Auditory cortical plasticity: a comparison with other sensory systems

The auditory cortex has a crucial role in higher cognitive functions, including the perception of speech, music and auditory space. Cortical plasticity, as in other sensory systems, is used in the fine tuning of the auditory system for these higher functions. Auditory cortical plasticity can also be demonstrated after lesions of the cochlea and it appears to participate in generating tinnitus. Early musical training leads to an expansion in the representation of complex harmonic sounds in the auditory cortex. Similarly, the early phonetic environment has a strong influence on speech development and, presumably, on the cortical organization of speech. In auditory spatial perception, the spectral cues generated by the head and outer ears vary between individuals and have to be calibrated by learning, which most probably takes place at the cortical level. The neural mechanisms of plasticity are likely to be the same across all cortical regions. It should be useful, therefore, to relate some of the findings and hypotheses about auditory cortical plasticity to previous studies of other sensory systems.     

Development of auditory cortical synaptic receptive fields

The central nervous system is plastic throughout life, but is most sensitive to the statistics of the sensory environment during critical periods of early postnatal development. In the auditory cortex, various forms of acoustic experience have been found to shape the formation of receptive fields and influence the overall rate of cortical organization. The synaptic mechanisms that control cortical receptive field plasticity are beginning to be described, particularly for frequency tuning in rodent primary auditory cortex. Inhibitory circuitry plays a major role in critical period regulation, and new evidence suggests that the formation of excitatory-inhibitory balance determines the duration of critical period plasticity for auditory cortical frequency tuning. Cortical inhibition is poorly tuned in the infant brain, but becomes co-tuned with excitation in an experience-dependent manner over the first postnatal month. We discuss evidence suggesting that this may be a general feature of the developing cortex, and describe the functional implications of such transient excitatory-inhibitory imbalance.     

Development,organization and plasticity of auditory circuits: Lessons from a cherished colleague

Ray Guillery was a neuroscientist known primarily for his ground‐breaking studies on the development of the visual pathways and subsequently on the nature of thalamocortical processing loops. The legacy of his work, however, extends well beyond the visual system. Thanks to Ray Guillery's pioneering anatomical studies, the ferret has become a widely used animal model for investigating the development and plasticity of sensory processing. This includes our own work on the auditory system, where experiments in ferrets have revealed the role of sensory experience during development in shaping the neural circuits responsible for sound localization, as well as the capacity of the mature brain to adapt to changes in inputs resulting from hearing loss. Our research has also built on Ray Guillery's ideas about the possible functions of the massive descending projections that link sensory areas of the cerebral cortex to the thalamus and other subcortical targets, by demonstrating a role for corticothalamic feedback in the perception of complex sounds and for corticollicular projection neurons in learning to accommodate altered auditory spatial cues. Finally, his insights into the organization and functions of transthalamic corticocortical connections have inspired a raft of research, including by our own laboratory, which has attempted to identify how information flows through the thalamus.     

The role of the auditory cortex in the spatial information processing

Sound localization is a computational process accomplished along the auditory pathway. Once the acoustic information received at each ear is analyzed independently (monaural cues) and comparatively (binaural cues), those cues are integrated to generate a coherent spatial percept. Using adult ferrets trained by positive conditioning in a spatial task, we aimed to study the role of the auditory cortex in the ability to localize sounds under both normal hearing and monaurally occluded conditions, the latter of which requires a reinterpretation of the values of the localization cues. Sound localization deficits were found after lesion or inactivation of the different auditory cortical regions, thereby indicating their participation in spatial processing. The differential impairments found in the approach-to-target and in the head movement responses reveal the complex relationship between cortex and midbrain which are putatively responsible for the voluntary and reflexive aspects of localization behaviour respectively. Furthermore, every auditory cortical region contributes to the adaptation process that follows monaural occlusion, indicating the key role that the auditory cortex plays in experience-dependent plasticity. Also, the selective lesion of the descending projections from the auditory cortex to the inferior colliculus by chromophore-targeted laser photolysis has revealed the essential function that descending pathways play in learning-induced localization plasticity.     

