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.

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.

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.

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.

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.

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.

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.

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.

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 deprivation alters expression of NMDA receptor subunit NR1 mRNA in the rat auditory cortex.

The expression of NMDA receptor NR1 subunit mRNA was studied in rat auditory cortex (AC) on different postnatal days using digoxigenin-labeled oligonucleotide probes. The results showed that NR1 expression increased from birth to postnatal day 35 (P35) and remained constant until P56. The most significant increases occurred between P7 and P14. Changes in NR1 mRNA expression in rats subjected to monaural hearing deprivation on P7, P21, P35, and P49 were examined on P56. Between P7 and P21, when the rat auditory system was still in a critical period of development, NR1 mRNA expression was lower in the contralateral AC, which received auditory signals from the plugged ear, than in the ipsilateral AC. However, no significant difference was observed between the rats deprived of hearing on P35 and those deprived of hearing on P42, the end of the critical period of auditory development. These results showed that monaural hearing deprivation during early postnatal development was associated with decreased NR1 mRNA expression in the contralateral AC and suggested the involvement of NR1 in auditory function during development. They also indicated that, during postnatal development, environmental factors changed the functional plasticity of neurons in the AC through NR1 receptor expression. Taken together, these findings provide a possible underlying mechanism for the development of postnatal auditory function.

Noise exposure at young age impairs the auditory object exploration behavior of rats in adulthood.

Environment noise is ubiquitous in our daily life. The aim of the present study was to determine the effect of postnatal exposure to moderate-level noise on the auditory object exploration behavior of adult rats by comparing the ability of three groups of rats to locate a sound source in a water maze. Two groups of rats, either in the critical period of hearing development or in adulthood, were exposed to 80 dB SPL interrupted white noise for 8 h per day for two weeks. The control group of rats was not exposed to the noise. The ability of the rats to locate a hidden platform that was situated near a sound source in a water maze was tested starting on postnatal day 77. A continuous improvement in the performance of control rats and rats exposed to noise in adulthood was observed during training, whereas rats exposed to noise at a young age exhibited a significantly worse performance. These findings indicated that long-term exposure of young rats to moderate-level noise caused significant impairment of their auditory object exploration behavior compared to exposure of adult animals to the same moderate-level noise.

Early music exposure modifies GluR2 protein expression in rat auditory cortex and anterior cingulate cortex.

GluR2, a major subunit in AMPA receptor, plays an important role in brain functional activity. We studied the effect of music exposure during development on the expression level of GluR2 proteins in the auditory cortex (AC) and anterior cingulate cortex (ACC) of SD rats. Rats were divided into three groups, Music1 (exposed to Nostalgy) group, Music2 (exposed to Wishmaster) group, and control (no music exposure) group. For music exposure groups, rats were exposed to music from postnatal day (PND) 14, and the expression levels of GluR2 proteins were determined at PND 28, 42 and 56. For the control group, the expression levels of GluR2 proteins were determined at PND1, 3, 5, 7, 9, 11, 14, 21, 28, 42, and 56. Results showed an age-dependent expression of GluR2 proteins in control rats. In AC, exposure to Music2 dramatically increased the expression of GluR2, while exposure to Music1 had no effect. In ACC, we found remarkable discrepancies in time-dependent expression of GluR2 between music exposed rats and control rats. These results indicate that exposure to music can modify the expression level of GluR2 protein in AC and ACC.

Modulation of frequency receptive field plasticity in rat auditory cortical neurons by electrical stimulation of medial prefrontal cortex.

Using conventional electrophysiological technique, we investigated the effects of stimulating the medial prefrontal cortex (mPFC) on plasticity of frequency receptive field (RF) in auditory cortical (AC) neurons in rats. When the mPFC was electrically stimulated, the RF plasticity of 51 (27.2%) neurons was not affected and that of 137 neurons (72.8%) was either inhibited (71 neurons, 37.7%) or facilitated (66 neurons, 35.1%). The modulation of RF plasticity by the stimulation of mPFC was dependent upon the time interval between acoustic and electrical stimuli. The best interval time that produced optimal modulation (inhibition or facilitation) ranged from 5 to 30 ms. The inhibitory modulation of mPFC prolonged RF shifting time and shortened RF recovery time. Conversely, the facilitatory modulation of mPFC shortened RF shifting time and prolonged RF recovery time. Our results suggest that the mPFC may affect the plasticity of functional activity in AC neurons, and also may participate in the process of auditory learning and memory.

GABAergic inhibition modulates intensity sensitivity of temporally patterned pulse trains in the inferior collicular neurons in big brown bats.

The echolocating big brown bats (Eptesicus fuscus) emit trains of frequency-modulated (FM) biosonar signals with duration, amplitude, repetition rate, and sweep structure changing systematically during interception of their prey. In the present study, the sound stimuli of temporally patterned pulse trains at three different pulse repetition rates (PRRs) were used to mimic the sounds received during search, approach, and terminal stages of echolocation. Electrophysiological method was adopted in recordings from the inferior colliculus (IC) of midbrain. By means of iontophoretic application of bicuculline, the effect of GABAergic inhibition on the intensity sensitivity of IC neurons responding to three different PRRs of 10, 30 and 90 pulses per second (pps) was examined. The rate-intensity functions (RIFs) were acquired. The dynamic range (DR) of RIFs was considered as a criterion of intensity sensitivity. Comparing the average DR of RIFs at different PRRs, we found that the intensity sensitivity of some neurons improved, but that of other neurons decayed when repetition rate of stimulus trains increased from 10 to 30 and 90 pps. During application of bicuculline, the number of impulses responding to the different pulse trains increased under all stimulating conditions, while the DR differences of RIFs at different PRRs were abolished. The results indicate that GABAergic inhibition was involved in modulating the intensity sensitivity of IC neurons responding to pulse trains at different PRRs. Before and during bicuculline application, the percentage of changes in responses was maximal in lower stimulus intensity near to the minimum threshold (MT), and decreased gradually with the increment of stimulus intensity. This observation suggests that GABAergic inhibition contributes more effectively to the intensity sensitivity of the IC neurons responding to pulse trains at lower sound level.

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.

Sound azimuth selectivity of inferior collicular neurons in juvenile bats, Myotis chinensis.

The directional selectivity of auditory neurons is one of the essential response properties that underlie sound localization, an important task performed by the mammalian auditory system. Here we evaluated the sound azimuth selectivity of inferior collicular neurons in juvenile bats, Myotis chinensis, at the age of 15 days under free-field stimulation conditions. Compared with those in adult bats, neurons in juvenile bats were broadly tuned to sound azimuth angles as indicated by both the type and width of the azimuth selectivity curves. Their best azimuth was distributed over a wide range and, moreover, the adult-like relationship between the best azimuth and the best frequency of these neurons was not developed. These data indicate that the directional selectivity of inferior collicular neurons, like other response properties examined previously, undergoes considerable change during postnatal maturation.