Auditory cortex interneuron development requires cadherins operating hair-cell mechanoelectrical transduction.

Many genetic forms of congenital deafness affect the sound reception antenna of cochlear sensory cells, the hair bundle. The resulting sensory deprivation jeopardizes auditory cortex (AC) maturation. Early prosthetic intervention should revive this process. Nevertheless, this view assumes that no intrinsic AC deficits coexist with the cochlear ones, a possibility as yet unexplored. We show here that many GABAergic interneurons, from their generation in the medial ganglionic eminence up to their settlement in the AC, express two cadherin-related (cdhr) proteins, cdhr23 and cdhr15, that form the hair bundle tip links gating the mechanoelectrical transduction channels. Mutant mice lacking either protein showed a major decrease in the number of parvalbumin interneurons specifically in the AC, and displayed audiogenic reflex seizures. Cdhr15- and Cdhr23-expressing interneuron precursors in Cdhr23-/- and Cdhr15-/- mouse embryos, respectively, failed to enter the embryonic cortex and were scattered throughout the subpallium, consistent with the cell polarity abnormalities we observed in vitro. In the absence of adhesion G protein-coupled receptor V1 (adgrv1), another hair bundle link protein, the entry of Cdhr23- and Cdhr15-expressing interneuron precursors into the embryonic cortex was also impaired. Our results demonstrate that a population of newborn interneurons is endowed with specific cdhr proteins necessary for these cells to reach the developing AC. We suggest that an "early adhesion code" targets populations of interneuron precursors to restricted neocortical regions belonging to the same functional area. These findings open up new perspectives for auditory rehabilitation and cortical therapies in patients.

EphA signaling impacts development of topographic connectivity in auditory corticofugal systems.

Auditory stimulus representations are dynamically maintained by ascending and descending projections linking the auditory cortex (Actx), medial geniculate body (MGB), and inferior colliculus. Although the extent and topographic specificity of descending auditory corticofugal projections can equal or surpass that of ascending corticopetal projections, little is known about the molecular mechanisms that guide their development. Here, we used in utero gene electroporation to examine the role of EphA receptor signaling in the development of corticothalamic (CT) and corticocollicular connections. Early in postnatal development, CT axons were restricted to a deep dorsal zone (DDZ) within the MGB that expressed low levels of the ephrin-A ligand. By hearing onset, CT axons had innervated surrounding regions of MGB in control-electroporated mice but remained fixed within the DDZ in mice overexpressing EphA7. In vivo neurophysiological recordings demonstrated a corresponding reduction in spontaneous firing rate, but no changes in sound-evoked responsiveness within MGB regions deprived of CT innervation. Structural and functional CT disruption occurred without gross alterations in thalamocortical connectivity. These data demonstrate a potential role for EphA/ephrin-A signaling in the initial guidance of corticofugal axons and suggest that "genetic rewiring" may represent a useful functional tool to alter cortical feedback without silencing Actx.

Activity-dependent cortical target selection by thalamic axons.

Connections in the developing nervous system are thought to be formed initially by an activity-independent process of axon pathfinding and target selection and subsequently refined by neural activity. Blockade of sodium action potentials by intracranial infusion of tetrodotoxin in cats during the early period when axons from the lateral geniculate nucleus (LGN) were in the process of selecting visual cortex as their target altered the pattern and precision of this thalamocortical projection. The majority of LGN neurons, rather than projecting to visual cortex, elaborated a significant projection within the subplate of cortical areas normally bypassed. Those axons that did project to their correct target were topographically disorganized. Thus, neural activity is required for initial targeting decisions made by thalamic axons as they traverse the subplate.

[Early hearing experience and sensitive developmental periods]. / Frühe Hörerfahrung und sensible Entwicklungsphasen.

