bilateral immunolesions affecting both the olivocochlear bundle and the VNTB (OCB/VNTB-lesioned). All experimental groups underwent ASR and PPI tests at several interstimulus intervals before the lesion and 7, 14, and 21 days after it. Our results show that the ASR amplitude remained unaffected both before and after the lesion across all experimental groups, suggesting that the VNTB does not contribute to the ASR. The%PPI increased across the time points of evaluation in the control and OCB-lesioned groups but not in the OCB/VNTB-lesioned group. At the ISI of 50 ms, the OCB-lesioned group exhibited a significant increase in%PPI (p < 0.01), which did not occur in the OCB/VNTB-lesioned group. Therefore, the ablation of cholinergic non-olivocochlear neurons in the OCB/VNTB-lesioned group suggests that these neurons contribute to the mediation of auditory PPI at the 50 ms ISI through their cholinergic projections to CRNs. Our study strongly reinforces the notion that auditory PPI encompasses a complex mechanism of top-down cholinergic modulation, effectively attenuating the ASR across different interstimulus intervals within multiple pathways.
Assuntos
Estimulação Acústica , Vias Auditivas , Inibição Pré-Pulso , Reflexo de Sobressalto , Corpo Trapezoide , Animais , Inibição Pré-Pulso/fisiologia , Masculino , Corpo Trapezoide/metabolismo , Corpo Trapezoide/fisiologia , Vias Auditivas/fisiologia , Vias Auditivas/metabolismo , Ratos Sprague-Dawley , Saporinas/metabolismo , Colina O-Acetiltransferase/metabolismo , Neurônios Colinérgicos/metabolismo , Neurônios Colinérgicos/fisiologia , Proteínas Inativadoras de Ribossomos Tipo 1 , Potenciais Evocados Auditivos do Tronco Encefálico , Imunotoxinas , Nervo Coclear/metabolismo , Nervo Coclear/fisiologia , RatosRESUMO
Unlike megabats, which rely on well-developed vision, microbats use ultrasonic echolocation to navigate and locate prey. To study ultrasound perception, here we compared the auditory cortices of microbats and megabats by constructing reference genomes and single-nucleus atlases for four species. We found that parvalbumin (PV)+ neurons exhibited evident cross-species differences and could respond to ultrasound signals, whereas their silencing severely affected ultrasound perception in the mouse auditory cortex. Moreover, megabat PV+ neurons expressed low levels of complexins (CPLX1-CPLX4), which can facilitate neurotransmitter release, while microbat PV+ neurons highly expressed CPLX1, which improves neurotransmission efficiency. Further perturbation of Cplx1 in PV+ neurons impaired ultrasound perception in the mouse auditory cortex. In addition, CPLX1 functioned in other parts of the auditory pathway in microbats but not megabats and exhibited convergent evolution between echolocating microbats and whales. Altogether, we conclude that CPLX1 expression throughout the entire auditory pathway can enhance mammalian ultrasound neurotransmission.
Assuntos
Córtex Auditivo , Vias Auditivas , Proteínas do Tecido Nervoso , Transmissão Sináptica , Animais , Masculino , Camundongos , Córtex Auditivo/metabolismo , Vias Auditivas/metabolismo , Ecolocação , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Parvalbuminas/metabolismo , Parvalbuminas/genéticaRESUMO
Cortical acetylcholine (ACh) release has been linked to various cognitive functions, including perceptual learning. We have previously shown that cortical cholinergic innervation is necessary for accurate sound localization in ferrets, as well as for their ability to adapt with training to altered spatial cues. To explore whether these behavioral deficits are associated with changes in the response properties of cortical neurons, we recorded neural activity in the primary auditory cortex (A1) of anesthetized ferrets in which cholinergic inputs had been reduced by making bilateral injections of the immunotoxin ME20.4-SAP in the nucleus basalis (NB) prior to training the animals. The pattern of spontaneous activity of A1 units recorded in the ferrets with cholinergic lesions (NB ACh-) was similar to that in controls, although the proportion of burst-type units was significantly lower. Depletion of ACh also resulted in more synchronous activity in A1. No changes in thresholds, frequency tuning or in the distribution of characteristic frequencies were found in these animals. When tested with normal acoustic inputs, the spatial sensitivity of A1 neurons in the NB ACh- ferrets and the distribution of their preferred interaural level differences also closely resembled those found in control animals, indicating that these properties had not been altered by sound localization training with one ear occluded. Simulating the animals' previous experience with a virtual earplug in one ear reduced the contralateral preference of A1 units in both groups, but caused azimuth sensitivity to change in slightly different ways, which may reflect the modest adaptation observed in the NB ACh- group. These results show that while ACh is required for behavioral adaptation to altered spatial cues, it is not required for maintenance of the spectral and spatial response properties of A1 neurons.
