Animals often listen selectively for particular sounds, a strategy that could alter neural encoding mechanisms to maximize the ability to detect the target. Here, we recorded auditory cortex neuron responses in well trained, freely moving gerbils as they performed a tone detection task. Each trial was initiated by the animal, providing a predictable time window during which to listen. No sound was presented on nogo trials, permitting us to assess spontaneous activity on trials in which a signal could have been expected, but was not delivered. Immediately after animals initiated a trial, auditory cortex neurons displayed a 26% reduction in spontaneous activity. Moreover, when stimulus-driven discharge rate was referenced to this reduced baseline, a larger fraction of auditory cortex neurons displayed a detection threshold within 10 dB of the behavioral threshold. These findings suggest that auditory cortex spontaneous discharge rate can be modulated transiently during task performance, thereby increasing the signal-to-noise ratio and enhancing signal detection.
attention; auditory cortex; auditory perception; detection threshold; expectation; spontaneous activity
Manipulations of the sensory environment typically induce greater changes to the developing nervous system than they do in adulthood. The relevance of these neural changes can be evaluated by examining the age-dependent effects of sensory experience on quantitative measures of perception. Here, we measured frequency modulation (FM) detection thresholds in adult gerbils and investigated whether diminished auditory experience during development or in adulthood influenced perceptual performance. Bilateral conductive hearing loss (CHL) of ≈30 dB was induced either at postnatal day 10 or after sexual maturation. All animals were then trained as adults to detect a 5 Hz FM embedded in a continuous 4 kHz tone. FM detection thresholds were defined as the minimum deviation from the carrier frequency that the animal could reliably detect. Normal-hearing animals displayed FM thresholds of 25 Hz. Inducing CHL, either in juvenile or adult animals, led to a deficit in FM detection. However, this deficit was greater for juvenile onset hearing loss (89 Hz) relative to adult onset hearing loss (64 Hz). The effects could not be attributed to sensation level, nor were they correlated with proxies for attention. The thresholds displayed by CHL animals were correlated with shallower psychometric function slopes, suggesting that hearing loss was associated with greater variance of the decision variable, consistent with increased internal noise. The results show that decreased auditory experience has a greater impact on perceptual skills when initiated at an early age and raises the possibility that altered development of CNS synapses may play a causative role.
critical period; deafness; frequency discrimination; temporal processing
Sensory experience during early development can shape the central nervous system and this is thought to influence adult perceptual skills. In the auditory system, early induction of conductive hearing loss (CHL) leads to deficits in central auditory coding properties in adult animals, and this is accompanied by diminished perceptual thresholds. In contrast, a brief regimen of auditory training during development can enhance the perceptual skills of animals when tested in adulthood. Here, we asked whether a brief period of training during development could compensate for the perceptual deficits displayed by adult animals reared with CHL. Juvenile gerbils with CHL, and age-matched controls, were trained on a frequency modulation (FM) detection task for 4 or 10 days. The performance of each group was subsequently assessed in adulthood, and compared to adults with normal hearing (NH) or adults raised with CHL that did not receive juvenile training. We show that as juveniles, both CHL and NH animals display similar FM detection thresholds that are not immediately impacted by the perceptual training. However, as adults, detection thresholds and psychometric function slopes of these animals were significantly improved. Importantly, CHL adults with juvenile training displayed thresholds that approached NH adults. Additionally, we found that hearing impaired animals trained for 10 days displayed adult thresholds closer to untrained adults than those trained for 4 days. Thus, a relatively brief period of auditory training may compensate for the deleterious impact of hearing deprivation on auditory perception on the trained task.