This article reviews the studies on functional deficits in the auditory cortex of congenitally deaf animals. It compares their results with psychophysical and imaging data obtained from prelingually deaf humans. The studies demonstrate that the development of the auditory cortex is affected by the absence of hearing experience. In humans, the restoration of hearing after congenital deafness shows a sensitive period of 4 years, whereas even within this sensitive period cortical plasticity is already decreasing with increasing age. The reasons for the sensitive period are developmental changes of synaptic plasticity, developmentally modified synaptogenesis and synaptic pruning as well as changes in connectivity of the auditory cortex. Absence of top-down interactions from higher order auditory areas is another cardinal reason for the sensitive period. All these mechanisms contribute to the decreasing capacity for cortical plasticity during postnatal development. From the developmental and neurophysiological point of view, an early identification of hearing loss is an important prerequisite for effective therapy.

Antenatal study of the Heschl's gyrus: The first step to understanding prenatal learning.

AIM: We located Heschl's gyrus (HG) in utero during antenatal development. The antenatal location of the HG will allow us to evaluate adaptations of the human foetal cortex in response to auditory stimuli. METHODS: We classified 244 human foetuses between 18 and 41 weeks' gestation using two-dimensional (2D) and three-dimensional (3D) ultrasounds according to foetal neurological development: Foetal Stage, Extremely Preterm, Very Preterm, Moderate to Late Preterm, and Term. We considered two HG shapes: single gyrus (SG) and duplicated gyrus (DG). We studied two subtypes of the DG shape: partial and complete duplicated gyrus. RESULTS: We found 156 cases (63.9%) of single gyrus and 88 cases (36.1%) of duplicated gyrus, of which 39 (44.3%) showed a partial duplication and 49 (55.7%) showed complete duplication. SG appeared in 93.5% of cases in the Foetal Stage and represented 75% of the Term group. DG increased during foetal life. In the Very Preterm group, the relation between SG and DG was detected in 50%, so that DG (59.1%) was more prevalent than SG (40.9%) in the Moderate to Late Preterm group, and the majority of foetuses were found to exhibit SG (75%) in the Term group. The observed increase in DG was due to the complete duplicated gyrus subtype. We did not find differences between hemispheres in any of the groups. CONCLUSION: We located the foetal Heschl's gyrus and the SG and DG shapes. The peculiar pattern in each foetal neurological stage could show a functional sign in a cortical area with a remarkable adaptation capacity.

Fetal cortical activation to sound at 33 weeks of gestation: a functional MRI study.

Hearing already functions before birth, but little is known about the neural basis of fetal life experiences. Recent imaging studies have validated the use of functional magnetic resonance imaging (fMRI) in pregnant women at 38-weeks of gestation. The aim of the present study was to examine fetal brain activation to sound, using fMRI at the beginning of the third trimester of pregnancy. 6 pregnant women between 28- and 34-weeks of gestation were scanned using a magnetic strength of 1.5 T, with an auditory stimulus applied to their abdomen. 3 fetuses with a gestational age of 33 weeks, showed significant activation to sound in the left temporal lobe, measured using a new data-driven approach (Independent Component Analysis for fMRI time series). Only 2 of these fetuses showed left temporal activation, when the standard voxel-wise analysis method was used (p=0.007; p=0.001). Moreover, motion parameters added as predictors of the General Linear Model confirmed that motion cannot account for the signal variance in the fetal temporal cortex (p=0.01). Comparison between the statistical maps obtained from MRI scans of the fetuses with those obtained from adults, made it possible to confirm our hypothesis, that there is brain activation in the primary auditory cortex in response to sound. Measurement of the fetal hemodynamic response revealed an average fMRI signal change of +3.5%. This study shows that it is possible to use fMRI to detect early fetal brain function, but also confirms that sound processing occurs beyond the reflexive sub-cortical level, at the beginning of the third trimester of pregnancy.

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.

Intrinsic and extrinsic factors that shape neocortical specification.