Contributions of the thalamocortical system towards sound-specific auditory plasticity

The function of the auditory cortex is dynamic. Although auditory cortical plasticity can be induced through various approaches such as learning, experience and sensory deprivation, a common property is the frequency-specificity; the change in neuronal receptive field or functional maps is highly specific to the frequency content of the acquired sound. This unique property suggests that precise frequency information must be relayed to the auditory cortex. It is well known that the auditory thalamocortical pathway is the only neural substrate that sends precise frequency information to the auditory cortex. This review addresses the impact of the auditory thalamocortical system on cortical plasticity. The frequency-specificity of auditory cortical plasticity and the tonotopic features of the auditory thalamocortical system are briefly presented. A discussion of the decisive role of thalamocortical system follows. After an exploration of a possible synaptic mechanism, a thalamocortical model is proposed to better interpret the neural mechanisms underlying frequency-specific plasticity of the auditory cortex.     

Absence of plasticity of the frequency map in dorsal cochlear nucleus of adult cats after unilateral partial cochlear lesions

In adult animals, lesions to parts of the auditory receptor organ, the cochlea, can produce plasticity of the topographic (cochleotopic) frequency map in primary auditory cortex and a restricted or patchy plasticity in the auditory midbrain. This effect is similar to the plasticity of topographic maps of the sensory surface seen in visual and somatosensory cortices after restricted damage to the appropriate receptor surface in these sensory systems. There is dispute about the extent to which subcortical effects contribute to cortical plasticity. Here, we have examined whether topographic map plasticity similar to that seen in the auditory cortex and the midbrain is observed in the adult auditory brainstem. When partial cochlear lesions were produced in the same manner as those that were produced in the cortex and midbrain studies, we found no plasticity of the frequency map in the dorsal cochlear nucleus (DCN). Small regions of the DCN that were deprived of their normal, most sensitive frequency (characteristic frequency; CF) input by the cochlear lesion appeared to have acquired new CFs at frequencies at or near the edge of the cochlear lesion. However, examination of thresholds at the new CFs established that the changes simply reflected the residue of prelesion input to those sites: The patterns of CF thresholds were very well predicted by simple calculations of the patterns that were expected from such residual input. The results of this study suggest that the DCN does not exhibit the type of plasticity that has been found in the auditory cortex and midbrain; therefore, it does not account for the changes in responsiveness observed in the higher level structures under similar experimental conditions. J. Comp. Neurol. 399:35–46, 1998. © 1998 Wiley-Liss, Inc.     

Sound‐specific plasticity in the primary auditory cortex as induced by the cholinergic pedunculopontine tegmental nucleus

Brain cholinergic modulation is essential for learning‐induced plasticity of the auditory cortex. The pedunculopontine tegmental nucleus (PPTg) is an important cholinergic nucleus in the brainstem, and appears to be involved in learning and subcortical plasticity. This study confirms the involvement of the PPTg in the plasticity of the auditory cortex in mice. We show here that electrical stimulation of the PPTg paired with a tone induced drastic changes in the frequency tunings of auditory cortical neurons. Importantly, the changes in frequency tuning were highly specific to the frequency of the paired tone; the best frequency of auditory cortical neurons shifted towards the frequency of the paired tone. We further demonstrated that such frequency‐specific plasticity was largely eliminated by either thalamic or cortical application of the muscarinic acetylcholine receptor antagonist atropine. Our finding suggests that the PPTg significantly contributes to auditory cortical plasticity via the auditory thalamus and cholinergic basal forebrain.     