conductive hearing loss; plasticity; auditory training; frequency modulation; development; perceptual learning
Principal neurons of the lateral superior olivary nucleus (LSO) respond selectively to interaural level differences (ILD). To perform this computation, LSO neurons integrate excitatory synaptic drive from the ipsilateral ear with inhibitory synaptic drive from the contralateral ear via the medial nucleus of the trapezoid body (MNTB). Previous research demonstrated that inhibitory terminals from the MNTB to the LSO are eliminated during development. Furthermore, MNTB synapses display an activity- and age-dependent long-term depression (iLTD) that may contribute to inhibitory synapse elimination. However, inhibitory synapses that are stabilized become stronger. Here, we asked whether MNTB synapses displayed activity-dependent strengthening. Whole-cell recordings were obtained from LSO neurons in a gerbil brain slice before and after hearing onset. The inhibitory MNTB afferents were stimulated at a low rate, similar to spontaneous discharge rates observed in vivo. The MNTB-evoked inhibitory responses were strengthened by 40–300% when synaptic activity was coupled with postsynaptic membrane depolarization, exogenous glutamate application, or activation of ipsilateral excitatory synaptic inputs. This inhibitory long-term potentiation (iLTP) was associated with increased spontaneous inhibitory postsynaptic current (IPSC) amplitude and frequency. One hour after iLTP induction, IPSCs could not be de-potentiated by the MNTB stimulation pattern that induces iLTD in control slices. iLTP could only be induced after hearing onset (>P12), and was blocked in the presence of a GABAB receptor antagonist. Together, these results suggest a developmental period during which the induction of iLTP depends on the conjoint activation of GABAB receptors and postsynaptic depolarization. We propose that iLTP may support stabilization of un-pruned MNTB connections and contribute to the emergence of ILD processing in the mature LSO.
GABA; glycine; GABAB; synaptic potentiation; plasticity; LSO
The auditory CNS is influenced profoundly by sounds heard during development. Auditory deprivation and augmented sound exposure can each perturb the maturation of neural computations as well as their underlying synaptic properties. However, we have learned little about the emergence of perceptual skills in these same model systems, and especially how perception is influenced by early acoustic experience. Here, we argue that developmental studies must take greater advantage of behavioral benchmarks. We discuss quantitative measures of perceptual development, and suggest how they can play a much larger role in guiding experimental design. Most importantly, including behavioral measures will allow us to establish empirical connections among environment, neural development, and perception.
hearing; perception; experience; deafness; auditory cortex; sensory coding; auditory processing; synaptic plasticity
Functional inhibitory synapses form in auditory cortex well before the onset of normal hearing. However, their properties change dramatically during normal development, and many of these maturational events are delayed by hearing loss. Here, we review recent findings on the developmental plasticity of inhibitory synapse strength, kinetics, and GABAA receptor localization in auditory cortex. Although hearing loss generally leads to a reduction of inhibitory strength, this depends on the type of presynaptic interneuron. Furthermore, plasticity of inhibitory synapses also depends on the postsynaptic target. Hearing loss leads reduced GABAA receptor localization to the membrane of excitatory, but not inhibitory neurons. A reduction in normal activity in development can also affect the use-dependent plasticity of inhibitory synapses. Even moderate hearing loss can disrupt inhibitory short- and long-term synaptic plasticity. Thus, the cortex did not compensate for the loss of inhibition in the brainstem, but rather exacerbated the response to hearing loss by further reducing inhibitory drive. Together, these results demonstrate that inhibitory synapses are exceptionally dynamic during development, and deafness-induced perturbation of inhibitory properties may have a profound impact on auditory processing.