Assuntos
Estimulação Acústica , Córtex Auditivo , Prosencéfalo Basal , Furões , Animais , Córtex Auditivo/metabolismo , Córtex Auditivo/fisiopatologia , Prosencéfalo Basal/metabolismo , Localização de Som , Acetilcolina/metabolismo , Masculino , Neurônios Colinérgicos/metabolismo , Neurônios Colinérgicos/patologia , Vias Auditivas/fisiopatologia , Vias Auditivas/metabolismo , Feminino , Imunotoxinas/toxicidade , Núcleo Basal de Meynert/metabolismo , Núcleo Basal de Meynert/fisiopatologia , Núcleo Basal de Meynert/patologia , Neurônios/metabolismo , Limiar Auditivo , Adaptação Fisiológica , Comportamento AnimalRESUMO
The auditory cortex is the source of descending connections providing contextual feedback for auditory signal processing at almost all levels of the lemniscal auditory pathway. Such feedback is essential for cognitive processing. It is likely that corticofugal pathways are degraded with aging, becoming important players in age-related hearing loss and, by extension, in cognitive decline. We are testing the hypothesis that surface, epidural stimulation of the auditory cortex during aging may regulate the activity of corticofugal pathways, resulting in modulation of central and peripheral traits of auditory aging. Increased auditory thresholds during ongoing age-related hearing loss in the rat are attenuated after two weeks of epidural stimulation with direct current applied to the surface of the auditory cortex for two weeks in alternate days (Fernández del Campo et al., 2024). Here we report that the same cortical electrical stimulation protocol induces structural and cytochemical changes in the aging cochlea and auditory brainstem, which may underlie recovery of age-degraded auditory sensitivity. Specifically, we found that in 18 month-old rats after two weeks of cortical electrical stimulation there is, relative to age-matched non-stimulated rats: a) a larger number of choline acetyltransferase immunoreactive neuronal cell body profiles in the ventral nucleus of the trapezoid body, originating the medial olivocochlear system.; b) a reduction of age-related dystrophic changes in the stria vascularis; c) diminished immunoreactivity for the pro-inflammatory cytokine TNFα in the stria vascularis and spiral ligament. d) diminished immunoreactivity for Iba1 and changes in the morphology of Iba1 immunoreactive cells in the lateral wall, suggesting reduced activation of macrophage/microglia; d) Increased immunoreactivity levels for calretinin in spiral ganglion neurons, suggesting excitability modulation by corticofugal stimulation. Altogether, these findings support that non-invasive neuromodulation of the auditory cortex during aging preserves the cochlear efferent system and ameliorates cochlear aging traits, including stria vascularis dystrophy, dysregulated inflammation and altered excitability in primary auditory neurons.