Auditory processing in schizophrenia during the middle latency period (10-50 ms): high-density electrical mapping and source analysis reveal subcortical antecedents to early cortical deficits

INTRODUCTION: Auditory sensory processing dysfunction is a core component of schizophrenia, with deficits occurring at 50 ms post-stimulus firmly established in the literature. Given that the initial afference of primary auditory cortex occurs at least 35 ms earlier, however, an essential question remains: how early in sensory processing do such deficits arise, and do they occur during initial cortical afference or earlier, which would implicate subcortical auditory dysfunction. OBJECTIVE: To establish the onset of the earliest deficits in auditory processing, we examined the time window demarcating the transition from subcortical to cortical processing: 10 ms to 50 ms during the so-called middle latency responses (MLRs). These remain to be adequately characterized in patients with schizophrenia. METHODS: We recorded auditory evoked potentials (AEPs) to simple tone-pips from 15 control subjects and 21 medicated patients with longer-term schizophrenia or schizoaffective disorder (illness duration 16 yr, standard deviation [SD] 9.4 yr), using high-density electrical scalp recordings. Between-group analyses assessed the integrity of the MLRs across groups. In addition, 2 source-localization models were conducted to address whether a distinction between subcortical and cortical generators of the MLRs can be made and whether evidence for differential dorsal and ventral pathway contributions to auditory processing deficits can be established. RESULTS: Robust auditory processing deficits were found for patients as early as 15 ms. Evidence for subcortical generators of the earliest MLR component (P20) was provided by source analysis. Topographical mapping and source localization also pointed to greater decrements in processing in the dorsal auditory pathway of patients, providing support for a theory of pervasive deficits that are organized along the lines of a dorsal-ventral distinction. CONCLUSIONS: Auditory sensory dysfunction in schizophrenia begins extremely early in processing, is evident during initial cortical afference and is also seen at earlier subcortical processing stages in the thalamus. The implication is that well-established sensory processing deficits in schizophrenia may be secondary to earlier subcortical dysfunction. Our findings do not preclude the possibility of even earlier deficits in auditory sensory processing during the auditory brainstem responses.     

Magnetoencephalographic studies of functional organization and plasticity of the human auditory cortex.

Magnetoencephalography has proven to be a powerful noninvasive tool for investigating the functional organization of the human auditory cortex and its plastic changes. The first part of this review summarizes some recent experiments on the tonotopic organization, which can be observed not only in the slow auditory evoked fields, but also in the middle-latency and the steady-state fields. In the second part of this review, recent studies on plasticity of the auditory cortex are outlined. These studies showed that the cortical representation of tones may change within hours after a reversible "functional deafferentation" (short-term plasticity) and that early musical training leads to an expansion in the cortical representation of complex harmonic sounds (long-term plasticity).     

A bold view of the lactating brain: functional magnetic resonance imaging studies of suckling in awake dams

Functional magnetic resonance imaging (fMRI) has been used to investigate the responsiveness of the maternal rat brain to pup-suckling under various experimental paradigms. Our research employing the lactating rat model has explored the cortical sensory processing of pup stimuli and the effect of suckling on the brain's reward system. Suckling was observed to increase blood-oxygen-level-dependent (BOLD) signal intensity in the midbrain, striatum and prefrontal cortex, which are areas that receive prominent dopaminergic inputs. The BOLD activation of the reward system occurs in parallel with the activation of extensive cortical sensory areas. The observed regions include the olfactory cortex, auditory cortex and gustatory cortex, and could correspond to cortical representations of pup odours, vocalisations and taste that are active during lactation. Activation patterns within reward regions are consistent with past research on maternal motivation and we explore the possibility that exposure to drugs of abuse might be disruptive of maternal neural responses to pups, particularly in the prefrontal cortex. Our ongoing fMRI studies support and extend past research on the maternal rat brain and its functional neurocircuitry.     