development; deafness; inhibitory interneuron; short-term depression; long-term potentiation; auditory cortex
Long-term synaptic plasticity is a putative mechanism for learning in adults. However, there is little understanding of how synaptic plasticity mechanisms develop or whether their maturation depends on experience. Since inhibitory synapses are particularly malleable to sensory stimulation, long-lasting potentiation of inhibitory synapses was characterized in auditory thalamocortical slices. Intracortical high frequency electrical stimulation led to a 67% increase in inhibitory synaptic currents. In the absence of stimulation, inhibitory potentiation was induced by a brief exposure to exogenous BDNF. BDNF exposure occluded any further potentiation by high frequency afferent stimulation, suggesting that BDNF signaling is sufficient to account for inhibitory potentiation. Moreover, inhibitory potentiation was reduced significantly by extracellular application of a BDNF scavenger or by intracellular blockade of BDNF receptor (TrkB) signaling. In contrast, glutamatergic or GABAergic antagonists did not prevent the induction of inhibitory potentiation. Since BDNF and TrkB expression are influenced strongly by activity, we predicted that inhibitory potentiation would be diminished by manipulations that decrease central auditory activity, such as hearing loss. Two forms of hearing loss were examined: conductive hearing loss in which the cochleae are not damaged or sensorineural hearing loss in which both cochleae are removed. Both forms of hearing loss were found to reduce significantly the magnitude of inhibitory potentiation. These data indicate that early experience is necessary for the normal development of BDNF-mediated long-lasting inhibitory potentiation, which may be associated with perceptual deficits at later ages.
hearing loss; inhibitory synaptic transmission; long-term potentiation; TrkB receptor; BDNF; auditory cortex
In the inferior colliculus (IC), a brief period of acoustic conditioning can transiently enhance evoked discharge rate. The cellular basis of this phenomenon was assessed with whole cell current-clamp recordings in a gerbil IC brain slice preparation. The current needed to elicit a single action potential was first established for each neuron. A 5s synaptic stimulus train was delivered to the lateral lemniscus (LL), and followed immediately by the initial current pulse to assess a change in postsynaptic gain. The majority of IC neurons (66%) displayed an increase in current-evoked action potentials (positive gain). Despite the blockade of ionotropic glutamate receptors, this effect was correlated with membrane depolarization that occurred during the synaptic train. The postsynaptic mechanism for positive gain was examined by selective blockade of specific neurotransmitter receptors. Gain in action potentials was enhanced by antagonists of metabotropic glutamate, acetylcholine, GABAA and glycine receptors. In contrast, the gain was blocked or reduced by an antagonist to ionotropic serotonin receptors (5-HT3R). Blocking voltage-activated calcium channels with verapamil also reduced the effect. These results suggest that 5-HT3R activation, coupled with increased intracellular calcium, can transiently alter postsynaptic excitability in IC neurons.
inferior colliculus; synaptic plasticity; serotonin; 5-HT3 receptor
Voltage-dependent membrane conductances support specific neurophysiological properties. To investigate the mechanisms of coincidence detection, we activated gerbil medial superior olivary (MSO) neurons with dynamic current-clamp stimuli in vitro. Spike-triggered reverse-correlation analysis for injected current was used to evaluate the integration of subthreshold noisy signals. Consistent with previous reports, the partial blockade of low-threshold potassium channels (IKLT) reduced coincidence detection by slowing the rise of current needed on average to evoke a spike. However, two factors point toward the involvement of a second mechanism. First, the reverse correlation currents revealed that spike generation was associated with a preceding hyperpolarization. Second, rebound action potentials are 45% larger compared to depolarization-evoked spikes in the presence of an IKLT antagonist. These observations suggest that the sodium current (INa) was substantially inactivated at rest. To test this idea, INa was enhanced by increasing extracellular sodium concentration. This manipulation reduced coincidence detection, as reflected by slower spike-triggering current, and diminished the hyperpolarization phase in the reverse-correlation currents. As expected, a small outward bias current decreased the pre-spike hyperpolarization phase, and TTX blockade of INa nearly eliminated the hyperpolarization phase in the reverse correlation current. A computer model including Hodgkin-Huxley type conductances for spike generation and for IKLT showed reduction in coincidence detection when IKLT was reduced or when INa was increased. We hypothesize that desirable synaptic signals first remove some inactivation of INa and reduce activation of IKLT to create a brief temporal window for coincidence detection of subthreshold noisy signals.
