Reversal of Age-Related Changes in Cortical Sound-Azimuth Selectivity with Training.

The compromised abilities to understand speech and localize sounds are two hallmark deficits in aged individuals. Earlier studies have shown that age-related deficits in cortical neural timing, which is clearly associated with speech perception, can be partially reversed with auditory training. However, whether training can reverse aged-related cortical changes in the domain of spatial processing has never been studied. In this study, we examined cortical spatial processing in ~21-month-old rats that were trained on a sound-azimuth discrimination task. We found that animals that experienced 1 month of training displayed sharper cortical sound-azimuth tuning when compared to the age-matched untrained controls. This training-induced remodeling in spatial tuning was paralleled by increases of cortical parvalbumin-labeled inhibitory interneurons. However, no measurable changes in cortical spatial processing were recorded in age-matched animals that were passively exposed to training sounds with no task demands. These results that demonstrate the effects of training on cortical spatial domain processing in the rodent model further support the notion that age-related changes in central neural process are, due to their plastic nature, reversible. Moreover, the results offer the encouraging possibility that behavioral training might be used to attenuate declines in auditory perception, which are commonly observed in older individuals.

Auditory Training Reverses Lead (Pb)-Toxicity-Induced Changes in Sound-Azimuth Selectivity of Cortical Neurons.

Lead (Pb) causes significant adverse effects on the developing brain, resulting in cognitive and learning disabilities in children. The process by which lead produces these negative changes is largely unknown. The fact that children with these syndromes also show deficits in central auditory processing, however, indicates a speculative but disturbing relationship between lead-exposure, impaired auditory processing, and behavioral dysfunction. Here we studied in rats the changes in cortical spatial tuning impacted by early lead-exposure and their potential restoration to normal by auditory training. We found animals that were exposed to lead early in life displayed significant behavioral impairments compared with naïve controls while conducting the sound-azimuth discrimination task. Lead-exposure also degraded the sound-azimuth selectivity of neurons in the primary auditory cortex. Subsequent sound-azimuth discrimination training, however, restored to nearly normal the lead-degraded cortical azimuth selectivity. This reversal of cortical spatial fidelity was paralleled by changes in cortical expression of certain excitatory and inhibitory neurotransmitter receptor subunits. These results in a rodent model demonstrate the persisting neurotoxic effects of early lead-exposure on behavioral and cortical neuronal processing of spatial information of sound. They also indicate that attention-demanding auditory training may remediate lead-induced cortical neurological deficits even after these deficits have occurred.

Positive impacts of early auditory training on cortical processing at an older age.

Progressive negative behavioral changes in normal aging are paralleled by a complex series of physical and functional declines expressed in the cerebral cortex. In studies conducted in the auditory domain, these degrading physical and functional cortical changes have been shown to be broadly reversed by intensive progressive training that improves the spectral and temporal resolution of acoustic inputs and suppresses behavioral distractors. Here we found older rats that were intensively trained on an attentionally demanding modulation-rate recognition task in young adulthood substantially retained training-driven improvements in temporal rate discrimination abilities over a subsequent 18-mo epoch-that is, forward into their older age. In parallel, this young-adult auditory training enduringly enhanced temporal and spectral information processing in their primary auditory cortices (A1). Substantially greater numbers of parvalbumin- and somatostatin-labeled inhibitory neurons (closer to the numbers recorded in young vigorous adults) were recorded in the A1 and hippocampus in old trained versus untrained age-matched rats. These results show that a simple form of training in young adulthood in this rat model enduringly delays the otherwise expected deterioration of the physical status and functional operations of the auditory nervous system, with evident training impacts generalized to the hippocampus.

Modulation of azimuth tuning plasticity in rat primary auditory cortex by medial prefrontal cortex.