Assuntos
Envelhecimento , Córtex Auditivo , Vias Auditivas , Cóclea , Estimulação Elétrica , Presbiacusia , Animais , Masculino , Fatores Etários , Envelhecimento/patologia , Envelhecimento/metabolismo , Córtex Auditivo/metabolismo , Córtex Auditivo/fisiopatologia , Vias Auditivas/fisiopatologia , Vias Auditivas/metabolismo , Limiar Auditivo , Proteínas de Ligação ao Cálcio , Colina O-Acetiltransferase/metabolismo , Cóclea/inervação , Cóclea/metabolismo , Cóclea/fisiopatologia , Cóclea/patologia , Modelos Animais de Doenças , Potenciais Evocados Auditivos do Tronco Encefálico , Audição , Proteínas dos Microfilamentos , Microglia/metabolismo , Microglia/patologia , Neurônios Eferentes/metabolismo , Núcleo Olivar/metabolismo , Presbiacusia/fisiopatologia , Presbiacusia/metabolismo , Presbiacusia/patologia , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Tinnitus is known to affect 10-15 % of the population, severely impacting 1-2 % of those afflicted. Canonically, tinnitus is generally a consequence of peripheral auditory damage resulting in maladaptive plastic changes in excitatory/inhibitory homeostasis at multiple levels of the central auditory pathway as well as changes in diverse nonauditory structures. Animal studies of primary auditory cortex (A1) generally find tinnitus-related changes in excitability across A1 layers and differences between inhibitory neuronal subtypes. Changes due to sound-exposure include changes in spontaneous activity, cross-columnar synchrony, bursting and tonotopic organization. Few studies in A1 directly correlate tinnitus-related changes in neural activity to an individual animal's behavioral evidence of tinnitus. The present study used an established condition-suppression sound-exposure model of chronic tinnitus and recorded spontaneous and driven single-unit responses from A1 layers 5 and 6 of awake Long-Evans rats. A1 units recorded from animals with behavioral evidence of tinnitus showed significant increases in spontaneous and sound-evoked activity which directly correlated to the animal's tinnitus score. Significant increases in the number of bursting units, the number of bursts/minute and burst duration were seen for A1 units recorded from animals with behavioral evidence of tinnitus. The present A1 findings support prior unit recording studies in auditory thalamus and recent in vitro findings in this same animal model. The present findings are consistent with sensory cortical studies showing tinnitus- and neuropathic pain-related down-regulation of inhibition and increased excitation based on plastic neurotransmitter and potassium channel changes. Reducing A1 deep-layer tinnitus-related hyperactivity is a potential target for tinnitus pharmacotherapy.
Assuntos
Córtex Auditivo , Zumbido , Ratos , Animais , Córtex Auditivo/fisiologia , Zumbido/metabolismo , Vigília , Ratos Long-Evans , Vias Auditivas/metabolismoRESUMO
Auditory dysfunction and increased neuronal activity in the auditory pathways have been reported in patients with temporal lobe epilepsy, but the cellular mechanisms involved are unknown. Here, we report that microglia play a role in the disinhibition of auditory pathways after status epilepticus in mice. We found that neuronal activity in the auditory pathways, including the primary auditory cortex and the medial geniculate body (MGB), was increased and auditory discrimination was impaired after status epilepticus. We further demonstrated that microglia reduced inhibitory synapses on MGB relay neurons over an 8-week period after status epilepticus, resulting in auditory pathway hyperactivity. In addition, we found that local removal of microglia from the MGB attenuated the increase in c-Fos+ relay neurons and improved auditory discrimination. These findings reveal that thalamic microglia are involved in auditory dysfunction in epilepsy.
Assuntos
Microglia , Estado Epiléptico , Camundongos , Humanos , Animais , Corpos Geniculados/metabolismo , Tálamo , Vias Auditivas/metabolismo , Estado Epiléptico/metabolismoRESUMO
Hyperacusis, i.e., an increased sensitivity to sounds, is described in several neurodevelopmental disorders (NDDs), including Fragile X Syndrome (FXS). The mechanisms underlying hyperacusis in FXS are still largely unknown and effective therapies are lacking. Big conductance calcium-activated potassium (BKCa) channels were proposed as a therapeutic target to treat several behavioral disturbances in FXS preclinical models, but their role in mediating their auditory alterations was not specifically addressed. Furthermore, studies on the acoustic phenotypes of FXS animal models mostly focused on central rather than peripheral auditory pathways. Here, we provided an extensive characterization of the peripheral auditory phenotype of the Fmr1-knockout (KO) mouse model of FXS at adulthood. We also assessed whether the acute administration of Chlorzoxazone, a BKCa agonist, could rescue the auditory abnormalities of adult mutant mice. Fmr1-KO mice both at 3 and 6 months showed a hyperacusis-like startle phenotype with paradoxically reduced auditory brainstem responses associated with a loss of ribbon synapses in the inner hair cells (IHCs) compared to their wild-type (WT) littermates. BKCa expression was markedly reduced in the IHCs of KOs compared to WT mice, but only at 6 months, when Chlorzoxazone rescued mutant auditory dysfunction. Our findings highlight the age-dependent and progressive contribution of peripheral mechanisms and BKCa channels to adult hyperacusis in FXS, suggesting a novel therapeutic target to treat auditory dysfunction in NDDs.