Neurons possess multiple voltage-dependent conductances specific for their function. To investigate how low-threshold outward currents improve the detection of small signals in a noisy background, we recorded from gerbil medial superior olivary (MSO) neurons in vitro. MSO neurons responded phasically, with a single spike to a step current injection. When bathed in dendrotoxin (DTX), most cells switched to tonic firing, suggesting that low-threshold potassium currents (IKLT ) participated in shaping these phasic responses. Neurons were stimulated with a computer-generated steady barrage of random inputs, mimicking weak synaptic conductance transients (the “noise”), together with a larger but still subthreshold postsynaptic conductance, EPSG (the “signal”). DTX reduced the signal-to-noise ratio (SNR), defined as the ratio of probability to fire in response to the EPSG and the probability to fire spontaneously in response to noise. The reduction was mainly attributable to the increase of spontaneous firing in DTX. The spike-triggered reverse correlation indicated that, for spike generation, the neuron with IKLT required faster inward current transients. This narrow temporal integration window contributed to superior phase locking of firing to periodic stimuli before application of DTX. A computer model including Hodgkin-Huxley type conductances for spike generation and for IKLT (Rathouz and Trussell, 1998) showed similar response statistics. The dynamic low-threshold outward current increased SNR and the temporal precision of integration of weak sub-threshold signals in auditory neurons by suppressing false positives.
medial superior olive; signal-to-noise ratio; phase locking; computer model; potassium conductance; slice recordings
Inhibitory synapse dysfunction may contribute to many developmental brain disorders, including the secondary consequences of sensory deprivation. In fact, developmental hearing loss leads to a profound reduction in the strength of inhibitory postsynaptic currents (IPSCs) in the auditory cortex, and this deficit persists into adulthood. This finding is consistent with the general theory that the emergence of mature synaptic properties requires activity during development. Therefore, we tested the prediction that inhibitory strength can be restored following developmental hearing loss by boosting GABAergic transmission in vivo. Conductive or sensorineural hearing loss was induced surgically in gerbils prior to hearing onset and GABA agonists were then administered for one week. IPSCs were subsequently recorded from pyramidal neurons in a thalamocortical brain slice preparation. Administration of either a GABAA receptor a1 subunit specific agonist (zolpidem), or a selective GABA reuptake inhibitor (SGRI), rescued IPSC amplitude in hearing loss animals. Furthermore, this restoration persisted in adults, long after drug treatment ended. In contrast, a GABAB receptor agonist baclofen did not restore inhibitory strength. IPSCs could also be restored when SGRI administration began 3 weeks after sensory deprivation. Together, these results demonstrate long-lasting restoration of cortical inhibitory strength in the absence of normal experience. This suggests that in vivo GABAA receptor activation is sufficient to promote maturation, and this principle may extend to other developmental disorders associated with diminished inhibitory function.
The acoustic rearing environment can alter central auditory coding properties, yet altered neural coding is seldom linked with specific deficits to adult perceptual skills. To test whether developmental hearing loss resulted in comparable changes to perception and sensory coding, we examined behavioral and neural detection thresholds for sinusoidally amplitude modulated (sAM) stimuli. Behavioral sAM detection thresholds for slow (5 Hz) modulations were significantly worse for animals reared with bilateral conductive hearing loss (CHL), as compared to controls. This difference could not be attributed to hearing thresholds, proficiency at the task, or proxies for attention. Detection thresholds across the groups did not differ for fast (100 Hz) modulations, a result paralleling that seen in humans. Neural responses to sAM stimuli were recorded in single auditory cortex neurons from separate groups of awake animals. Neurometric analyses indicated equivalent thresholds for the most sensitive neurons, but a significantly poorer detection threshold for slow modulations across the population of CHL neurons as compared to controls. The magnitude of the neural deficit matched that of the behavioral differences, suggesting that a reduction of sensory information can account for limitations to perceptual skills.