Cortical microstimulation in auditory cortex of rat elicits best-frequency dependent behaviors

Electrical activation of the auditory cortex has been shown to elicit an auditory sensation; however, the perceptual effects of auditory cortical microstimulation delivered through penetrating microelectrodes have not been clearly elucidated. This study examines the relationship between electrical microstimulus location within the adult rat auditory cortex and the subsequent behavior induced. Four rats were trained on an auditory frequency discrimination task and their lever-pressing behavior in response to stimuli of intermediate auditory frequencies was quantified. Each trained rat was then implanted with a microwire array in the auditory cortex of the left hemisphere. Best frequencies (BFs) of each electrode in the array were determined by both local field potential and multi-unit spike-rate activity evoked by pure tone stimuli. A cross-dimensional psychophysical generalization paradigm was used to evaluate cortical microstimulation-induced behavior. Using the BFs of each electrode, the microstimulation-induced behavior was evaluated relative to the auditory-induced behavior. Microstimulation resulted in behavior that was dependent on the BFs of the electrodes used for stimulation. These results are consistent with recent reports indicating that electrophysiological recordings of neural responses to sensory stimuli may provide insight into the sensation generated by electrical stimulation of the same sensory neural tissue.     

The fiber connections of the temporal lobe with emphasis on the rhesus monkey

The temporal lobe has three functionally distinct areas which have minimal interconnections within the lobe, but extensive connections with other parts of the brain. The superior temporal gyrus contains primary and association auditory areas. Inferotemporal cortex is exclusively a visual association area. The temporal pole is involved in social behavior. In addition, the superior temporal sulcus functions as a sensory integration area. From a review of the literature, a schema is proposed for organizing the reciprocal connections of the three functional areas into a series of loops which follow both cortical and subcortical routes. The afferent and efferent connections of the temporal lobe, phylogenesis, and deficits from lesions are discussed.     

Compromise of auditory cortical tuning and topography after cross-modal invasion by visual inputs

Brain damage resulting in loss of sensory stimulation can induce reorganization of sensory maps in cerebral cortex. Previous research on recovery from brain damage has focused primarily on adaptive plasticity within the affected modality. Less attention has been paid to maladaptive plasticity that may arise as a result of ectopic innervation from other modalities. Using ferrets in which neonatal midbrain damage results in diversion of retinal projections to the auditory thalamus, we investigated how auditory cortical function is impacted by the resulting ectopic visual activation. We found that, although auditory neurons in cross-modal auditory cortex (XMAC) retained sound frequency tuning, their thresholds were increased, their tuning was broader, and tonotopic order in their frequency maps was disturbed. Multisensory neurons in XMAC also exhibited frequency tuning, but they had longer latencies than normal auditory neurons, suggesting they arise from multisynaptic, non-geniculocortical sources. In a control group of animals with neonatal deafferentation of auditory thalamus but without redirection of retinal axons, tonotopic order and sharp tuning curves were seen, indicating that this aspect of auditory function had developed normally. This result shows that the compromised auditory function in XMAC results from invasion by ectopic visual inputs and not from deafferentation. These findings suggest that the cross-modal plasticity that commonly occurs after loss of sensory input can significantly interfere with recovery from brain damage and that mitigation of maladaptive effects is critical to maximizing the potential for recovery.     

Scanning mutagenesis of the I-II loop of the Cav2.2 calcium channel identifies residues Arginine 376 and Valine 416 as molecular determinants of voltage dependent G protein inhibition

The sensory cortex is subject to continuous remodelling during early development and throughout adulthood. This process is important for establishing normal brain function and is dependent on cholinergic modulation via muscarinic receptors. Five muscarinic receptor genes encode five unique receptor subtypes (M_1-5). The distributions and functions of each subtype vary in central and peripheral systems. In the brain, the M₁ receptor is most abundant in the cerebral cortex, where its immunoreactivity peaks transiently during early development. This likely signifies the importance of M₁ receptor in the development and maintenance of normal cortical function. Several lines of study have outlined the roles of M₁ receptors in the development and plasticity of the auditory cortex. For example, M₁-knockout reduces experience-dependent plasticity and disrupts tonotopic mapping in the adult mouse auditory cortex. Further evidence demonstrates a role for M₁ in neurite outgrowth and hence determining the structure of cortical neurons. The disruption of tonotopic maps in M₁-knockout mice may be linked to alterations in thalamocortical connectivity, because the targets of thalamocortical afferents (layer IV cortical neurons) appear less mature in M₁ knockouts. Herein we review the literature to date concerning M₁ receptors in the auditory cortex and consider some future directions that will contribute to our understanding.     

