Hearing loss often results in tinnitus and auditory cortical map changes, leading to the prevailing view that the phantom perception is associated with cortical reorganization. However, we show here ...that tinnitus is mediated by a cortical area lacking map reorganization. High-frequency hearing loss results in two distinct cortical regions: a sensory-deprived region characterized by a decrease in inhibitory synaptic transmission and a normal hearing region showing increases in inhibitory and excitatory transmission and map reorganization. Hearing-lesioned animals displayed tinnitus with a pitch in the hearing loss range. Furthermore, drugs that enhance inhibition, but not those that reduce excitation, reversibly eliminated the tinnitus behavior. These results suggest that sensory deprivation-induced homeostatic down-regulation of inhibitory synapses may contribute to tinnitus perception. Enhancing sensory input through map reorganization may plausibly alleviate phantom sensation.
Exposure to loud noises results in neuroinflammatory responses in the central auditory pathway. Noise-induced neuroinflammation is implicated in auditory processing deficits such as impairment in gap ...detection. In this study, we examined whether strain differences between the FVB and C57BL/6 mice in noise-induced impairment in gap detection are correlated with strain differences in neuroinflammatory responses. We found that noise induced more robust TNF-α expression in C57BL/6 than in FVB mice. Noise-induced microglial deramification was observed in C57BL/6 mice, but not in FVB mice. Furthermore, noise exposure resulted in a reduction in parvalbumin-positive (PV+) neuron density in the C57BL/6 mice, but not in FVB mice. These results suggest that neuroinflammatory responses and loss of PV+ neurons may contribute to strain differences in noise-induced impairment in gap detection.
Neuroinflammation has been implicated in noise-induced auditory processing disorder and tinnitus. Certain non-auditory neurological disorders can also increase the levels of proinflammatory cytokines ...in the brain. To investigate the impact of increased brain proinflammatory cytokine levels on the central auditory pathway, we infused recombinant TNF-α into the right lateral cerebral ventricle, and examined auditory processing and cytoarchitecture of the auditory cortex. Microglial deramification was observed in the auditory cortex of mice that had received both TNF-α infusion and exposure to an 86-dB noise, but not in mice that had received either TNF-α infusion or noise exposure alone. In addition, we observed reduced cortical PV+ neuron density and impaired performances in gap detection and prepulse inhibition (PPI) only in mice that received both TNF-α infusion and the noise exposure. These results suggest that disease-related increase in brain proinflammatory cytokine release could be a risk factor for noise-induced auditory processing disorder and tinnitus.
Hearing loss is a major risk factor for tinnitus, hyperacusis, and central auditory processing disorder. Although recent studies indicate that hearing loss causes neuroinflammation in the auditory ...pathway, the mechanisms underlying hearing loss-related pathologies are still poorly understood. We examined neuroinflammation in the auditory cortex following noise-induced hearing loss (NIHL) and its role in tinnitus in rodent models. Our results indicate that NIHL is associated with elevated expression of proinflammatory cytokines and microglial activation-two defining features of neuroinflammatory responses-in the primary auditory cortex (AI). Genetic knockout of tumor necrosis factor alpha (TNF-α) or pharmacologically blocking TNF-α expression prevented neuroinflammation and ameliorated the behavioral phenotype associated with tinnitus in mice with NIHL. Conversely, infusion of TNF-α into AI resulted in behavioral signs of tinnitus in both wild-type and TNF-α knockout mice with normal hearing. Pharmacological depletion of microglia also prevented tinnitus in mice with NIHL. At the synaptic level, the frequency of miniature excitatory synaptic currents (mEPSCs) increased and that of miniature inhibitory synaptic currents (mIPSCs) decreased in AI pyramidal neurons in animals with NIHL. This excitatory-to-inhibitory synaptic imbalance was completely prevented by pharmacological blockade of TNF-α expression. These results implicate neuroinflammation as a therapeutic target for treating tinnitus and other hearing loss-related disorders.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cortical sensory representation is highly adaptive to the environment, and prevalent or behaviorally important stimuli are often overrepresented. One class of such stimuli is species-specific ...vocalizations. Rats vocalize in the ultrasonic range >30 kHz, but cortical representation of this frequency range has not been systematically examined. We recorded in vivo cortical electrophysiological responses to ultrasonic pure-tone pips, natural ultrasonic vocalizations, and pitch-shifted vocalizations to assess how rats represent this ethologically relevant frequency range. We find that nearly 40% of the primary auditory cortex (AI) represents an octave-wide band of ultrasonic vocalization frequencies (UVFs; 32-64 kHz) compared with <20% for other octave bands <32 kHz. These UVF neurons respond preferentially and reliably to ultrasonic vocalizations. The UVF overrepresentation matures in the cortex before it develops in the central nucleus of inferior colliculus, suggesting a cortical origin and corticofugal influences. Furthermore, the development of cortical UVF overrepresentation depends on early acoustic experience. These results indicate that natural sensory experience causes large-scale cortical map reorganization and improves representations of species-specific vocalizations.