Sensory experience during development can modify the central nervous system and alter adult perceptual skills. While this principle draws support from deprivation or chronic stimulus exposure studies, the effect of training is addressed only in adults. Here, we asked whether a brief period of training during development can exert a unique impact on adult perceptual skills. Juvenile gerbils were trained to detect amplitude modulation (AM), a stimulus feature elemental to animal communication sounds. When the performance of these juvenile-trained animals was subsequently assessed in adulthood, it was superior to a control group that received an identical regimen of training as adults. The juvenile-trained animals displayed significantly better AM detection thresholds. This was not observed in an adult group that received only exposure to AM stimuli as juveniles. To determine whether enhanced adult performance was due solely to learning the conditioned avoidance procedure, juveniles were trained on frequency modulation (FM) detection, and subsequently assessed on AM detection as adults. These animals displayed significantly poorer AM detection thresholds than all other groups. Thus, training on a specific auditory task (AM detection) during development provided a benefit to performance on that task in adulthood, whereas an identical training regimen in adulthood did not bring about this enhancement. In contrast, there was a cost, in adulthood, following developmental training on a different task (FM detection). Together, the results demonstrate a period of heightened sensitivity in the developing CNS such that behavioral training in juveniles has a unique impact on adult behavioral capabilities.
In humans, auditory perception reaches maturity over a broad age range, extending through adolescence. Despite this slow maturation, children are considered to be outstanding learners, suggesting that immature perceptual skills might actually be advantageous to improvement on an acoustic task as a result of training (perceptual learning). Previous non-human studies have not employed an identical task when comparing perceptual performance of young and mature subjects, making it difficult to assess learning. Here, we used an identical procedure on juvenile and adult gerbils to examine the perception of amplitude modulation (AM), a stimulus feature that is an important component of most natural sounds. On average, Adult animals could detect smaller fluctuations in amplitude (i.e. smaller modulation depths) than Juveniles, indicating immature perceptual skills in Juveniles. However, the population variance was much greater for Juveniles, a few animals displaying adult-like AM detection. To determine whether immature perceptual skills facilitated learning, we compared naïve performance on the AM detection task with the amount of improvement following additional training. The amount of improvement in Adults correlated with naïve performance: those with the poorest naïve performance improved the most. In contrast, the naïve performance of Juveniles did not predict the amount of learning. Those Juveniles with immature AM detection thresholds did not display greater learning than Adults. Furthermore, for several of the Juveniles with adult-like thresholds, AM detection deteriorated with repeated testing. Thus, immature perceptual skills in young animals were not associated with greater learning.
auditory perception; development; detection; amplitude modulation; perceptual learning
During development, detection for many percepts matures gradually. This provides a natural system in which to investigate the neural mechanisms underlying performance differences: those aspects of neural activity that mature in conjunction with behavioral performance are more likely to subserve detection. In principle, the limitations on performance could be due to either immature sensory encoding mechanisms or an immature decoding of an already-mature sensory representation. To evaluate these alternatives in awake gerbil auditory cortex, we measured neural detection of sinusoidally amplitude modulated (sAM) stimuli, for which behavioral detection thresholds display a prolonged maturation. A comparison of single unit responses in juveniles and adults revealed that encoding of static tones was adult-like in juveniles, but responses to sAM depth were immature. Since perceptual performance may reflect the activity of an animal’s most sensitive neurons, we analyzed the d prime curves of single neurons, and found an equivalent percentage with highly sensitive thresholds in juvenile and adult animals. In contrast, perceptual performance may reflect the pooling of information from neurons with a range of sensitivities. We evaluated a pooling model that assumes convergence of a population of inputs at a downstream target neuron, and found poorer sAM detection thresholds for juveniles. Thus, if sAM detection is based on the most sensitive neurons, then immature behavioral performance is best explained by an immature decoding mechanism. However, if sAM detection is based on a population response, then immature detection thresholds are more likely due to an inadequate sensory representation.