Development and critical period plasticity of the barrel cortex

In primary sensory neocortical areas of mammals, the distribution of sensory receptors is mapped with topographic precision and amplification in proportion to the peripheral receptor density. The visual, somatosensory and auditory cortical maps are established during a critical period in development. Throughout this window in time, the developing cortical maps are vulnerable to deleterious effects of sense organ damage or sensory deprivation. The rodent barrel cortex offers an invaluable model system with which to investigate the mechanisms underlying the formation of topographic maps and their plasticity during development. Five rows of mystacial vibrissa (whisker) follicles on the snout and an array of sinus hairs are represented by layer IV neural modules ('barrels') and thalamocortical axon terminals in the primary somatosensory cortex. Perinatal damage to the whiskers or the sensory nerve innervating them irreversibly alters the structural organization of the barrels. Earlier studies emphasized the role of the sensory periphery in dictating whisker-specific brain maps and patterns. Recent advances in molecular genetics and analyses of genetically altered mice allow new insights into neural pattern formation in the neocortex and the mechanisms underlying critical period plasticity. Here, we review the development and patterning of the barrel cortex and the critical period plasticity.     

The neurobiology of sound-specific auditory plasticity: A core neural circuit

Auditory learning or experience induces large-scale neural plasticity in not only the auditory cortex but also in the auditory thalamus and midbrain. Such plasticity is guided by acquired sound (sound-specific auditory plasticity). The mechanisms involved in this process have been studied from various approaches and support the presence of a core neural circuit consisting of a subcortico-cortico-subcortical tonotopic loop supplemented by neuromodulatory (e.g., cholinergic) inputs. This circuit has three key functions essential for establishing large-scale and sound-specific plasticity in the auditory cortex, auditory thalamus and auditory midbrain. They include the presence of sound information for guiding the plasticity, the communication between the cortex, thalamus and midbrain for coordinating the plastic changes and the adjustment of the circuit status for augmenting the plasticity. This review begins with an overview of sound-specific auditory plasticity in the central auditory system. It then introduces the core neural circuit which plays an essential role in inducing sound-specific auditory plasticity. Finally, the core neural circuit and its relationship to auditory learning and experience are discussed.     

Modulation of motor cortex excitability by sustained peripheral stimulation: The interaction between the motor cortex and the cerebellum

The excitability of cortical neurons in the motor cortex is determined by their membrane potential and by the level of intracortical inhibition. The excitability of the motor cortex as a whole is a function of single cell excitability, synaptic strength, and the balance between excitatory cells and inhibitory cells. It is now established that a sustained period of somatosensory stimulation increases the excitability of motor cortex areas controlling muscles in those body parts that received the stimulation prior to excitability testing. So far, it has been supposed that the sensorimotor cortex was the anatomical substrate of these excitability changes, which could represent an early change in cortical network function before structural plasticity occurs. Recent experimental studies highlight that the cerebellum, especially the interpositus nucleus, plays a key role in the adaptation of the motor cortex to repeated trains of stimulation. Interpositus neurons, which receive inputs from both sensorimotor cortex and the spinal cord, are involved in somesthetic reflex behaviors and assist the cerebral cortex in transforming sensory signals to motor-oriented commands by acting via the cerebello-thalamo-cortical projections. Moreover, climbing fibers originating in the inferior olivary complex and innervating the nucleus interpositus mediate highly integrated sensorimotor information derived from spinal modules. It appears that the interpositus nucleus is a main subcortical modulator of the excitability changes occurring in the motor cortex, which may be a substrate of early plasticity effective in motor learning and recovery from lesion.     