Assuntos
Síndrome do Cromossomo X Frágil , Hiperacusia , Animais , Camundongos , Vias Auditivas/metabolismo , Clorzoxazona , Modelos Animais de Doenças , Proteína do X Frágil da Deficiência Intelectual/genética , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/metabolismo , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta , Camundongos KnockoutRESUMO
Acoustic communication relies crucially on accurate interpretation of information about the intensity, frequency, timing, and location of diverse sound stimuli in the environment. To meet this demand, neurons along different levels of the auditory system form precisely organized neural circuits. The assembly of these precise circuits requires tight regulation and coordination of multiple developmental processes. Several groups of axon guidance molecules have proven critical in controlling these processes. Among them, the family of Eph receptors and their ephrin ligands emerge as one group of key players. They mediate diverse functions at multiple levels of the auditory pathway, including axon guidance and targeting, topographic map formation, as well as cell migration and tissue pattern formation. Here, we review our current knowledge of how Eph and ephrin molecules regulate different processes in the development and maturation of central auditory circuits.
Assuntos
Vias Auditivas , Efrinas , Vias Auditivas/metabolismo , Neurônios/metabolismo , Receptores da Família Eph/metabolismo , Transdução de Sinais/fisiologiaRESUMO
Exposure to nontraumatic noise in vivo drives long-lasting changes in auditory nerve synapses, which may influence hearing, but the induction mechanisms are not known. We mimicked activity in acute slices of the cochlear nucleus from mice of both sexes by treating them with high potassium, after which voltage-clamp recordings from bushy cells indicated that auditory nerve synapses had reduced EPSC amplitude, quantal size, and vesicle release probability (P r). The effects of high potassium were prevented by blockers of nitric oxide (NO) synthase and protein kinase A. Treatment with the NO donor, PAPA-NONOate, also decreased P r, suggesting NO plays a central role in inducing synaptic changes. To identify the source of NO, we activated auditory nerve fibers specifically using optogenetics. Strobing for 2 h led to decreased EPSC amplitude and P r, which was prevented by antagonists against ionotropic glutamate receptors and NO synthase. This suggests that the activation of AMPA and NMDA receptors in postsynaptic targets of auditory nerve fibers drives release of NO, which acts retrogradely to cause long-term changes in synaptic function in auditory nerve synapses. This may provide insight into preventing or treating disorders caused by noise exposure.SIGNIFICANCE STATEMENT Auditory nerve fibers undergo long-lasting changes in synaptic properties in response to noise exposure in vivo, which may contribute to changes in hearing. Here, we investigated the cellular mechanisms underlying induction of synaptic changes using high potassium and optogenetic stimulation in vitro and identified important signaling pathways using pharmacology. Our results suggest that auditory nerve activity drives postsynaptic depolarization through AMPA and NMDA receptors, leading to the release of nitric oxide, which acts retrogradely to regulate presynaptic neurotransmitter release. These experiments revealed that auditory nerve synapses are unexpectedly sensitive to activity and can show dramatic, long-lasting changes in a few hours that could affect hearing.