Neurons in the primary auditory cortex (A1) of adult animals exhibit short-term plasticity of frequency selectivity and tonotopic organization in behavioral contexts ranging from classical conditioning to attention tasks. However, it is still largely unknown whether short-term plasticity of spatial tuning takes place in A1 of adult animals and whether this spatial turning plasticity in A1 of adults is mediated by medial prefrontal cortex (mPFC) as there are reciprocal connection between mPFC and auditory cortex (AC). In the present study, we used extracellular recordings to test whether azimuth tuning in A1 of anesthetized rats can be reshaped by repeated sound stimuli at neurons' non-preferred azimuth. We also identified whether and how such A1 azimuth tuning plasticity was modulated by the neural activities of mPFC. Our results showed that A1 neurons in adult rats have azimuth tuning plasticity when repeated acoustic stimuli were delivered at the azimuth with a deviation by less than 15° from the best azimuth (BA). The BA shifted toward the exposure azimuth when repeated acoustic stimuli were played for 20-60min and plasticity decayed within one hour. The less the angle deviated from the BA, the shorter exposure time and longer decay time were required to induce azimuth tuning plasticity. Neural activity in mPFC modulated azimuth tuning plasticity of A1 neurons as reflected by the shorter induction time when mPFC was activated by focal electrical stimulation and the longer induction time when mPFC was inactivated by drug application. Our results suggest that spatial location selectivity in A1 neurons remains plastic in mature animals and that short-term plasticity of spatial tuning can be modulated by the neural activities of mPFC.

Perceptual Training Restores Impaired Cortical Temporal Processing Due to Lead Exposure.

Low-level lead exposure is a risk factor for cognitive and learning disabilities in children and has been specifically associated with deficits in auditory temporal processing that impair aural language and reading abilities. Here, we show that rats exposed to low levels of lead in early life display a significant behavioral impairment in an auditory temporal rate discrimination task. Lead exposure also results in a degradation of the neuronal repetition-rate following capacity and response synchronization in primary auditory cortex. A modified go/no-go repetition-rate discrimination task applied in adult animals for ∼50 days nearly restores to normal these lead-induced deficits in cortical temporal fidelity. Cortical expressions of parvalbumin, brain-derived neurotrophic factor, and NMDA receptor subunits NR2a and NR2b, which are down-regulated in lead-exposed animals, are also partially reversed with training. These studies in an animal model identify the primary auditory cortex as a novel target for low-level lead exposure and demonstrate that perceptual training can ameliorate lead-induced deficits in cortical discrimination between sound sequences.

Behavioral training reverses global cortical network dysfunction induced by perinatal antidepressant exposure.

Abnormal cortical circuitry and function as well as distortions in the modulatory neurological processes controlling cortical plasticity have been argued to underlie the origin of autism. Here, we chemically distorted those processes using an antidepressant drug-exposure model to generate developmental neurological distortions like those characteristics expressed in autism, and then intensively trained altered young rodents to evaluate the potential for neuroplasticity-driven renormalization. We found that young rats that were injected s.c. with the antidepressant citalopram from postnatal d 1-10 displayed impaired neuronal repetition-rate following capacity in the primary auditory cortex (A1). With a focus on recovering grossly degraded auditory system processing in this model, we showed that targeted temporal processing deficits induced by early-life antidepressant exposure within the A1 were almost completely reversed through implementation of a simple behavioral training strategy (i.e., a modified go/no-go repetition-rate discrimination task). Degraded parvalbumin inhibitory GABAergic neurons and the fast inhibitory actions that they control were also renormalized by training. Importantly, antidepressant-induced degradation of serotonergic and dopaminergic neuromodulatory systems regulating cortical neuroplasticity was sharply reversed. These findings bear important implications for neuroplasticity-based therapeutics in autistic patients.

Environmental acoustic enrichment promotes recovery from developmentally degraded auditory cortical processing.