Auditory cortex; Development; Discrimination; Detection; Behavior; Temporal coding; Neuronal ensembles; Neurometrics
Short-term changes in synaptic gain support information processing throughout the CNS, yet we know little about the developmental regulation of such plasticity. Here we report that auditory experience is necessary for the normal maturation of synaptic inhibitory short-term plasticity (iSTP) in the auditory cortex, and that presynaptic GABAB receptors regulate this development. Moderate or severe hearing loss was induced in gerbils, and iSTP was characterized by measuring inhibitory synaptic current amplitudes in response to repetitive stimuli. We reveal a profound developmental shift of iSTP from depressing to facilitating after the onset of hearing. Even moderate hearing loss prevented this shift. This iSTP change was mediated by a specific class of inhibitory interneurons, the low-threshold spiking cells. Further, using paired recordings, we reveal that presynaptic GABAB receptors at interneuron-pyramidal connections regulate iSTP in an experience-dependent manner. This novel synaptic mechanism may support the emergence of mature temporal processing in the auditory cortex.
In order to localize sounds in the environment, the auditory system detects and encodes differences in signals between each ear. The exquisite sensitivity of auditory brain stem neurons to the differences in rise time of the excitation signals from the two ears allows for neuronal encoding of microsecond interaural time differences.
Low-frequency sound localization depends on the neural computation of interaural time differences (ITD) and relies on neurons in the auditory brain stem that integrate synaptic inputs delivered by the ipsi- and contralateral auditory pathways that start at the two ears. The first auditory neurons that respond selectively to ITD are found in the medial superior olivary nucleus (MSO). We identified a new mechanism for ITD coding using a brain slice preparation that preserves the binaural inputs to the MSO. There was an internal latency difference for the two excitatory pathways that would, if left uncompensated, position the ITD response function too far outside the physiological range to be useful for estimating ITD. We demonstrate, and support using a biophysically based computational model, that a bilateral asymmetry in excitatory post-synaptic potential (EPSP) slopes provides a robust compensatory delay mechanism due to differential activation of low threshold potassium conductance on these inputs and permits MSO neurons to encode physiological ITDs. We suggest, more generally, that the dependence of spike probability on rate of depolarization, as in these auditory neurons, provides a mechanism for temporal order discrimination between EPSPs.
Animals can locate the source of a sound by detecting microsecond differences in the arrival time of sound at the two ears. Neurons encoding these interaural time differences (ITDs) receive an excitatory synaptic input from each ear. They can perform a microsecond computation with excitatory synapses that have millisecond time scale because they are extremely sensitive to the input's “rise time,” the time taken to reach the peak of the synaptic input. Current theories assume that the biophysical properties of the two inputs are identical. We challenge this assumption by showing that the rise times of excitatory synaptic potentials driven by the ipsilateral ear are faster than those driven by the contralateral ear. Further, we present a computational model demonstrating that this disparity in rise times, together with the neurons' sensitivity to excitation's rise time, can endow ITD-encoding with microsecond resolution in the biologically relevant range. Our analysis also resolves a timing mismatch. The difference between contralateral and ipsilateral latencies is substantially larger than the relevant ITD range. We show how the rise time disparity compensates for this mismatch. Generalizing, we suggest that phasic-firing neurons—those that respond to rapidly, but not to slowly, changing stimuli—are selective to the temporal ordering of brief inputs. In a coincidence-detection computation the neuron will respond more robustly when a faster input leads a slower one, even if the inputs are brief and have similar amplitudes.
Although the auditory system has limited information processing resources, the acoustic environment is infinitely variable. To properly encode the natural environment, the developing central auditory system becomes somewhat specialized through experience-dependent adaptive mechanisms that operate during a sensitive time window. Recent studies have demonstrated that cellular and synaptic plasticity occurs throughout the central auditory pathway. Acoustic-rearing experiments can lead to an over-representation of the exposed sound frequency, and this is associated with specific changes in frequency discrimination. These forms of cellular plasticity are manifest in brain regions, such as midbrain and cortex, that interact through feed-forward and feedback pathways. Hearing loss leads to a profound re-weighting of excitatory and inhibitory synaptic gain throughout the auditory CNS, and this is associated with an over-excitability that is observed in vivo. Further behavioral and computational analyses may provide insights into how theses cellular and systems plasticity effects underlie the development of cognitive functions such as speech perception.