The neurobiology of sound-specific auditory plasticity: A core neural circuit

Auditory learning or experience induces large-scale neural plasticity in not only the auditory cortex but also in the auditory thalamus and midbrain. Such plasticity is guided by acquired sound (sound-specific auditory plasticity). The mechanisms involved in this process have been studied from various approaches and support the presence of a core neural circuit consisting of a subcortico-cortico-subcortical tonotopic loop supplemented by neuromodulatory (e.g., cholinergic) inputs. This circuit has three key functions essential for establishing large-scale and sound-specific plasticity in the auditory cortex, auditory thalamus and auditory midbrain. They include the presence of sound information for guiding the plasticity, the communication between the cortex, thalamus and midbrain for coordinating the plastic changes and the adjustment of the circuit status for augmenting the plasticity. This review begins with an overview of sound-specific auditory plasticity in the central auditory system. It then introduces the core neural circuit which plays an essential role in inducing sound-specific auditory plasticity. Finally, the core neural circuit and its relationship to auditory learning and experience are discussed.     

Role of attention in the generation and modulation of tinnitus

Neural mechanisms that detect changes in the auditory environment appear to rely on processes that predict sensory state. Here we propose that in tinnitus there is a disparity between what the brain predicts it should be hearing (this prediction based on aberrant neural activity occurring in cortical frequency regions affected by hearing loss and underlying the tinnitus percept) and the acoustic information that is delivered to the brain by the damaged cochlea. The disparity between the predicted and delivered inputs activates a system for auditory attention that facilitates through subcortical neuromodulatory systems neuroplastic changes that contribute to the generation of tinnitus. We review behavioral and functional brain imaging evidence for persisting auditory attention in tinnitus and present a qualitative model for how attention operates in normal hearing and may be triggered in tinnitus accompanied by hearing loss. The viewpoint has implications for the role of cochlear pathology in tinnitus, for neural plasticity and the contribution of forebrain neuromodulatory systems in tinnitus, and for tinnitus management and treatment.     

A Novel Layer 4 Corticofugal Cell Type/Projection Involved in Thalamo-Cortico-Striatal Sensory Processing

In sensory cortices, the information flow has been thought to be processed vertically across cortical layers, with layer 4 being the major thalamo-recipient which relays thalamic signals to layer 2/3, which in turn transmits thalamic information to layer 5 and 6 to then leave the cortex to reach subcortical and cortical long-range structures. Although several exceptions to this model have been described, neurons in layer 4 are still considered to establish only local (i.e., interlaminar and short-range) connections. Here, taking advantage of anatomic, electrophysiological, and optogenetic techniques, we describe, for the first time, a long-range corticostriatal class of pyramidal neurons in layer 4 (CS-L4) of the mouse auditory cortex that receive direct thalamic inputs. The CS-L4 neurons are embedded in a feedforward inhibitory circuit involving local parvalbumin neurons and establish connections in the posterior striatum in yet another feedforward inhibitory thalamo→cortico(L4)→striatal circuit which potentially contributes in controlling control the output of striatal spiny projection neurons.SIGNIFICANCE STATEMENT The assumption has been that layer 4 neurons are the main thalamic recipient layer, projecting to the upper cortical layer 2/3. However, no study has revealed a detailed understanding of the circuit mechanisms by which layer 4 sends a projection to a subcortical structure, such as the striatum, and differentially innervate the spiny projection neurons (SPNs) and intrastriatal parvalbumin-expressing neurons. For the first time, our results demonstrate that the auditory cortex projects to the posterior part of the dorsal striatum via pyramidal neurons located in layer 4 (CS-L4 neurons). Here we propose a new wiring diagram that implemented the old one, in which layer 4 is not only involved in the transfer of thalamic input to the upper layer 2/3, but can also exert a direct top-down control, bypassing intracortical processing of subcortical structures, such as the posterior part of the dorsal striatum. This poses a new conceptual cell element (CS-L4 neurons) for experimental and theoretical work of the cortical function.