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1.
Hear Res ; 447: 109025, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38733712

ABSTRACT

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.


Subject(s)
Acoustic Stimulation , Auditory Cortex , Basal Forebrain , Ferrets , Animals , Auditory Cortex/metabolism , Auditory Cortex/physiopathology , Basal Forebrain/metabolism , Sound Localization , Acetylcholine/metabolism , Male , Cholinergic Neurons/metabolism , Cholinergic Neurons/pathology , Auditory Pathways/physiopathology , Auditory Pathways/metabolism , Female , Immunotoxins/toxicity , Basal Nucleus of Meynert/metabolism , Basal Nucleus of Meynert/physiopathology , Basal Nucleus of Meynert/pathology , Neurons/metabolism , Auditory Threshold , Adaptation, Physiological , Behavior, Animal
2.
Hear Res ; 447: 109008, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38636186

ABSTRACT

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.


Subject(s)
Aging , Auditory Cortex , Auditory Pathways , Cochlea , Electric Stimulation , Presbycusis , Animals , Auditory Cortex/metabolism , Auditory Cortex/physiopathology , Cochlea/innervation , Cochlea/metabolism , Cochlea/physiopathology , Cochlea/pathology , Presbycusis/physiopathology , Presbycusis/metabolism , Presbycusis/pathology , Auditory Pathways/physiopathology , Auditory Pathways/metabolism , Male , Aging/pathology , Aging/metabolism , Disease Models, Animal , Age Factors , Neurons, Efferent/metabolism , Microglia/metabolism , Microglia/pathology , Auditory Threshold , Choline O-Acetyltransferase/metabolism , Olivary Nucleus/metabolism , Evoked Potentials, Auditory, Brain Stem , Hearing , Rats, Sprague-Dawley , Tumor Necrosis Factor-alpha/metabolism , Calcium-Binding Proteins , Microfilament Proteins
3.
Hear Res ; 445: 108993, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38518392

ABSTRACT

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.


Subject(s)
Auditory Cortex , Tinnitus , Rats , Animals , Auditory Cortex/physiology , Tinnitus/metabolism , Wakefulness , Rats, Long-Evans , Auditory Pathways/metabolism
4.
Glia ; 72(2): 274-288, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37746760

ABSTRACT

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.


Subject(s)
Microglia , Status Epilepticus , Mice , Humans , Animals , Geniculate Bodies/metabolism , Thalamus , Auditory Pathways/metabolism , Status Epilepticus/metabolism
5.
Int J Mol Sci ; 24(14)2023 Jul 24.
Article in English | MEDLINE | ID: mdl-37511622

ABSTRACT

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.


Subject(s)
Fragile X Syndrome , Hyperacusis , Animals , Mice , Auditory Pathways/metabolism , Chlorzoxazone , Disease Models, Animal , Fragile X Mental Retardation Protein/genetics , Fragile X Mental Retardation Protein/metabolism , Fragile X Syndrome/drug therapy , Fragile X Syndrome/genetics , Fragile X Syndrome/metabolism , Large-Conductance Calcium-Activated Potassium Channel alpha Subunits , Mice, Knockout
6.
Dev Dyn ; 252(1): 10-26, 2023 01.
Article in English | MEDLINE | ID: mdl-35705527

ABSTRACT

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.


Subject(s)
Auditory Pathways , Ephrins , Auditory Pathways/metabolism , Neurons/metabolism , Receptors, Eph Family/metabolism , Signal Transduction/physiology
7.
J Neurosci ; 42(32): 6211-6220, 2022 08 10.
Article in English | MEDLINE | ID: mdl-35790402

ABSTRACT

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.


Subject(s)
Cochlear Nucleus , Nitric Oxide , Animals , Auditory Pathways/metabolism , Cochlear Nerve/physiology , Cochlear Nucleus/physiology , Female , Male , Mice , Neuronal Plasticity/physiology , Nitric Oxide/metabolism , Potassium/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Synapses/physiology , Synaptic Transmission/physiology , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolism
8.
Front Neural Circuits ; 16: 882485, 2022.
Article in English | MEDLINE | ID: mdl-35463204

ABSTRACT

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.


Subject(s)
Auditory Pathways , Inferior Colliculi , Animals , Auditory Pathways/embryology , Auditory Pathways/metabolism , Glutamate Decarboxylase/metabolism , Inferior Colliculi/embryology , Inferior Colliculi/metabolism , Mice , Neurogenesis/physiology
9.
Neurobiol Learn Mem ; 189: 107589, 2022 03.
Article in English | MEDLINE | ID: mdl-35124220

ABSTRACT

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.