It has previously been shown that environmental enrichment can enhance structural plasticity in the brain and thereby improve cognitive and behavioral function. In this study, we reared developmentally noise-exposed rats in an acoustic-enriched environment for ∼4 weeks to investigate whether or not enrichment could restore developmentally degraded behavioral and neuronal processing of sound frequency. We found that noise-exposed rats had significantly elevated sound frequency discrimination thresholds compared with age-matched naive rats. Environmental acoustic enrichment nearly restored to normal the behavioral deficit resulting from early disrupted acoustic inputs. Signs of both degraded frequency selectivity of neurons as measured by the bandwidth of frequency tuning curves and decreased long-term potentiation of field potentials recorded in the primary auditory cortex of these noise-exposed rats also were reversed partially. The observed behavioral and physiological effects induced by enrichment were accompanied by recovery of cortical expressions of certain NMDA and GABAA receptor subunits and brain-derived neurotrophic factor. These studies in a rodent model show that environmental acoustic enrichment promotes recovery from early noise-induced auditory cortical dysfunction and indicate a therapeutic potential of this noninvasive approach for normalizing neurological function from pathologies that cause hearing and associated language impairments in older children and adults.

Refining cortical representation of sound azimuths by auditory discrimination training.

Although training-based auditory cortical plasticity in the adult brain has been previously demonstrated in multiparametric sound domains, neurochemical mechanisms responsible for this form of plasticity are not well understood. In this study, we trained adult rats to identify a target sound stimulus at a specific azimuth angle by using a reward-contingent auditory discrimination task. We found that auditory spatial discrimination training significantly enhanced representation of sound azimuths in the primary auditory cortex, as shown by sharper azimuth-selective curves and more evenly distributed best angles of cortical neurons. Training also facilitated long-term potentiation of field potentials in the primary auditory cortex induced by theta burst stimulation of the white matter. In parallel, there were significant alterations in expression levels of certain cortical GABA(A) and NMDA receptor subunits, resulting in a marked decrease in the level of GABA(A) relative to NMDA receptors. These changes in the expression profile of inhibitory and excitatory neurotransmitter receptor subunits might enhance synaptic transmission, thereby facilitating training-induced cortical plasticity in the spatial domain.

The impact of preceding noise on the frequency tuning of rat auditory cortex neurons.

BACKGROUND: In a natural environment, contextual noise frequently occurs with a signal sound for detection or discrimination in a temporal relation. However, the representation of sound frequency by auditory cortical neurons in a noisy environment is not fully understood. Therefore, the purpose of this study was to explore the impact of contextual noise on the cortical tuning to signal sound frequency in order to better understand the mechanism of cortical frequency coding in a complex acoustical environment. RESULTS: We compared the excitatory frequency-level receptive fields (FLRFs) of neurons in the rat primary auditory cortex determined under both quiet and preceding noise conditions. Based on the changes of minimum threshold and the extent of FLRF of auditory cortical neurons, we found that the FLRFs of a cortical neuron were modulated dynamically by a varying preceding noise. When the interstimulus interval between noise and the probe tone was constant, the modulation of the FLRF increased as the level of noise was increased. If the preceding noise level was constant, the modulation decreased when the interstimulus interval was increased. Preceding noise sharpened the bandwidth of the FLRFs of 47.6% tested neurons. Moreover, preceding noise shifted the CFs of 47.6% neurons by more than 0.25 octaves, while the CFs of the rest of the neurons remained relatively unchanged. CONCLUSIONS: The results indicate that the cortical representation of sound frequency is dynamically modulated by contextual acoustical environment, and that there are cortical neurons whose characteristic frequencies were resistant to the interference of contextual noise.

Auditory discrimination training rescues developmentally degraded directional selectivity and restores mature expression of GABA(A) and AMPA receptor subunits in rat auditory cortex.

