Changes in NMDA receptor expression in auditory cortex after learning

Extensive practice on auditory learning tasks dramatically alters the functional organization and response properties of neurons in the auditory cortex. The cellular mechanisms responsible for this auditory learning-induced cortical plasticity are unclear; however, changes in synaptic function involving NMDA receptors have been strongly implicated. To test this hypothesis, we measured the change in gene expression of NMDA receptors and associated proteins in the auditory cortex of adult rats trained to perform an auditory identification task. NMDA receptor 2A and 2B gene expression in auditory cortex decreased significantly as auditory discrimination improved whereas expression of Arc, an immediate early gene involved in memory stabilization, increased. These results suggest that changes in NMDA receptors 2A and 2B and Arc enhance synaptic plasticity, thereby facilitating experience-dependent cortical remodeling and auditory learning.     

Background sounds contribute to spectrotemporal plasticity in primary auditory cortex

The mammalian auditory system evolved to extract meaningful information from complex acoustic environments. Spectrotemporal selectivity of auditory neurons provides a potential mechanism to represent natural sounds. Experience-dependent plasticity mechanisms can remodel the spectrotemporal selectivity of neurons in primary auditory cortex (A1). Electrical stimulation of the cholinergic nucleus basalis (NB) enables plasticity in A1 that parallels natural learning and is specific to acoustic features associated with NB activity. In this study, we used NB stimulation to explore how cortical networks reorganize after experience with frequency-modulated (FM) sweeps, and how background stimuli contribute to spectrotemporal plasticity in rat auditory cortex. Pairing an 8–4 kHz FM sweep with NB stimulation 300 times per day for 20 days decreased tone thresholds, frequency selectivity, and response latency of A1 neurons in the region of the tonotopic map activated by the sound. In an attempt to modify neuronal response properties across all of A1 the same NB activation was paired in a second group of rats with five downward FM sweeps, each spanning a different octave. No changes in FM selectivity or receptive field (RF) structure were observed when the neural activation was distributed across the cortical surface. However, the addition of unpaired background sweeps of different rates or direction was sufficient to alter RF characteristics across the tonotopic map in a third group of rats. These results extend earlier observations that cortical neurons can develop stimulus specific plasticity and indicate that background conditions can strongly influence cortical plasticity     

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.     

Competition and convergence between auditory and cross-modal visual inputs to primary auditory cortical areas

Sensory neocortex is capable of considerable plasticity after sensory deprivation or damage to input pathways, especially early in development. Although plasticity can often be restorative, sometimes novel, ectopic inputs invade the affected cortical area. Invading inputs from other sensory modalities may compromise the original function or even take over, imposing a new function and preventing recovery. Using ferrets whose retinal axons were rerouted into auditory thalamus at birth, we were able to examine the effect of varying the degree of ectopic, cross-modal input on reorganization of developing auditory cortex. In particular, we assayed whether the invading visual inputs and the existing auditory inputs competed for or shared postsynaptic targets and whether the convergence of input modalities would induce multisensory processing. We demonstrate that although the cross-modal inputs create new visual neurons in auditory cortex, some auditory processing remains. The degree of damage to auditory input to the medial geniculate nucleus was directly related to the proportion of visual neurons in auditory cortex, suggesting that the visual and residual auditory inputs compete for cortical territory. Visual neurons were not segregated from auditory neurons but shared target space even on individual target cells, substantially increasing the proportion of multisensory neurons. Thus spatial convergence of visual and auditory input modalities may be sufficient to expand multisensory representations. Together these findings argue that early, patterned visual activity does not drive segregation of visual and auditory afferents and suggest that auditory function might be compromised by converging visual inputs. These results indicate possible ways in which multisensory cortical areas may form during development and evolution. They also suggest that rehabilitative strategies designed to promote recovery of function after sensory deprivation or damage need to take into account that sensory cortex may become substantially more multisensory after alteration of its input during development.     