Hearing loss during development leads to central deficits that persist even after the restoration of peripheral function. One key class of deficits is due to changes in central inhibitory synapses, which play a fundamental role in all aspects of auditory processing. This review focuses on the anatomical and physiological alterations of inhibitory connections at several regions within the central auditory pathway following hearing loss. Such aberrant inhibitory synaptic function may be linked to deficits in encoding binaural and spectral cues. Understanding the cellular changes that occur at inhibitory synapses following hearing loss may provide specific loci that can be targeted to improve function.
auditory cortex; deafness; development; excitability; frequency tuning; inferior colliculus; LSO; MSO; sound localization
We have shown previously that auditory experience regulates the maturation of excitatory synapses in the auditory cortex (ACx). In this study, we used electron microscopic immunocytochemistry to determine whether the heightened excitability of the ACx following neonatal sensorineural hearing loss (SNHL) also involves pre- or postsynaptic alterations of GABAergic synapses. SNHL was induced in gerbils just prior to the onset of hearing (postnatal day 10). At P17, the gamma-aminobutyri acid type A (GABAA) receptor's β2/3-subunit (GABAAβ2/3) clusters residing at plasma membranes in layers 2/3 of ACx was reduced significantly in size (P < 0.05) and number (P < 0.005), whereas the overall number of immunoreactive puncta (intracellular + plasmalemmal) remained unchanged. The reduction of GABAAβ2/3 was observed along perikaryal plasma membranes of excitatory neurons but not of GABAergic interneurons. This cell-specific change can contribute to the enhanced excitability of SNHL ACx. Presynaptically, GABAergic axon terminals were significantly larger but less numerous and contained 47% greater density of glutamic acid decarboxylase immunoreactivity (P < 0.05). This suggests that GABA synthesis may be upregulated by a retrograde signal arising from lowered levels of postsynaptic GABAAR. Thus, both, the pre- and postsynaptic sides of inhibitory synapses that form upon pyramidal neurons of the ACx are regulated by neonatal auditory experience.
β2/3 subunits; deafness; development; electron microscopy; immunocytochemistry
Manganese-enhanced MRI (MEMRI) has been developed to image brain activity in small animals, including normal and genetically modified mice. Here, we report the use of a MEMRI-based statistical parametric mapping method to analyze sound-evoked activity in the mouse auditory midbrain, the inferior colliculus (IC). Acoustic stimuli with defined frequency and amplitude components were shown to activate and enhance neuronal ensembles in the IC. These IC activity patterns were analyzed quantitatively using voxel-based statistical comparisons between groups of mice with or without sound stimulation. Repetitive 40-kHz pure tone stimulation significantly enhanced ventral IC regions, which was confirmed in the statistical maps showing active regions whose volumes increased in direct proportion to the amplitude of the sound stimuli (65dB, 77dB, and 89dB peak sound pressure level). The peak values of the activity-dependent MEMRI signal enhancement also increased from 7 to 20% for the sound amplitudes employed. These results demonstrate that MEMRI statistical mapping can be used to analyze both the 3D spatial patterns and the magnitude of activity evoked by sound stimuli carrying different energy. This represents a significant advance in the development of MEMRI for quantitative and unbiased analysis of brain function in the deep brain nuclei of mice.