Auditory frequency discrimination training can remediate deteriorated frequency representations and temporal information processing in the adult primary auditory cortex induced by early post-natal pulsed noise exposure. In this study, we investigated the neural mechanisms underlying the restoration of directional selectivity by auditory spatial discrimination training. Rats exposed to pulsed noise during a post-natal critical period demonstrated reduced auditory directional selectivity but could be successfully trained to identify a target sound stimulus at a specific azimuth angle using a reward-contingent auditory discrimination task (EXP rats). In contrast, rats passively exposed to the training procedure but no reward for correct identification of the azimuth angle (PNR rats) showed no improvement and behavioral performance remained significantly below EXP rats and control (CON) rats reared under a normal sonic environment. The expression levels of GABA(A) receptor subunits α1, α3, ß2, and ß3, and the AMPA GluR2 subunit were significantly altered in the auditory cortex of untrained noise-raised (NR and PNR) rats compared to age-matched CON rats, while trained noise-raised (EXP) rats exhibited levels of expression not significantly different from CON rats. Thus, reward-contingent sound-azimuth discrimination training may remediate directional selectivity by restoring the proper expression profile of neurotransmitter receptor subunits in the auditory cortex, allowing for normal spatial selectivity by cortical neurons. The development of auditory directional selectivity depends on the regulated expression of these excitatory and inhibitory neurotransmitter receptor subunits; early pulsed noise may disrupt the normal development of directional selectivity by interfering with receptor expression.

Developmentally degraded directional selectivity of the auditory cortex can be restored by auditory discrimination training in adults.

Sound localization is one of the most important tasks performed by the auditory system. Studies have shown that intensive training can remediate deteriorated frequency representations and temporal information processing in the adult primary auditory cortex (A1) induced by early post-natal pulsed noise exposure. Here we demonstrate that intensive sound location discrimination training improved the dysfunctional sound azimuth selectivity degraded by early post-natal pulsed noise exposure. Rats exposed to pulsed white noise during a post-natal critical period were successfully trained to identify a target sound stimulus with specific azimuth angle that changed daily on a random schedule. Consistent with recovery of behavioral accuracy for sound-azimuth discriminations, we found that the average angular range (AR) of A1 neuronal azimuth selective curves in trained noise-raised rats was not significantly different from that measured in control rats, while the average AR of A1 neurons in untrained noise-raised rats was significantly higher, indicating that these neurons were less direction selective. Directional selectivity of A1 neurons was normalized by training, thus demonstrating the benefits of sensory discrimination training as a strategy for restoring auditory function in adult mammals damaged by sensory disruption during critical periods of cortical development.

Maintenance of enriched environment-induced changes of auditory spatial sensitivity and expression of GABAA, NMDA, and AMPA receptor subunits in rat auditory cortex.

Enriched environment (EE) has an important role in the development and plasticity of the brain. In this study, we investigated the maintenance of early EE exposure-induced changes of spatial sensitivity, and the possible underlying mechanisms of this maintenance. We found that, compared with the age-matched control, the spatial sensitivity of A1 neurons was still enhanced after EE rats had been returned to the normal condition for 2 months. The enhancement was expressed by a sharper frequency tuning curve, smaller spatial receptive field, and a more selective directional curve of the early EE-exposed rats. Simultaneously, we detected significant increases in GABA(A) receptor α1, ß3 subunits; NMDA receptor NR2A, NR2B subunits; AMPA receptor GluR2 subunit protein expression; and in the ratios of GABA(A)α1/GABA(A)α3 and NR2A/NR2B. In particular, the expression ratio change of the GABA(A)α1/GABA(A)α3 was significant greater than that of NR2A/NR2B in early EE-exposed rats. These observations indicate that the persistent higher expression levels of the GABAergic and glutamatergic receptors expression induced by early EE exposure, especially enhancement of GABAergic inhibition in the auditory cortex, might be responsible for the maintenance of improved effects in auditory spatial sensitivity after the rats had been returned to the normal condition.

[Sound level of conditioned stimulus differs the plasticity of characteristic frequency in the rat cortical neurons].