Assuntos
Núcleo Coclear , Óxido Nítrico , Animais , Vias Auditivas/metabolismo , Nervo Coclear/fisiologia , Núcleo Coclear/fisiologia , Feminino , Masculino , Camundongos , Plasticidade Neuronal/fisiologia , Óxido Nítrico/metabolismo , Potássio/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/metabolismoRESUMO
The lateral cortex of the inferior colliculus (LCIC) is a multimodal subdivision of the midbrain inferior colliculus (IC) that plays a key role in sensory integration. The LCIC is compartmentally-organized, exhibiting a series of discontinuous patches or modules surrounded by an extramodular matrix. In adult mice, somatosensory afferents target LCIC modular zones, while auditory afferents terminate throughout the encompassing matrix. Recently, we defined an early LCIC critical period (birth: postnatal day 0 to P12) based upon the concurrent emergence of its neurochemical compartments (modules: glutamic acid decarboxylase, GAD+; matrix: calretinin, CR+), matching Eph-ephrin guidance patterns, and specificity of auditory inputs for its matrix. Currently lacking are analogous experiments that address somatosensory afferent shaping and the construction of discrete LCIC multisensory maps. Combining living slice tract-tracing and immunocytochemical approaches in a developmental series of GAD67-GFP knock-in mice, the present study characterizes: (1) the targeting of somatosensory terminals for emerging LCIC modular fields; and (2) the relative separation of somatosensory and auditory inputs over the course of its established critical period. Results indicate a similar time course and progression of LCIC projection shaping for both somatosensory (corticocollicular) and auditory (intracollicular) inputs. While somewhat sparse and intermingling at birth, modality-specific projection patterns soon emerge (P4-P8), coincident with peak guidance expression and the appearance of LCIC compartments. By P12, an adult-like arrangement is in place, with fully segregated multimodal afferent arrays. Quantitative measures confirm increasingly distinct input maps, exhibiting less projection overlap with age. Potential mechanisms whereby multisensory LCIC afferent systems recognize and interface with its emerging modular-matrix framework are discussed.
Assuntos
Vias Auditivas , Colículos Inferiores , Animais , Vias Auditivas/embriologia , Vias Auditivas/metabolismo , Glutamato Descarboxilase/metabolismo , Colículos Inferiores/embriologia , Colículos Inferiores/metabolismo , Camundongos , Neurogênese/fisiologiaRESUMO
Increasing evidence has shown that noise overexposure could lead to impaired hippocampal function. Hippocampal alteration is also observed in several auditory deficits, including hearing loss, and tinnitus. Therefore, the functions of hearing and cognition interact with each other. Here, we summarize the evidence that noise affects the hippocampus from aspects of behavior, neurogenesis, ultrastructure, neurotransmission, other biomarkers, and electrophysiology. We also address hippocampal alterations in auditory disorders, including hearing loss and tinnitus. Based on the current state of the field, we point out several aspects that need further investigation. This review is not only to provide a comprehensive summary of the current state of the field but to emphasize that hearing matters in cognition and pave the way for future research.
Assuntos
Vias Auditivas , Zumbido , Vias Auditivas/metabolismo , Hipocampo/metabolismo , Humanos , Neurogênese , Ruído , Zumbido/metabolismoRESUMO
Behaviorally relevant sounds are often composed of distinct acoustic units organized into specific temporal sequences. The meaning of such sound sequences can therefore be fully recognized only when they have terminated. However, the neural mechanisms underlying the perception of sound sequences remain unclear. Here, we use two-photon calcium imaging in the auditory cortex of behaving mice to test the hypothesis that neural responses to termination of sound sequences ("Off-responses") encode their acoustic history and behavioral salience. We find that auditory cortical Off-responses encode preceding sound sequences and that learning to associate a sound sequence with a reward induces enhancement of Off-responses relative to responses during the sound sequence ("On-responses"). Furthermore, learning enhances network-level discriminability of sound sequences by Off-responses. Last, learning-induced plasticity of Off-responses but not On-responses lasts to the next day. These findings identify auditory cortical Off-responses as a key neural signature of acquired sound-sequence salience.