Subject(s)
Auditory Pathways , Tinnitus , Auditory Pathways/metabolism , Hippocampus/metabolism , Humans , Neurogenesis , Noise , Tinnitus/metabolism
10.
Cell Rep ; 37(5): 109927, 2021 11 02.
Article in English | MEDLINE | ID: mdl-34731615

ABSTRACT

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.


Subject(s)
Appetitive Behavior , Auditory Cortex/physiology , Auditory Pathways/physiology , Auditory Perception , Evoked Potentials, Auditory , Acoustic Stimulation , Animals , Auditory Cortex/diagnostic imaging , Auditory Cortex/metabolism , Auditory Pathways/diagnostic imaging , Auditory Pathways/metabolism , Brain Mapping , Calcium/metabolism , Calcium Signaling , Discrimination, Psychological , Female , Learning , Male , Mice, Inbred C57BL , Mice, Transgenic , Microscopy, Fluorescence, Multiphoton , Neuronal Plasticity , Reward , Time Factors
11.
Front Neural Circuits ; 15: 714780, 2021.
Article in English | MEDLINE | ID: mdl-34366798

ABSTRACT

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.


Subject(s)
Auditory Cortex/metabolism , Auditory Pathways/metabolism , GABAergic Neurons/metabolism , Motor Cortex/physiology , Vasoactive Intestinal Peptide/biosynthesis , Animals , Auditory Cortex/chemistry , Auditory Pathways/chemistry , Female , GABAergic Neurons/chemistry , Male , Mice , Mice, Transgenic , Organ Culture Techniques
12.
J Comp Neurol ; 529(15): 3477-3496, 2021 10.
Article in English | MEDLINE | ID: mdl-34180540

ABSTRACT

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.


Subject(s)
Auditory Pathways/growth & development , Auditory Pathways/metabolism , Gene Expression Regulation, Developmental/physiology , MicroRNAs/biosynthesis , Rhombencephalon/growth & development , Rhombencephalon/metabolism , Animals , Auditory Pathways/embryology , Chickens , Female , Male , MicroRNAs/genetics , Rhombencephalon/embryology
13.
Elife ; 102021 05 24.
Article in English | MEDLINE | ID: mdl-34028350

ABSTRACT

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.


Subject(s)
Auditory Cortex/physiology , Auditory Pathways/physiology , Auditory Perception , Cortical Synchronization , Hearing , Sensory Gating , Synaptic Transmission , Thalamic Nuclei/physiology , Acoustic Stimulation , Animals , Auditory Cortex/metabolism , Auditory Pathways/metabolism , Electric Stimulation , Evoked Potentials, Auditory , Female , Male , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Neural Inhibition , Thalamic Nuclei/metabolism , Time Factors
14.
J Comp Neurol ; 529(11): 3076-3097, 2021 08 01.
Article in English | MEDLINE | ID: mdl-33797066

ABSTRACT

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.


Subject(s)
Astrocytes/metabolism , Brain Stem/metabolism , CX3C Chemokine Receptor 1/genetics , Mutation/genetics , Synapses/genetics , Synapses/metabolism , Animals , Auditory Pathways/metabolism , CX3C Chemokine Receptor 1/deficiency , Evoked Potentials, Auditory, Brain Stem/physiology , Female , Gene Expression , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Neuronal Plasticity/physiology , Reaction Time/physiology
15.
Int J Mol Sci ; 22(6)2021 Mar 11.
Article in English | MEDLINE | ID: mdl-33799503

ABSTRACT

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.


Subject(s)
Auditory Pathways/metabolism , Growth Hormone/genetics , Hearing Loss, Functional/genetics , Hearing Loss, Sensorineural/genetics , Hippocampus/metabolism , Insulin-Like Growth Factor I/genetics , Animals , Auditory Cortex/metabolism , Auditory Cortex/pathology , Auditory Pathways/pathology , Cochlea/metabolism , Cochlea/pathology , Cochlear Nerve/metabolism , Cochlear Nerve/pathology , Gene Expression Regulation , Growth Hormone/metabolism , Hearing Loss, Functional/metabolism , Hearing Loss, Functional/physiopathology , Hearing Loss, Sensorineural/metabolism , Hearing Loss, Sensorineural/physiopathology , Hippocampus/pathology , Humans , Insulin-Like Growth Factor I/metabolism , Nerve Regeneration/physiology , Noise/prevention & control
16.
Proc Natl Acad Sci U S A ; 118(10)2021 03 09.
Article in English | MEDLINE | ID: mdl-33658359