OBJECTIVE: Try to observe the plasticity of neuron in primary cortex of rat evoked by conditioned stimulus of different sound level. METHODS: Applying conventional electrophysiological technique of extracellular recording to investigate the plasticity of characteristic frequency (CF) and frequency turning curve (FIC) of neurons in rat auditory cortex (AC) by determining CF shifts of neurons caused by sound stimulus of different sound level. RESULTS: When the frequency difference between conditioned stimulus (CS) frequency and the CF of neuron was in 1.0 kHz, the plasticity of CF induced by CS was associated with sound level. The probability of the plasticity of CF evoked by CS of higher sound lever was more than the lower. And the probability was dependent on frequency turning curve (FTC) and almost independent on the sound level of conditioned signal. CONCLUSION: Sound level of conditioned stimulus differs the plasticity of characteristic frequency of neurons in rat auditory cortex.

Early APV chronic blocked alters experience-dependent plasticity of auditory spatial representation in rat auditory cortical neurons.

Development of auditory function can be affected by environment and experience. In this study, we investigated whether the NMDA receptor mediates the plasticity of auditory spatial representation during development of the rat auditory cortex. We found that early auditory experience significantly increased the auditory spatial sensitivity of A1 neurons and induced training-dependent plasticity. Implantation of Elvax-APV in the auditory cortex gradually reduced the auditory spatial sensitivity of A1 neurons and blocked the auditory spatial plasticity induced by early auditory experience. These results indicate that the NMDA receptor has a key role in experience-dependent plasticity of auditory cortical circuits immediately after birth.

Early continuous white noise exposure alters l-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor subunit glutamate receptor 2 and gamma-aminobutyric acid type a receptor subunit beta3 protein expression in rat auditory cortex.

Auditory experience during the postnatal critical period is essential for the normal maturation of auditory function. Previous studies have shown that rearing infant rat pups under conditions of continuous moderate-level noise delayed the emergence of adult-like topographic representational order and the refinement of response selectivity in the primary auditory cortex (A1) beyond normal developmental benchmarks and indefinitely blocked the closure of a brief, critical-period window. To gain insight into the molecular mechanisms of these physiological changes after noise rearing, we studied expression of the AMPA receptor subunit GluR2 and GABA(A) receptor subunit beta3 in the auditory cortex after noise rearing. Our results show that continuous moderate-level noise rearing during the early stages of development decreases the expression levels of GluR2 and GABA(A)beta3. Furthermore, noise rearing also induced a significant decrease in the level of GABA(A) receptors relative to AMPA receptors. However, in adult rats, noise rearing did not have significant effects on GluR2 and GABA(A)beta3 expression or the ratio between the two units. These changes could have a role in the cellular mechanisms involved in the delayed maturation of auditory receptive field structure and topographic organization of A1 after noise rearing.

Early continuous white noise exposure alters auditory spatial sensitivity and expression of GAD65 and GABAA receptor subunits in rat auditory cortex.

Sensory experiences have important roles in the functional development of the mammalian auditory cortex. Here, we show how early continuous noise rearing influences spatial sensitivity in the rat primary auditory cortex (A1) and its underlying mechanisms. By rearing infant rat pups under conditions of continuous, moderate level white noise, we found that noise rearing markedly attenuated the spatial sensitivity of A1 neurons. Compared with rats reared under normal conditions, spike counts of A1 neurons were more poorly modulated by changes in stimulus location, and their preferred locations were distributed over a larger area. We further show that early continuous noise rearing induced significant decreases in glutamic acid decarboxylase 65 and gamma-aminobutyric acid (GABA)(A) receptor alpha1 subunit expression, and an increase in GABA(A) receptor alpha3 expression, which indicates a returned to the juvenile form of GABA(A) receptor, with no effect on the expression of N-methyl-D-aspartate receptors. These observations indicate that noise rearing has powerful adverse effects on the maturation of cortical GABAergic inhibition, which might be responsible for the reduced spatial sensitivity.

Environmental enrichment enhances directional selectivity of primary auditory cortical neurons in rats.