Selective enhancement of GABAergic inhibition is thought to impact many vital brain functions and interferes with the genesis and/or progression of numerous brain disorders. Here, we show that ...selectively increasing NMDA receptor activity in inhibitory neurons using an NMDAR positive allosteric modulator (PAM) elevates spiking activity of inhibitory neurons in vitro and in vivo. In vivo infusion of PAM increases spontaneous and sound-evoked spiking in inhibitory and decreases spiking in excitatory neurons, and increases signal-to-noise ratio in the primary auditory cortex. In addition, PAM infusion prior to noise trauma prevents the occurrence of tinnitus and reduction in GABAergic inhibition. These results reveal that selectively enhancing endogenous NMDAR activity on the GABAergic neurons can effectively enhance inhibitory activity and alter excitatory-inhibitory balance, and may be useful for preventing diseases that involve reduced inhibition as the major cause.
Experience-dependent plasticity during development results in the emergence of highly adapted representations of the external world in the adult brain. Previous studies have convincingly shown that ...the primary auditory cortex (A1) of the rat possesses a postnatal period of sensory input-driven plasticity but its precise timing (onset, duration, end) has not been defined. In the present study, we examined the effects of pure-tone exposure on the auditory cortex of developing rat pups at different postnatal ages with a high temporal resolution. We found that pure-tone exposure resulted in profound, persistent alterations in sound representations in A1 only if the exposure occurred during a brief period extending from postnatal day 11 (P11) to P13. We also found that postnatal sound exposure in this epoch led to striking alterations in the cortical representation of sound intensity.
Exposure to sounds during early development causes enlarged cortical representations of those sounds, leading to the commonly held view that the size of stimulus representations increases with ...stimulus exposure. However, representing stimuli based solely on their prevalence may be inefficient, because many frequent environmental sounds are behaviorally irrelevant. Here, we show that cortical plasticity depends not only on exposure time but also on the temporal modulation rate of the stimulus set. We examined cortical plasticity induced by early exposure to 7 kHz tone pips repeated at a slow (2 Hz), fast (15 Hz), or ethological (6 Hz) rate. Certain rat calls are modulated near 6 Hz. We found that spectral representation of 7 kHz increased only in the ethological-rate-reared animals, whereas improved entrainment of cortical neurons was seen in animals reared in the slow- and fast-rate condition. This temporal rate dependence of spectral plasticity may serve as a filtering mechanism to selectively enlarge representations of species-specific vocalizations. Furthermore, our results indicate that spectral and temporal plasticity can be separately engaged depending on the statistical properties of the input stimuli.
Abstract
Cortical maps, which are indicative of cognitive status, are shaped by the organism’s experience. Previous mapping tools, such as penetrating electrodes and imaging techniques, are limited ...in their ability to be used to assess high-resolution brain maps largely owing to their invasiveness and poor spatiotemporal resolution, respectively. In this study, we developed a flexible graphene-based multichannel electrode array for electrocorticography (ECoG) recording, which enabled us to assess cortical maps in a time- and labor-efficient manner. The flexible electrode array, formed by chemical vapor deposition (CVD)-grown graphene, provided low impedance and electrical noise because a good interface between the graphene and brain tissue was created, which improved the detectability of neural signals. Furthermore, cortical map remodeling was induced upon electrical stimulation at the cortical surface through a subset of graphene spots. This result demonstrated the macroscale plasticity of cortical maps, suggesting perceptual enhancement via electrical rehabilitation at the cortical surface.
The mammalian neocortex is a highly interconnected network of different types of neurons organized into both layers and columns. Overlaid on this structural organization is a pattern of functional ...connectivity that can be rapidly and flexibly altered during behavior. Parvalbumin-positive (PV+) inhibitory neurons, which are implicated in cortical oscillations and can change neuronal selectivity, may play a pivotal role in these dynamic changes. We found that optogenetic activation of PV+ neurons in the auditory cortex enhanced feedforward functional connectivity in the putative thalamorecipient circuit and in cortical columnar circuits. In contrast, stimulation of PV+ neurons induced no change in connectivity between sites in the same layers. The activity of PV+ neurons may thus serve as a gating mechanism to enhance feedforward, but not lateral or feedback, information flow in cortical circuits. Functionally, it may preferentially enhance the contribution of bottom-up sensory inputs to perception.
•Ising models recover known canonical circuit connectivity in the auditory cortex•PV+ neuron activity increases functional connectivity in cortical columns•PV+ neuron activity does not change horizontal connectivity in cortical layers•PV+ neuron activity may increase bottom-up sensory input for perception
The neocortex contains neurons of many subtypes arranged into layers and columns, but how this structure relates to network activity remains unknown. Hamilton et al. show that optogenetically activating PV+ inhibitory interneurons enhances feedforward functional connectivity in the auditory cortex.
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