大鼠听皮质NMDA受体亚单位NR2B蛋白质的年龄-依赖性表达

目的：研究sD大鼠生后发育过程中,听皮质神经元NMDA受体亚单位NR2B蛋白质的表达规律。方法：采用免疫组织化学反应和蛋白质印迹技术,分别检测生后1、2、3周和成年动物听皮质神经元NMDA受体亚单位NR2B蛋白质的表达。结果：NR2B阳性神经元在生后第1周密度最高,随着生后周龄增长,NR2B阳性神经元密度递减．3周龄后降至成年动物的低表达水平。结论：大鼠生后发育过程巾．听皮质NR2B亚单位蛋白质呈现年龄-依赖性表达,此结果与mRNA水平上的表达趋势一致。     

A critical period for auditory thalamocortical connectivity

Neural circuits are shaped by experience during periods of heightened brain plasticity in early postnatal life. Exposure to acoustic features produces age-dependent changes through largely unresolved cellular mechanisms and sites of origin. We isolated the refinement of auditory thalamocortical connectivity by in vivo recordings and day-by-day voltage-sensitive dye imaging in an acute brain slice preparation. Passive tone-rearing modified response strength and topography in mouse primary auditory cortex (A1) during a brief, 3-d window, but did not alter tonotopic maps in the thalamus. Gene-targeted deletion of a forebrain-specific cell-adhesion molecule (Icam5) accelerated plasticity in this critical period. Consistent with its normal role of slowing spinogenesis, loss of Icam5 induced precocious stubby spine maturation on pyramidal cell dendrites in neocortical layer 4 (L4), identifying a primary locus of change for the tonotopic plasticity. The evolving postnatal connectivity between thalamus and cortex in the days following hearing onset may therefore determine a critical period for auditory processing.     

Corticofugal modulation of the midbrain frequency map in the bat auditory system

The auditory system, like the visual and somatosensory systems, contains topographic maps in its central neural pathways. These maps can be modified by sensory deprivation, injury and experience in both young and adult animals. Such plasticity has been explained by changes in the divergent and convergent projections of the ascending sensory system. Another possibility, however, is that plasticity may be mediated by descending corticofugal connections. We have investigated the role of descending connections from the cortex to the inferior colliculus of the big brown bat. Electrical stimulation of the auditory cortex causes a downward shift in the preferred frequencies of collicular neurons toward that of the stimulated cortical neurons. This results in a change in the frequency map within the colliculus. Moreover, similar changes can be induced by repeated bursts of sound at moderate intensities. Thus, one role of the mammalian corticofugal system may be to modify subcortical sensory maps in response to sensory experience.     

Developmental stability of taurine's activation on glycine receptors in cultured neurons of rat auditory cortex

Taurine is an endogenous amino acid that can activate glycine and/or gamma-aminobutyric acid type A (GABA(A)) receptors in the central nervous system. During natural development, taurine's receptor target undergoes a shift from glycine receptors to GABA(A) receptors in cortical neurons. Here, we demonstrate that taurine's receptor target in cortical neurons remains stable during in vitro development. With whole-cell patch-clamp recordings, we found that taurine always activated glycine receptors, rather than GABA(A) receptors, in neurons of rat auditory cortex cultured for 5-22 days. Our results suggest that the functional sensitivity of glycine and GABA(A) receptors to taurine is critically regulated by their developmental environments.     

Neurons in cat primary auditory cortex sensitive to correlates of auditory motion in three-dimensional space

Summary Amplitude modulation at the receiver's ears is a characteristic of moving sound sources. When a sound source moves from side to side, stimulus intensity decreases in one ear and increases in the other. When a sound source moves toward or away from the organism, the two ears receive correlated increases or decreases in sound level. We recorded from single cells in the auditory cortex while presenting amplitude modulated pure tones to the two ears which simulated motion either toward or away from the organism, or from side to side. Our results indicate that auditory cortex neurons can be highly sensitive to these correlates of auditory motion in three dimensional space. Three major classes of neurons were encountered. These included 1) neurons sensitive to azimuthal stimulus motion, 2) neurons sensitive to motion directly toward or away from the organism, and 3) monaural-like neurons. More toward-preferring neurons than away-preferring neurons were encountered, and more units preferred contralateral-directed than ipsilateral-directed movement. The different classes of direction-selective neurons were spatially segregated from each other within the cortex and appear to occur in columns. In addition to their selectivity for different directions of simulated sound source motion, auditory cortex neurons could also be highly selective to AM ramp rate and excursion; these are correlates of sound source velocity.This research was supported by MRC of Canada grant no MA-9856 to M.S.C., and a MRC Studentship to E.S.     

Spatial and non-spatial auditory processing in the lateral intraparietal area

We tested the responses of neurons in the lateral parietal area (area LIP) for their sensitivity to the spatial and non-spatial attributes of an auditory stimulus. We found that the firing rates of LIP neurons were modulated by both of these attributes. These data indicate that, while area LIP is involved in spatial processing, non-spatial processing is not restricted to independent channels.     