Environment enrichment (EE) has an important role in brain plasticity. Previous research has shown that EE increases the response strength of auditory cortical neurons, but it remains unknown whether EE can affect the directional selectivity of auditory neurons. In this study, rats were exposed to EE conditions during the developmental critical period (EE1) or after the critical period (EE2). By in vivo extracellular recording, we found that EE enhanced the directional selectivity of primary auditory cortical neurons in EE1 rats, which showed a sharper azimuth selectivity curve of auditory cortical neurons compared with normal rats. However, there was no significant difference in directional selectivity between the EE2 rats and age-matched control rats. Our findings indicate that early exposure to EE enhances the directional sensitivity of primary auditory cortical neurons. These results provide an insight into developmental plasticity in the auditory system.

The effect of postnatal exposure to noise on sound level processing by auditory cortex neurons of rats in adulthood.

Most people are exposed daily to some level and duration of environmental noise. The aim of the present study was to determine the effect of postnatal exposure to a moderate level of noise on sound level processing by neurons in the primary auditory cortex of rats in adulthood. The cortical neuron response to sound stimuli was investigated in three groups of rats. Two groups, either in the critical period of postnatal hearing development or in adulthood, were exposed to 80 dB SPL interrupted white noise for 8 h/day for 2 weeks. The control group consisted of adult rats that were not exposed to the white noise. Seven weeks later, the minimum threshold, the first spike latency, the dynamic range and the slope of the rate-level functions of cortical neuron response to a sound stimulus were determined. The cortical neurons in young rats exposed to the noise had a significantly higher minimum threshold, a longer first spike latency, a shorter dynamic range and a bigger slope in rate-level functions compared with the control group. The group in which adult rats were exposed to the white noise, however, did not have a significant change of sound level processing by the auditory cortical neurons. These results demonstrated that young rats were more susceptible to noise exposure affecting the cortical neuron processing of sound levels.

Environmental enrichment improves behavioral performance and auditory spatial representation of primary auditory cortical neurons in rat.

Environmental enrichment (EE) has an important role in brain plasticity. Early research has shown that EE increases the response strength of neurons in the auditory cortex, but it remains unknown whether EE can influence the process of spatial localization in the auditory system. In this study, we raised rats in enriched and standard conditions from postnatal day 10 to day 56. By testing behavioral tasks via auditory cues, we have shown that EE improved the number of correct scores, but decreased the reaction time and azimuth deviation in behavioral performance of sound-azimuth discrimination. By in vivo extracellular recording, we have shown that EE enhanced the directional sensitivity of neurons in the primary auditory cortex. For example, EE rats had a smaller spatial receptive field, sharper frequency tuning curve and directional selective curve of auditory neurons compared with normal rats. Our findings indicate that early exposure to EE increases directional sensitivity. These results provide an insight into developmental plasticity in the auditory system.

Early auditory experience-induced composition/ratio changes of N-methyl-D-aspartate receptor subunit expression and effects of D-2-amino-5-phosphonovaleric acid chronic blockade in rat auditory cortex.

Auditory function can be affected by many factors, including environment and experience. In this study, we investigated whether early auditory experience mediates the regulation of the composition/ratio changes of the N-methyl-D-aspartic acid (NMDA) receptor subunits during development of the rat auditory cortex. We found that early sound exposure can increase expression of the NMDA receptor subunits and increase the composition/ratios of NMDA receptor subunits during the postnatal critical period. D-2-amino-5-phosphonovaleric acid (D-APV) could block and reverse the auditory experience-mediated changes, and there were marked reductions in expression levels and the composition/ratios of NMDA receptor subunits. These results indicate that the experience-dependent plasticity of the auditory cortex in the critical period during postnatal development has a marked influence on NMDA receptor expression in the rat and that changes in NMDA receptor subunit composition/ratios might mediate the early auditory experience-dependent plasticity crucial to auditory function.