Increasing evidence points to the importance of intrinsic molecular cues in specifying the regional identity of mammalian neocortex. Few such cues, however, have been found to be restricted to individual functionally defined cortical areas before the arrival of afferent information. In contrast, thalamocortical axons are specifically targeted to individual cortical areas, raising the possibility that they can instruct some aspects of cortical areal identity. Cortical structure and function can be altered by modifying the source or pattern of activity in thalamocortical afferents. In particular, studies of cross-modal plasticity have shown that in many respects, one sensory cortical area can substitute for another after a switch of input modality during development. Afferent inputs might therefore direct the formation of their own processing circuitry, a possibility that has important implications for brain development, plasticity and evolution.

A novel role for p75NTR in subplate growth cone complexity and visual thalamocortical innervation.

In cortical development, subplate axons pioneer the pathway from neocortex to the internal capsule, leading to the proposal that they are required for subsequent area-specific innervation of cortex by thalamic axons. A role for p75 neutrophin receptor (NTR) in area-specific thalamic innervation of cortex is suggested by the observation that p75NTR expression is restricted to subplate neurons in a low-rostral to high-caudal gradient throughout the period of thalamocortical innervation. In vitro, neurotrophin 3 binding to p75NTR increases neurite length and filopodial formation of immunopurified subplate neurons, suggesting a role for p75NTR in subplate growth cone morphology and function in vivo. Consistent with this idea, subplate growth cones have markedly fewer filopodia in mice lacking p75NTR than in wild type mice. Despite this gross morphologic defect, many subplate axons in knock-out mice pioneer the projection to the internal capsule as they do in wild-type mice. However a few subplate axons in the knock-out mice make ectopic projections rostral in the intermediate zone and frontal cortex. Concomitant with the altered morphology of subplate growth cones, mice lacking p75NTR have diminished innervation of visual cortex from the lateral geniculate nucleus, with markedly reduced or absent connections in 48% of knock-out mice. Thalamic projections to auditory and somatosensory cortex are normal, consistent with the gradient of p75NTR expression. Our present results are unusual in that they argue that p75NTR functions in a novel way in subplate neurons, that is, in growth cone morphology and function rather than in axon extension or neuronal survival.

Development of auditory evoked fields in human fetuses and newborns: a longitudinal MEG study.

OBJECTIVE: To investigate the maturation of the auditory cortex by non-invasive recording of auditory evoked magnetic fields in human fetuses and newborns with the relatively novel and completely non-invasive technology of MEG. METHODS: Serial recordings were performed every 2 weeks on 18 fetuses beginning from week 27 of gestational age until term with a follow-up recording on the newborn. Auditory stimulation consisted of tone bursts in an oddball design with standard tones and deviant tones. RESULTS: In 52 of 63 fetal and in all of the neonatal recordings an auditory evoked magnetic field was obtained. A decrease in latency with increasing age of the subjects was observed in the combined analysis of fetuses and neonates. CONCLUSIONS: With advanced study using MEG, 83% of the measurements showed auditory evoked fields in fetuses that correspond with existing literature in electrophysiology in the past. These findings indicate that MEG is a technique that can be used to investigate maturation of the auditory cortex based on auditory evoked fields in fetuses and neonates. SIGNIFICANCE: Maturational changes have been examined in the past. With the use of this novel technique, applied to a serial study, it is possible to trace the development of auditory responses in utero and newborns.

Auditory learning: a developmental method.

Motivated by the human autonomous development process from infancy to adulthood, we have built a robot that develops its cognitive and behavioral skills through real-time interactions with the environment. We call such a robot a developmental robot. In this paper, we present the theory and the architecture to implement a developmental robot and discuss the related techniques that address an array of challenging technical issues. As an application, experimental results on a real robot, self-organizing, autonomous, incremental learner (SAIL), are presented with emphasis on its audition perception and audition-related action generation. In particular, the SAIL robot conducts the auditory learning from unsegmented and unlabeled speech streams without any prior knowledge about the auditory signals, such as the designated language or the phoneme models. Neither available before learning starts are the actions that the robot is expected to perform. SAIL learns the auditory commands and the desired actions from physical contacts with the environment including the trainers.