Polysynaptic excitatory pathways induce heterosynaptic depression in the rat auditory cortex

Short-term plasticity, the effect of a preceding synaptic response on the following response in a pair, in layers II/III of the rat auditory cortex slice after application of repetitive stimuli to layer IV, was investigated using a multichannel extracellular recording system. Paired-pulse depression, which is induced to a moderate degree in standard artificial cerebrospinal fluid, was markedly facilitated in the presence of bicuculline, a GABA(A) receptor antagonist, concurrent with the emergence of a polysynaptic component of the EPSP (polyEPSP) in the first response in a pair. This depression (bicuculline-facilitated synaptic depression, BFSD) was maximal at the minimum interval tested (50 ms), reduced as the interval was increased, and persisted beyond an interval of 2 s. The occurrence of BFSD was dependent on the presence of a polyEPSP regardless of the presence of the monosynaptic component of the EPSP, indicating that BFSD is induced by a heterosynaptic mechanism. D-AP5, an NMDA receptor antagonist, partially eliminated polyEPSPs and reversed BFSD. These results suggest that activation of polysynaptic excitatory pathways induces a heterosynaptic depression in the range of a few seconds and that NMDA receptor activity is involved in this heterosynaptic depression.     

Differential synaptic processing separates stationary from transient inputs to the auditory cortex.

Sound features are blended together en route to the central nervous system before being discriminated for further processing by the cortical synaptic network. The mechanisms underlying this synaptic processing, however, are largely unexplored. Intracortical processing of the auditory signal was investigated by simultaneously recording from pairs of connected principal neurons in layer II/III in slices from A1 auditory cortex. Physiological patterns of stimulation in the presynaptic cell revealed two populations of postsynaptic events that differed in mean amplitude, failure rate, kinetics and short-term plasticity. In contrast, transmission between layer II/III pyramidal neurons in barrel cortex were uniformly of large amplitude and high success (release) probability (Pr). These unique features of auditory cortical transmission may provide two distinct mechanisms for discerning and separating transient from stationary features of the auditory signal at an early stage of cortical processing.     

Development of human visual cortex: a balance between excitatory and inhibitory plasticity mechanisms

Formation of neural circuitry in the developing visual cortex is shaped by experience during the critical period. A number of mechanisms, including N-methyl-D-aspartate (NMDA) receptor activation and gamma-aminobutyric acid (GABA)-mediated inhibition, are crucial in determining onset and closure of the critical period for visual plasticity. Animal models have shown that a threshold level of tonic inhibition must be reached for critical period plasticity to occur and that NMDA receptors contribute to Hebbian synaptic plasticity in the developing visual cortex. There are a number of developmental changes in these glutamatergic and GABAergic mechanisms that have been linked to plasticity; however, those changes have been shown only in animal models, and their development in the human visual cortex is not known. We have addressed this question by studying the expression of the major glutamatergic receptors, GABA(A) receptors, and glutamic acid decarboxylase (GAD) isoforms during the first 6 years of postnatal development of human visual cortex. There are significant changes in the expression of these proteins during postnatal development of human visual cortex. The time course of the changes is quite prolonged and suggests that it may set the pace for the prolonged critical period in human visual development. The changes also affect the nature of spatial and temporal integration in visual cortical neurons and thereby contribute to the maturation of visual functions.     

Sensory input directs spatial and temporal plasticity in primary auditory cortex.