ABSTRACT

The central nucleus of the inferior colliculus (ICC) integrates information about different features of sound and then distributes this information to thalamocortical circuits. However, the lack of clear definitions of circuit elements in the ICC has limited our understanding of the nature of these circuit transformations. Here, we combine virus-based genetic access with electrophysiological and optogenetic approaches to identify a large family of excitatory, cholecystokinin-expressing thalamic projection neurons in the ICC of the Mongolian gerbil. We show that these neurons form a distinct cell type, displaying uniform morphology and intrinsic firing features, and provide powerful, spatially restricted excitation exclusively to the ventral auditory thalamus. In vivo, these neurons consistently exhibit V-shaped receptive field properties but strikingly diverse temporal responses to sound. Our results indicate that temporal response diversity is maintained within this population of otherwise uniform cells in the ICC and then relayed to cortex through spatially restricted thalamic subdomains.


Subject(s)
Auditory Pathways/metabolism , Cholecystokinin/metabolism , Evoked Potentials, Auditory , Mesencephalon/metabolism , Neurons/metabolism , Thalamus/metabolism , Animals , Female , Gerbillinae , Male
17.
J Neurosci ; 41(13): 2930-2943, 2021 03 31.
Article in English | MEDLINE | ID: mdl-33574178

ABSTRACT

Cochlear outer hair cells (OHCs) are known to uniquely participate in auditory processing through their electromotility, and like inner hair cells, are also capable of releasing vesicular glutamate onto spiral ganglion (SG) neurons: in this case, onto the sparse Type II SG neurons. However, unlike glutamate signaling at the inner hair cell-Type I SG neuron synapse, which is robust across a wide spectrum of sound intensities, glutamate signaling at the OHC-Type II SG neuron synapse is weaker and has been hypothesized to occur only at intense, possibly damaging sound levels. Here, we tested the ability of the OHC-Type II SG pathway to signal to the brain in response to moderate, nondamaging sound (80 dB SPL) as well as to intense sound (115 dB SPL). First, we determined the VGluTs associated with OHC signaling and then confirmed the loss of glutamatergic synaptic transmission from OHCs to Type II SG neurons in KO mice using dendritic patch-clamp recordings. Next, we generated genetic mouse lines in which vesicular glutamate release occurs selectively from OHCs, and then assessed c-Fos expression in the cochlear nucleus in response to sound. From these analyses, we show, for the first time, that glutamatergic signaling at the OHC-Type II SG neuron synapse is capable of activating cochlear nucleus neurons, even at moderate sound levels.SIGNIFICANCE STATEMENT Evidence suggests that cochlear outer hair cells (OHCs) release glutamate onto Type II spiral ganglion neurons only when exposed to loud sound, and that Type II neurons are activated by tissue damage. Knowing whether moderate level sound, without tissue damage, activates this pathway has functional implications for this fundamental auditory pathway. We first determined that OHCs rely largely on VGluT3 for synaptic glutamate release. We then used a genetically modified mouse line in which OHCs, but not inner hair cells, release vesicular glutamate to demonstrate that moderate sound exposure activates cochlear nucleus neurons via the OHC-Type II spiral ganglion pathway. Together, these data indicate that glutamate signaling at the OHC-Type II afferent synapse participates in auditory function at moderate sound levels.


Subject(s)
Acoustic Stimulation/methods , Cochlear Nucleus/metabolism , Glutamic Acid/metabolism , Hair Cells, Auditory, Outer/metabolism , Neurons/metabolism , Spiral Ganglion/metabolism , Afferent Pathways/metabolism , Amino Acid Transport Systems, Acidic/genetics , Amino Acid Transport Systems, Acidic/metabolism , Animals , Auditory Pathways/metabolism , Excitatory Postsynaptic Potentials/physiology , Female , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic
18.
eNeuro ; 8(2)2021.
Article in English | MEDLINE | ID: mdl-33558268

ABSTRACT

Signaling between neurons and glia is necessary for the formation of functional neural circuits. A role for microglia in the maturation of connections in the medial nucleus of the trapezoid body (MNTB) was previously demonstrated by postnatal microglial elimination using a colony stimulating factor 1 receptor (CSF1R). Defective pruning of calyces of Held and significant reduction of the mature astrocyte marker glial fibrillary acidic protein (GFAP) were observed after hearing onset. Here, we investigated the time course required for microglia to populate the mouse MNTB after cessation of CSF1R inhibitor treatment. We then examined whether defects seen after microglial depletion were rectified by microglial repopulation. We found that microglia returned to control levels at four weeks of age (18 d postcessation of treatment). Calyceal innervation of MNTB neurons was comparable to control levels at four weeks and GFAP expression recovered by seven weeks. We further investigated the effects of microglia elimination and repopulation on auditory function using auditory brainstem recordings (ABRs). Temporary microglial depletion significantly elevated auditory thresholds in response to 4. 8, and 12 kHz at four weeks. Treatment significantly affected latencies, interpeak latencies, and amplitudes of all the ABR peaks in response to many of the frequencies tested. These effects largely recovered by seven weeks. These findings highlight the functions of microglia in the formation of auditory neural circuits early in development. Further, the results suggest that microglia retain their developmental functions beyond the period of circuit refinement.