Timing and topography of nucleus magnocellularis innervation by the cochlear ganglion.

This series of experiments examined the arrival and organization of cochlear nerve axons in the primary auditory brainstem nucleus, nucleus magnocellularis (NM), of the chick. DiI and DiD were injected into the cochlear nerve, cochlear ganglion, and basilar papilla (i.e., avian cochlea) in fixed tissue and labeled axons were studied in NM and its vicinity. Cochlear nerve axons first penetrate NM between stages 29 (E6) and 36 (E10). Axons penetrate NM in a middle-to-posterior-to-anterior developmental sequence; the anterior, high-frequency region of NM receives axons last. When cochlear nerve axons arrive in the NM, they are already organized in a topographic map related to the position of their cell bodies along the basilar papilla, foreshadowing the tonotopic mapping observed between NM and the basilar papilla later in development. Evidence of a topographic map was also observed in the other primary auditory brainstem nucleus, nucleus angularis. These results indicate that topographic mapping of position (and ultimately characteristic frequency) between the basilar papilla and NM is established as cochlear nerve axons arrive in the NM prior to the onset of synaptic activity. .

Regional differences in synaptogenesis in human cerebral cortex.

The formation of synaptic contacts in human cerebral cortex was compared in two cortical regions: auditory cortex (Heschl's gyrus) and prefrontal cortex (middle frontal gyrus). Synapse formation in both cortical regions begins in the fetus, before conceptual age 27 weeks. Synaptic density increases more rapidly in auditory cortex, where the maximum is reached near postnatal age 3 months. Maximum synaptic density in middle frontal gyrus is not reached until after age 15 months. Synaptogenesis occurs concurrently with dendritic and axonal growth and with myelination of the subcortical white matter. A phase of net synapse elimination occurs late in childhood, earlier in auditory cortex, where it has ended by age 12 years, than in prefrontal cortex, where it extends to midadolescence. Synaptogenesis and synapse elimination in humans appear to be heterochronous in different cortical regions and, in that respect, appears to differ from the rhesus monkey, where they are concurrent. In other respects, including overproduction of synaptic contacts in infancy, persistence of high levels of synaptic density to late childhood or adolescence, the absolute values of maximum and adult synaptic density, and layer specific differences, findings in the human resemble those in rhesus monkeys.

Development of adult-type inhibitory glycine receptors in the central auditory system of rats.

Inhibitory synaptic activity is crucial for many aspects of acoustic information processing and mainly mediated by glycine and gamma-aminobutyric acid, the two principal inhibitory neurotransmitters in the auditory system. Glycine exerts its inhibitory action via binding to postsynaptic receptors existing in various isoforms. Here we have investigated the spatiotemporal distribution of adult-type, strychnine-sensitive glycine receptors (GlyRs) in the rat auditory system by using a specific antibody against the ligand-binding alpha1 GlyR subunit. In adults, alpha1 GlyRs were found at all relay stations of the auditory pathway except for the medial geniculate body and the auditory cortex. In most brainstem nuclei, labeling was characterized by dense clusters of heavily immunoreactive puncta outlining the somata and proximal dendrites, indicative of a powerful glycinergic inhibition. No alpha1 immunoreactivity was seen in the auditory system of fetal rats, consistent with results obtained by others in the spinal cord. At birth, labeling was weak and restricted to defined nuclei of the cochlear nuclear complex and the superior olivary complex. By postnatal day 8, labeling was seen in all brainstem nuclei. At the first appearance of immunoreactivity, alpha1 GlyRs were diffusely distributed on the neuronal surface, yet they became clustered with age, finally densely incrusting the somata and proximal dendrites between the 3rd and 4th postnatal week, when the mature pattern of immunoreactivity was established. We never observed an overexpression of alpha1 GlyRs or a transient appearance in areas that are devoid of the receptor in adults. The late formation of glycinergic synapses harboring the adult-type GlyRs in the auditory system, at a time when internuclear connections have already formed, indicates that alpha1 GlyRs do not participate in early synaptogenesis.