Assuntos
Comportamento Apetitivo , Córtex Auditivo/fisiologia , Vias Auditivas/fisiologia , Percepção Auditiva , Potenciais Evocados Auditivos , Estimulação Acústica , Animais , Córtex Auditivo/diagnóstico por imagem , Córtex Auditivo/metabolismo , Vias Auditivas/diagnóstico por imagem , Vias Auditivas/metabolismo , Mapeamento Encefálico , Cálcio/metabolismo , Sinalização do Cálcio , Discriminação Psicológica , Feminino , Aprendizagem , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia de Fluorescência por Excitação Multifotônica , Plasticidade Neuronal , Recompensa , Fatores de TempoRESUMO
Anatomical and physiological studies have described the cortex as a six-layer structure that receives, elaborates, and sends out information exclusively as excitatory output to cortical and subcortical regions. This concept has increasingly been challenged by several anatomical and functional studies that showed that direct inhibitory cortical outputs are also a common feature of the sensory and motor cortices. Similar to their excitatory counterparts, subsets of Somatostatin- and Parvalbumin-expressing neurons have been shown to innervate distal targets like the sensory and motor striatum and the contralateral cortex. However, no evidence of long-range VIP-expressing neurons, the third major class of GABAergic cortical inhibitory neurons, has been shown in such cortical regions. Here, using anatomical anterograde and retrograde viral tracing, we tested the hypothesis that VIP-expressing neurons of the mouse auditory and motor cortices can also send long-range projections to cortical and subcortical areas. We were able to demonstrate, for the first time, that VIP-expressing neurons of the auditory cortex can reach not only the contralateral auditory cortex and the ipsilateral striatum and amygdala, as shown for Somatostatin- and Parvalbumin-expressing long-range neurons, but also the medial geniculate body and both superior and inferior colliculus. We also demonstrate that VIP-expressing neurons of the motor cortex send long-range GABAergic projections to the dorsal striatum and contralateral cortex. Because of its presence in two such disparate cortical areas, this would suggest that the long-range VIP projection is likely a general feature of the cortex's network.
Assuntos
Córtex Auditivo/metabolismo , Vias Auditivas/metabolismo , Neurônios GABAérgicos/metabolismo , Córtex Motor/fisiologia , Peptídeo Intestinal Vasoativo/biossíntese , Animais , Córtex Auditivo/química , Vias Auditivas/química , Feminino , Neurônios GABAérgicos/química , Masculino , Camundongos , Camundongos Transgênicos , Técnicas de Cultura de ÓrgãosRESUMO
The avian auditory hindbrain is a longstanding model for studying neural circuit development. Information on gene regulatory network (GRN) components underlying this process, however, is scarce. Recently, the spatiotemporal expression of 12 microRNAs (miRNAs) was investigated in the mammalian auditory hindbrain. As a comparative study, we here investigated the spatiotemporal expression of the orthologous miRNAs during development of the chicken auditory hindbrain. All miRNAs were expressed both at E13, an immature stage, and P14, a mature stage of the auditory system. In most auditory nuclei, a homogeneous expression pattern was observed at both stages, like the mammalian system. An exception was the nucleus magnocellularis (NM). There, at E13, nine miRNAs showed a differential expression pattern along the cochleotopic axis with high expression at the rostromedial pole. One of them showed a gradient expression whereas eight showed a spatially selective expression at the rostral pole that reflected the different rhombomeric origins of this composite nucleus. The miRNA differential expression persisted in the NM to the mature stage, with the selective expression changed to linear gradients. Bioinformatics analysis predicted mRNA targets that are associated with neuronal developmental processes such as neurite and synapse organization, calcium and ephrin-Eph signaling, and neurotransmission. Overall, this first analysis of miRNAs in the chicken central auditory system reveals shared and strikingly distinct features between chicken and murine orthologues. The embryonic gradient expression of these GRN elements in the NM adds miRNA patterns to the list of cochleotopic and developmental gradients in the central auditory system.