Subject(s)
Brain Stem , Microglia , Animals , Astrocytes/metabolism , Auditory Pathways/metabolism , Brain Stem/metabolism , Mice , Microglia/metabolism , Neuroglia/metabolism , Neurons/metabolism , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism
19.
Exp Mol Pathol ; 119: 104605, 2021 04.
Article in English | MEDLINE | ID: mdl-33453279

ABSTRACT

Acoustic trauma damages inner ear neural structures including cochlear hair cells which result in hearing loss and neurotransmitter imbalances within the synapses of the central auditory pathway. Disruption of GABA/glutamate levels underlies, tinnitus, a phantom perception of sound that persists post-exposure to blast noise which may manifest in tandem with acute/chronic loss of hearing. Many putative theories explain tinnitus physiology based on indirect and direct assays in animal models and humans, although there is no comprehensive evidence to explain the phenomenon. Here, GABA/glutamate levels were imaged and quantified in a blast overpressure model of chinchillas using Fourier transform ion cyclotron resonance mass spectrometry imaging. The direct measurement from whole-brain sections identified the relative levels of GABA/glutamate in the central auditory neuraxis centers including the cochlear nucleus, inferior colliculus, and auditory cortex. These preliminary results provide insight on the homeostasis of GABA/glutamate within whole-brain sections of chinchilla for investigation of the pathomechanism of blast-induced tinnitus.


Subject(s)
Auditory Pathways/metabolism , Glutamic Acid/metabolism , Mass Spectrometry , Pressure , gamma-Aminobutyric Acid/metabolism , Animals , Auditory Pathways/diagnostic imaging , Chinchilla , Ions , Male
20.
Neural Plast ; 2021: 8833087, 2021.
Article in English | MEDLINE | ID: mdl-33510780

ABSTRACT

Accumulating evidence implicates a role for brain structures outside the ascending auditory pathway in tinnitus, the phantom perception of sound. In addition to other factors such as age-dependent hearing loss, high-level sound exposure is a prominent cause of tinnitus. Here, we examined how noise exposure altered the distribution of excitatory and inhibitory synaptic inputs in the guinea pig hippocampus and determined whether these changes were associated with tinnitus. In experiment one, guinea pigs were overexposed to unilateral narrow-band noise (98 dB SPL, 2 h). Two weeks later, the density of excitatory (VGLUT-1/2) and inhibitory (VGAT) synaptic terminals in CA1, CA3, and dentate gyrus hippocampal subregions was assessed by immunohistochemistry. Overall, VGLUT-1 density primarily increased, while VGAT density decreased significantly in many regions. Then, to assess whether the noise-induced alterations were persistent and related to tinnitus, experiment two utilized a noise-exposure paradigm shown to induce tinnitus and assessed tinnitus development which was assessed using gap-prepulse inhibition of the acoustic startle (GPIAS). Twelve weeks after sound overexposure, changes in excitatory synaptic terminal density had largely recovered regardless of tinnitus status, but the recovery of GABAergic terminal density was dramatically different in animals expressing tinnitus relative to animals resistant to tinnitus. In resistant animals, inhibitory synapse density recovered to preexposure levels, but in animals expressing tinnitus, inhibitory synapse density remained chronically diminished. Taken together, our results suggest that noise exposure induces striking changes in the balance of excitatory and inhibitory synaptic inputs throughout the hippocampus and reveal a potential role for rebounding inhibition in the hippocampus as a protective factor leading to tinnitus resilience.


Subject(s)
GABAergic Neurons/metabolism , Hippocampus/metabolism , Noise/adverse effects , Tinnitus/metabolism , Vesicular Glutamate Transport Proteins/metabolism , Vesicular Inhibitory Amino Acid Transport Proteins/metabolism , Acoustic Stimulation/adverse effects , Animals , Auditory Pathways/metabolism , Auditory Pathways/pathology , Female , GABAergic Neurons/chemistry , Glutamic Acid/analysis , Glutamic Acid/metabolism , Guinea Pigs , Hippocampus/pathology , Male , Synapses/chemistry , Synapses/metabolism , Tinnitus/pathology , Vesicular Glutamate Transport Proteins/analysis , Vesicular Inhibitory Amino Acid Transport Proteins/analysis
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