Time course of embryonic midbrain and thalamic auditory connection development in mice as revealed by carbocyanine dye tracing.

Central auditory connections develop in mice before the onset of hearing, around postnatal day 7. Two previous studies have investigated the development of auditory nuclei projections and lateral lemniscal nuclear projections in embryonic rats, respectively. Here, we provide detail for the first time of the initiation and progression of projections from the inferior colliculus (IC) to the medial geniculate body (MGB) and from the MGB to the auditory cortex (AC). Overall, the developmental progression of projections follows that of terminal mitoses in various nuclei, suggesting the consistent use of a developmental timetable at a given nucleus, independent of that of other nuclei. Our data further suggest that neurons project specifically and reciprocally from the MGB to the AC as early as embryonic day 14.5. These projections develop approximately a day before the reciprocal connections between the MGB and IC and before development of projections from the auditory nuclei to the IC. The development of IC projections is prolonged and progresses from rostral to caudal areas. Brainstem nuclear projections to the IC arrive first from the lateral lemniscus nuclei then the superior olive and finally the cochlear nuclei. Overall, the auditory connection development strongly suggests that most of the overall specificity of nuclear connections is set up at least 2 weeks before the onset of sound-mediated cochlea responses in mice and, thus, is likely governed predominantly by molecular genetic clues.

Cytoarchitectural and axonal maturation in human auditory cortex.

This study followed the maturation of human auditory cortex from the beginning of the second trimester of gestation to young adulthood. Histological and immunohistochemical techniques were used to trace the development of a laminar cytoarchitecture and an adult pattern of axonal neurofilament expression. From the 16th fetal week to the 4th postnatal month, the cortex progresses from a marginal layer and an undifferentiated cortical plate to incipient lamination. Between the 22nd fetal week and the 4th postnatal month, a two-tiered band of neurofilament-immunoreactive axons develops in layer I, but subsequent to the 4th month, the number of immunopositive axons in this layer is greatly reduced. Between the middle of the first year of life and age 3 years, the laminar pattern of cytoarchitecture becomes fully mature and a network of immunostained axons develops in layers VI, V, IV, and IlIc. This axonal plexus in the deep cortical layers continues to increase in density until age 5. Beginning at 5 years of age, a network of neurofilament-positive axons develops in the superficial layers IIIb, IIIa, and II, and by 11-12 years of age, overall axonal density is equivalent to that seen in young adulthood. This extended time span of axonal maturation has implications for the emergence of auditory cortical function.

Developmental impairment of auditory evoked N1/P2 component in rats undernourished in utero: its relation to brain serotonin activity.

In utero undernourishment produces an elevation of L-tryptophan and serotonin in the brain, including the auditory cortex (A1), such changes seem to be related to an increase in the free fraction (FFT) of plasma L-tryptophan that is transported into the brain through the blood-brain barrier, where it is taken up by serotonergic neurons for serotonin synthesis. Our observations support that FFT has a positive correlation with L-tryptophan (L-Trp) and serotonin levels in the auditory cortex (r=0.95 and 0.82, respectively). Interestingly, a decreased intensity dependence of the auditory evoked N1/P2 component was found in gestationally undernourished animals during their postnatal development. The N1/P2 component had a negative correlation (r=0.81) with A1 serotonin, such that it reflects changes in the neurotransmitter concentration. The present observations suggest a relevant role of serotonin in modulating the activity of the auditory cortex. Since the N1/P2 component is mainly associated with the activity of A1 neurons, it may well be that perception of auditory information is impaired during this developmental period, in the early undernourished animals, possibly affecting cognitive processes. This may be relevant to humans since low birth weight babies that also suffered gestational undernourishment (fetal-placental insufficiency) present an increase in plasma FFT from birth up to 3 months of age. These findings support that the plasma FFT and the intensity dependence of the auditory evoked N1/P2 component relate one another and may be markers of changes of the brain serotonergic activity.