The cortical representation of the sensory environment is continuously modified by experience. Changes in spatial (receptive field) and temporal response properties of cortical neurons underlie many forms of natural learning. The scale and direction of these changes appear to be determined by specific features of the behavioral tasks that evoke cortical plasticity. The neural mechanisms responsible for this differential plasticity remain unclear partly because important sensory and cognitive parameters differ among these tasks. In this report, we demonstrate that differential sensory experience directs differential plasticity using a single paradigm that eliminates the task-specific variables that have confounded direct comparison of previous studies. Electrical activation of the basal forebrain (BF) was used to gate cortical plasticity mechanisms. The auditory stimulus paired with BF stimulation was systematically varied to determine how several basic features of the sensory input direct plasticity in primary auditory cortex (A1) of adult rats. The distributed cortical response was reconstructed from a dense sampling of A1 neurons after 4 wk of BF-sound pairing. We have previously used this method to show that when a tone is paired with BF activation, the region of the cortical map responding to that tone frequency is specifically expanded. In this report, we demonstrate that receptive-field size is determined by features of the stimulus paired with BF activation. Specifically, receptive fields were narrowed or broadened as a systematic function of both carrier-frequency variability and the temporal modulation rate of paired acoustic stimuli. For example, the mean bandwidth of A1 neurons was increased (+60%) after pairing BF stimulation with a rapid train of tones and decreased (-25%) after pairing unmodulated tones of different frequencies. These effects are consistent with previous reports of receptive-field plasticity evoked by natural learning. The maximum cortical following rate and minimum response latency were also modified as a function of stimulus modulation rate and carrier-frequency variability. The cortical response to a rapid train of tones was nearly doubled if BF stimulation was paired with rapid trains of random carrier frequency, while no following rate plasticity was observed if a single carrier frequency was used. Finally, we observed significant increases in response strength and total area of functionally defined A1 following BF activation paired with certain classes of stimuli and not others. These results indicate that the degree and direction of cortical plasticity of temporal and receptive-field selectivity are specified by the structure and schedule of inputs that co-occur with basal forebrain activation and suggest that the rules of cortical plasticity do not operate on each elemental stimulus feature independently of others.     

Rapid, experience-dependent expression of synaptic NMDA receptors in visual cortex in vivo

Sensory experience is crucial in the refinement of synaptic connections in the brain during development. It has been suggested that some forms of experience-dependent synaptic plasticity in vivo are associated with changes in the complement of postsynaptic glutamate receptors, although direct evidence has been lacking. Here we show that visual experience triggers the rapid synaptic insertion of new NMDA receptors in visual cortex. The new receptors have a higher proportion of NR2A subunits and, as a consequence, different functional properties. This effect of experience requires NMDA receptor activation and protein synthesis. Thus, rapid regulation of postsynaptic glutamate receptors is one mechanism for developmental plasticity in the brain. Changes in NMDA receptor expression provide a mechanism by which brief sensory experience can regulate the properties of NMDA receptor-dependent plasticity in visual cortex.     

An electrophysiological study of neural pathways for corticofugally inhibited neurons in the central nucleus of the inferior colliculus of the big brown bat, Eptesicus fuscus

This electrophysiological study tests the hypothesis that one possible neural pathway for corticofugally inhibited neurons in the central nucleus of the inferior colliculus (ICc) of the big brown bat, Eptesicus fuscus, is mediated through excitatory projections from the auditory cortex (AC) to the external nucleus of the IC (ICx), which then sends inhibitory inputs to the ICc. This study shows that all neurons in the ICx are broadly tuned to stimulus frequency. Electrical stimulation in the AC typically increases the number of impulses, expands the auditory spatial response areas, and broadens the frequency tuning curves (FTCs) of neurons in the ICx. This corticofugal facilitation is mediated at least in part through NMDA receptors, since application of DL-2-amino-5-phosphonovaleric acid (APV), an antagonist for NMDA, decreases these response properties of neurons in the ICx. Electrical stimulation in the ICx typically decreases the number of impulses, reduces the auditory spatial response areas, and narrows the FTCs of neurons in the ICc. This inhibition is mediated at least in part through GABA_A receptors, since application of bicuculline, an antagonist for GABA, increases these response properties of neurons in the ICc. These data suggest that corticofugal facilitation of the ICx and the inhibition of the ICx to the ICc may be one of the polysynaptic pathways for corticofugal inhibition of neurons in the ICc. Possible functions of this polysynaptic pathway in acoustic orientation and signal processing are discussed. Electronic Publication     

Early phase of spatial mismatch negativity is localized to a posterior “where” auditory pathway

The auditory mismatch negativity (MMN) is an event-related potential that reflects early processing of changes in acoustic stimulus features. Although the MMN has been well characterized by previous work, the number, roles, and anatomical locations of its cortical generators remain unresolved. Here, we report that the MMN elicited by occasional deviations in sound location is comprised of two temporally and anatomically distinct phases: an early phase with a generator posterior to auditory cortex and contralateral to the deviant stimulus, and a later phase with generators that are more frontal and bilaterally symmetric. The posterior location of the early-phase generator suggests the engagement of neurons within a putative “where” pathway for processing spatial auditory information.     