Developmental hearing impairments compromise sound discrimination, speech acquisition, and cognitive function; however, the adjustments of functional properties in the primary auditory cortex (A1) remain unknown. We induced sensorineural hearing loss (SNHL) in developing gerbils and then reared the animals for several days. The intrinsic membrane and synaptic properties of layer 2/3 pyramidal neurons were subsequently examined in a thalamocortical brain slice preparation with whole-cell recordings and electron microscopic immunocytochemistry. SNHL neurons displayed a depolarized resting membrane potential, an increased input resistance, and a higher incidence of sustained firing. They also exhibited significantly larger thalamocortically and intracortically evoked excitatory synaptic responses, including a greater susceptibility to the NMDA receptor antagonist AP-5 and the NR2B subunit antagonist ifenprodil. This correlated with an increase in NR2B labeling of asymmetric synapses, as visualized ultrastructurally. Furthermore, decreased frequency and increased amplitude of miniature EPSCs (mEPSCs) in SNHL neurons suggest that a decline in presynaptic release properties is compensated by an increased excitatory response. To verify that the increased thalamocortical excitation was elicited by putative monosynaptic connections, minimum amplitude ventral medial geniculate nucleus-evoked EPSCs were recorded. These minimum-evoked responses were of larger amplitude, and the NMDAergic currents were also larger and longer in SNHL neurons. These findings were supported by significantly longer AP-5-sensitive durations and larger amplitudes of mEPSCs. Last, the amplitudes of intracortically evoked monosynaptic and polysynaptic GABAergic inhibitory synaptic responses were significantly smaller in SNHL neurons. These alterations in cellular properties after deafness reflect an attempt by A1 to sustain an operative level of cortical excitability that may involve homeostatic mechanisms.
homeostasis; synaptic plasticity; GABAA; NMDA receptor; mEPSC; disuse
Inhibitory neurotransmission is a critical determinant of neuronal network gain and dynamic range, suggesting that network properties are shaped by activity during development. A previous study demonstrated that sensorineural hearing loss (SNHL) in gerbils leads to smaller inhibitory potentials in L2/3 pyramidal neurons in the thalamorecipient auditory cortex, ACx. Here, we explored the mechanisms that account for proper maturation of γ-amino butyric acid (GABA)ergic transmission. SNHL was induced at postnatal day (P) 10, and whole-cell voltage-clamp recordings were obtained from layer 2/3 pyramidal neurons in thalamocortical slices at P16–19. SNHL led to an increase in the frequency of GABAzine-sensitive (antagonist) spontaneous (s) and miniature (m) inhibitory postsynaptic currents (IPSCs), accompanied by diminished amplitudes and longer durations. Consistent with this, the amplitudes of minimum-evoked IPSCs were also reduced while their durations were longer. The α1- and β2/3 subunit–specific agonists zolpidem and loreclezole increased control but not SNHL sIPSC durations. To test whether SNHL affected the maturation of GABAergic transmission, sIPSCs were recorded at P10. These sIPSCs resembled the long SNHL sIPSCs. Furthermore, zolpidem and loreclezole were ineffective in increasing their durations. Together, these data strongly suggest that the presynaptic release properties and expression of key postsynaptic GABAA receptor subunits are coregulated by hearing.
α1 and β2/3 subunits; auditory cortex; development; GABAA receptor; hearing impairment
There are currently no noninvasive imaging methods available for auditory brain mapping in mice, despite the increasing use of genetically engineered mice to study auditory brain development and hearing loss. We developed a manganese-enhanced MRI (MEMRI) method to map regions of accumulated sound-evoked activity in awake, normally behaving mice. To demonstrate its utility for high-resolution (100-μm) brain mapping, we used MEMRI to show the tonotopic organization of the mouse inferior colliculus. To test its efficacy in an experimental setting, we acquired data from mice experiencing unilateral conductive hearing loss at different ages. Larger and persistent changes in auditory brainstem activity resulted when hearing loss occurred before the onset of hearing, showing that early hearing loss biases the response toward the functional ear. Thus, MEMRI provides a sensitive and effective method for mapping the mouse auditory brainstem and has great potential for a range of functional neuroimaging studies in normal and mutant mice.