Transient developmental expression of CD15 in the motor and auditory cortex of the mouse.

The distribution of the glycoprotein CD15 (FAL, SSEA-1, Le(x)) in the developing cortex of the mouse has been examined by immunohistochemistry of paraffin sections. The pattern of CD15 immunoreactivity was observed to occur in 4 stages. In the first stage, the presumptive subplate region in the lateral and rostral parts of the developing isocortex was transiently labelled at E12. In the second stage, between E13 and E17, very faint label was found only in the ventricular germinal zone, possibly within radial glial fibres. The third stage began at E18, when transient labelling of several discrete cortical areas was apparent; the motor cortex (from E18 to P3), an area in the temporal lobe (presumptive primary auditory cortex; from E18 to P5.5) and the piriform and entorhinal cortices (from E18 to P3). The final stage began at P2, when a mosaic camouflage pattern of labelling started to appear throughout the developing cortex, particularly in layer I. The distribution of the transient label in the motor cortex during the perinatal period suggests that it may be associated with early events in corticospinal or other projection neuron maturation (apical dendrite growth and differentiation). The labelling in the presumptive auditory cortex (Te1) may also be involved in the differentiation of neurons in the upper cortical plate.

Basic fibroblast growth factor (FGF-2) affects development of acoustico-vestibular neurons in the chick embryo brain in vitro.

The effects of basic fibroblast growth factor (FGF-2) on presumptive auditory and vestibular neurons from the medulla were studied in primary cell cultures. The part of the rhombic lip that forms nucleus magnocellularis (homologue of the mammalian anteroventral cochlear nucleus) was explanted from white leghorn chicken embryos at Hamburger-Hamilton stage 28 (E5.5), the time when precursors of the magnocellularis bushy cells migrate and begin to differentiate in situ. In vitro the neuroblasts migrated onto 2-D substrates of purified collagen, differentiated, and expressed neuronal markers. One-half of the cultures were supplemented with human recombinant FGF-2 (10 ng/ml daily) for 5-7 days; the others, with fetal bovine serum. FGF-2 more than doubled the length of neurite outgrowth during the first 3 day treatment compared to serum, but the number of migrating neuroblasts was unaffected. Although neurites attained greater lengths in FGF-2, they usually degenerated after 4-5 days; in serum their growth continued for several weeks. Differentiation of neuronal structure, including axons and dendrites, began within 1-2 days in bFGF but required at least 5-7 days in serum. Histochemical observations in vitro and in situ with antibodies to FGF receptor demonstrated immunopositive patches on acoustico-vestibular neuroblasts at stage 28, when they are migrating and first forming their axons. The findings suggest that FGF-2 stimulates neurite outgrowth in the cochlear and vestibular nuclei. FGF-2 may accelerate cell death by overstimulating neuroblasts, but other factors are needed to sustain their further development.

Canadian Association of Neuroscience Review: development and plasticity of the auditory cortex.

The functions of the cerebral cortex are predominantly established during the critical period of development. One obvious developmental feature is its division into different functional areas that systematically represent different environmental information. This is the result of interactions between intrinsic (genetic) factors and extrinsic (environmental) factors. Following this critical period, the cerebral cortex attains its adult form but it will continue to adapt to environmental changes. Thus, the cerebral cortex is constantly adapting to the environment (plasticity) from its embryonic stages to the last minute of life. This review details important factors that contribute to the development and plasticity of the auditory cortex. The instructive role of thalamocortical innervation, the regulatory role of cholinergic projection of the basal forebrain and the potential role of the corticofugal modulation are presented.