Spatial sensitivity in field PAF of cat auditory cortex

We compared the spatial tuning properties of neurons in two fields [primary auditory cortex (A1) and posterior auditory field (PAF)] of cat auditory cortex. Broadband noise bursts of 80-ms duration were presented from loudspeakers throughout 360 degrees in the horizontal plane (azimuth) or 260 degrees in the vertical median plane (elevation). Sound levels varied from 20 to 40 dB above units' thresholds. We recorded neural spike activity simultaneously from 16 sites in field PAF and/or A1 of alpha-chloralose-anesthetized cats. We assessed spatial sensitivity by examining the dependence of spike count and response latency on stimulus location. In addition, we used an artificial neural network (ANN) to assess the information about stimulus location carried by spike patterns of single units and of ensembles of 2-32 units. The results indicate increased spatial sensitivity, more uniform distributions of preferred locations, and greater tolerance to changes in stimulus intensity among PAF units relative to A1 units. Compared to A1 units, PAF units responded at significantly longer latencies, and latencies varied more strongly with stimulus location. ANN analysis revealed significantly greater information transmission by spike patterns of PAF than A1 units, primarily reflecting the information transmitted by latency variation in PAF. Finally, information rates grew more rapidly with the number of units included in neural ensembles for PAF than A1. The latter finding suggests more accurate population coding of space in PAF, made possible by a more diverse population of neural response types.     

Enhanced NR2A subunit expression and decreased NMDA receptor decay time at the onset of ocular dominance plasticity in the ferret.

Enhanced NR2A subunit expression and decreased NMDA receptor decay time at the onset of ocular dominance plasticity in the ferret. The NMDA subtype of glutamate receptor is known to exhibit marked changes in subunit composition and functional properties during neural development. The prevailing idea is that NMDA receptor-mediated synaptic responses decrease in duration after the peak of cortical plasticity in rodents. Accordingly, it is believed that shortening of the NMDA receptor-mediated current underlies the developmental reduction of ocular dominance plasticity. However, some previous evidence actually suggests that the duration of NMDA receptor currents decreases before the peak of plasticity. In the present study, we have examined the time course of NMDA receptor changes and how they correlate with the critical period of ocular dominance plasticity in the visual cortex of a highly binocular animal, the ferret. The expression of NMDA receptor subunits NR1, NR2A, and NR2B was examined in animals ranging in age from postnatal day 16 to adult using Western blotting. Functional properties of NMDA receptors in layer IV cortical neurons were studied using whole cell patch-clamp techniques in an in vitro slice preparation of ferret primary visual cortex. We observed a remarkable increase in NR1 and NR2A, but not NR2B, expression after eye opening. The NMDA receptor-mediated synaptic currents showed an abrupt decrease in decay time concurrent with the increase in NR2A subunit expression. Importantly, these changes occurred in parallel with increased ocular dominance plasticity reported in the ferret. In conclusion, molecular changes leading to decreased duration of the NMDA receptor excitatory postsynaptic current may be a requirement for the onset, rather than the end, of the critical period of ocular dominance plasticity.     

Modulation of thalamic auditory neurons by the primary auditory cortex

The central auditory system consists of the lemniscal and nonlemniscal pathways or systems, which are anatomically and physiologically different from each other. In the thalamus, the ventral division of the medial geniculate body (MGBv) belongs to the lemniscal system, whereas its medial (MGBm) and dorsal (MGBd) divisions belong to the nonlemniscal system. Lemniscal neurons are sharply frequency-tuned and provide highly frequency-specific information to the primary auditory cortex (AI), whereas nonlemniscal neurons are generally broadly frequency-tuned and project widely to cortical auditory areas including AI. These two systems are presumably different not only in auditory signal processing, but also in eliciting cortical plastic changes. Electric stimulation of narrowly frequency-tuned MGBv neurons evokes the shift of the frequency-tuning curves of AI neurons toward the tuning curves of the stimulated MGBv neurons (tone-specific plasticity). In contrast, electric stimulation of broadly frequency-tuned MGBm neurons augments the auditory responses of AI neurons and broadens their frequency-tuning curves (nonspecific plasticity). In our current studies, we found that electric stimulation of AI evoked tone-specific plastic changes of the MGBv neurons, whereas it degraded the frequency tuning of MGBm neurons by inhibiting their auditory responses. AI apparently modulates the lemniscal and nonlemniscal thalamic neurons in quite different ways. High MGBm activity presumably makes AI neurons less favorable for fine auditory signal processing, whereas high MGBv activity makes AI neurons more suitable for fine processing of specific auditory signals and reduces MGBm activity.