Assuntos
Vias Auditivas/crescimento & desenvolvimento , Vias Auditivas/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , MicroRNAs/biossíntese , Rombencéfalo/crescimento & desenvolvimento , Rombencéfalo/metabolismo , Animais , Vias Auditivas/embriologia , Galinhas , Feminino , Masculino , MicroRNAs/genética , Rombencéfalo/embriologiaRESUMO
The mechanisms that govern thalamocortical transmission are poorly understood. Recent data have shown that sensory stimuli elicit activity in ensembles of cortical neurons that recapitulate stereotyped spontaneous activity patterns. Here, we elucidate a possible mechanism by which gating of patterned population cortical activity occurs. In this study, sensory-evoked all-or-none cortical population responses were observed in the mouse auditory cortex in vivo and similar stochastic cortical responses were observed in a colliculo-thalamocortical brain slice preparation. Cortical responses were associated with decreases in auditory thalamic synaptic inhibition and increases in thalamic synchrony. Silencing of corticothalamic neurons in layer 6 (but not layer 5) or the thalamic reticular nucleus linearized the cortical responses, suggesting that layer 6 corticothalamic feedback via the thalamic reticular nucleus was responsible for gating stochastic cortical population responses. These data implicate a corticothalamic-thalamic reticular nucleus circuit that modifies thalamic neuronal synchronization to recruit populations of cortical neurons for sensory representations.
Assuntos
Córtex Auditivo/fisiologia , Vias Auditivas/fisiologia , Percepção Auditiva , Sincronização Cortical , Audição , Filtro Sensorial , Transmissão Sináptica , Núcleos Talâmicos/fisiologia , Estimulação Acústica , Animais , Córtex Auditivo/metabolismo , Vias Auditivas/metabolismo , Estimulação Elétrica , Potenciais Evocados Auditivos , Feminino , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibição Neural , Núcleos Talâmicos/metabolismo , Fatores de TempoRESUMO
The precise and specialized circuitry in the auditory brainstem develops through adaptations of cellular and molecular signaling. We previously showed that elimination of microglia during development impairs synaptic pruning that leads to maturation of the calyx of Held, a large encapsulating synapse that terminates on neurons of the medial nucleus of the trapezoid body (MNTB). Microglia depletion also led to a decrease in glial fibrillary acidic protein (GFAP), a marker for mature astrocytes. Here, we investigated the role of signaling through the fractalkine receptor (CX3CR1), which is expressed by microglia and mediates communication with neurons. CX3CR1-/- and wild-type mice were studied before and after hearing onset and at 9 weeks of age. Levels of GFAP were significantly increased in the MNTB in mutants at 9 weeks. Pruning was unaffected at the calyx of Held, but we found an increase in expression of glycinergic synaptic marker in mutant mice at P14, suggesting an effect on maturation of inhibitory inputs. We observed disrupted tonotopic gradients of neuron and calyx size in MNTB in mutant mice. Auditory brainstem recording (ABR) revealed that CX3CR1-/- mice had normal thresholds and amplitudes but decreased latencies and interpeak latencies, particularly for the highest frequencies. These results demonstrate that disruption of fractalkine signaling has a significant effect on auditory brainstem development. Our findings highlight the importance of neuron-microglia-astrocyte communication in pruning of inhibitory synapses and establishment of tonotopic gradients early in postnatal development.
Assuntos
Astrócitos/metabolismo , Tronco Encefálico/metabolismo , Receptor 1 de Quimiocina CX3C/genética , Mutação/genética , Sinapses/genética , Sinapses/metabolismo , Animais , Vias Auditivas/metabolismo , Receptor 1 de Quimiocina CX3C/deficiência , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Feminino , Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasticidade Neuronal/fisiologia , Tempo de Reação/fisiologiaRESUMO
Growth hormone (GH) plays an important role in auditory development during the embryonic stage. Exogenous agents such as sound, noise, drugs or trauma, can induce the release of this hormone to perform a protective function and stimulate other mediators that protect the auditory pathway. In addition, GH deficiency conditions hearing loss or central auditory processing disorders. There are promising animal studies that reflect a possible regenerative role when exogenous GH is used in hearing impairments, demonstrated in in vivo and in vitro studies, and also, even a few studies show beneficial effects in humans presented and substantiated in the main text, although they should not exaggerate the main conclusions.