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.

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.

Repetitive auditory stimulation at a critical prenatal period modulates the postnatal functional development of the auditory as well as visual system in chicks (Gallus domesticus).

The extrinsic sensory stimulation plays a crucial role in the formation and integration of sensory modalities during development. Postnatal behavior is thereby influenced by the type and timing of presentation of prenatal sensory stimuli. In this study, fertilized eggs of white Leghorn chickens during incubation were exposed to either species-specific calls or no sound. To find the prenatal critical period when auditory stimulation can modulate visual system development, the former group was divided into three subgroups: in subgroup A (SGA), the stimulus was provided during embryonic day (E)10 to E16, in SGB E17- hatching, and in SGC E10-hatching. The auditory and visual perceptual learning was recorded at posthatch day (PH) 1-3, whereas synaptic plasticity (evident from synaptophysin and PSD-95 expression), was observed at E19, E20, and PH 1-3. An increased number of responders were observed in both auditory and visual preference tests at PH 1 following stimulation. Although a decrease in latency of entry and an increase in total time spent were observed in all stimulated groups, it was most significant in SGC in auditory preference and in SGB and SGC in visual preference test. The auditory cortex of SGC and visual Wulst of SGB and SGC revealed higher expression of synaptic proteins, compared to control and SGA. A significant inter-hemispheric and gender-based difference in expression was also found in all groups. These results indicate facilitation of postnatal behaviour and synaptogenesis in both auditory and visual systems following prenatal repetitive auditory stimulation, only when given during prenatal critical period of development.

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.

d-Methionine protects against cisplatin-induced neurotoxicity in cortical networks.

Cisplatin is a platinum-based chemotherapeutic agent widely used for the treatment of various types of cancer. Patients undergoing cisplatin treatment often suffer from a condition known as "chemobrain", ototoxicity, peripheral neuropathy, weight loss, nausea, vomiting, nephrotoxicity, seizures, hearing loss and tinnitus. d-Methionine (d-Met), a sulfur-containing nucleophilic antioxidant, has been shown to prevent cisplatin-induced side effects in animals without antitumor interference. In this study, we have used an in vitro model of cortical networks (CNs), enriched in auditory cortex cells; to quantify cisplatin neurotoxicity and the protective effects of d-Met. Dissociated neurons from auditory cortices of mouse embryos were grown on microelectrode arrays with 64 transparent indium-tin oxide electrodes, which enabled continuous optical and electrophysiological monitoring of network neurons. Cisplatin at 0.10-0.25 mM induced up to a 200% increase in spontaneous spiking activity, while concentrations at or above 0.5mM caused irreversible loss of neuronal activity, accompanied by cell death. Pretreatment with d-Met, at a concentration of 1.0mM, prevented the cisplatin-induced excitation at 0.10-0.25 mM, caused sustained excitation without occurrence of cell death at 0.5mM, and delayed cell death at 0.75 mM cisplatin. l-Methionine, the optical isomer, showed lower potency and less efficacy than d-Met, was less protective against 0.1mM cisplatin, and proved ineffective at a concentration of 0.5mM cisplatin. Pre-exposure time of d-Met was associated with the protective effects at 0.1 and 0.5mM cisplatin, with longer pre-exposure times exhibiting better protection. This study quantifies as a function of concentration and time that d-Met protects central nervous system tissue from acute cisplatin toxicity.

Developmental plasticity of auditory cortical inhibitory synapses.

Functional inhibitory synapses form in auditory cortex well before the onset of normal hearing. However, their properties change dramatically during normal development, and many of these maturational events are delayed by hearing loss. Here, we review recent findings on the developmental plasticity of inhibitory synapse strength, kinetics, and GABAA receptor localization in auditory cortex. Although hearing loss generally leads to a reduction of inhibitory strength, this depends on the type of presynaptic interneuron. Furthermore, plasticity of inhibitory synapses also depends on the postsynaptic target. Hearing loss leads reduced GABAA receptor localization to the membrane of excitatory, but not inhibitory neurons. A reduction in normal activity in development can also affect the use-dependent plasticity of inhibitory synapses. Even moderate hearing loss can disrupt inhibitory short- and long-term synaptic plasticity. Thus, the cortex did not compensate for the loss of inhibition in the brainstem, but rather exacerbated the response to hearing loss by further reducing inhibitory drive. Together, these results demonstrate that inhibitory synapses are exceptionally dynamic during development, and deafness-induced perturbation of inhibitory properties may have a profound impact on auditory processing.

Evolutionary significance of delayed neurogenesis in the core versus shell auditory areas of Mus musculus.

Early comparative embryogenesis can reflect the organization and evolutionary origins of brain areas. Neurogenesis in the auditory areas of sauropsids displays a clear core-to-shell distinction, but it remains unclear in mammals. To address this issue, [3H]-thymidine was injected into pregnant mice on consecutive embryonic (E) days (E10-E19) to date neuronal birthdays. Immunohistochemistry for substance P, calbindin, and parvalbumin was conducted to distinguish the core and shell auditory regions. The results showed that: 1) cell generation began at E13 in the external or dorsal nucleus of the inferior colliculus (IC), but it did not start in the caudomedial portion of the central nucleus of IC, and significantly fewer cells were produced in the medial and rostromedial portions of the central nucleus of IC; 2) cells were generated at E11 in the dorsal and medial divisions of the medial geniculate complex (MGd and MGm, respectively), whereas cell generation was absent in the medial and rostromedial portions of the ventral medial geniculate complex (MGv), and fewer cells were produced in the caudomedial portion of MGv; 3) in the telencephalic auditory cortex, cells were produced at E11 or E12 in layer I and the subplate, which receive projections from the MGd and MGm. However, cell generation occurred at E13-E18 in layers II-VI, including the area receiving projections from the MGv. The core-to-shell distinction of neurogenesis is thus present in the mesencephalic to telencephalic auditory areas in the mouse. This distinction of neurogenesis is discussed from an evolutionary perspective.

[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.

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.

The human auditory system: a timeline of development.

This review traces the structural maturation of the human auditory system, and compares the timeline of anatomical development with cotemporaneous physiological and behavioral events. During the embryonic period, there is formation of basic structure at all levels of the system, i.e. the inner ear, the brainstem pathway, and the cortex. The second trimester is a time of rapid growth and development, and by the end of this period, the cochlea has acquired a very adult-like configuration. During the perinatal period, the brainstem reaches a mature state, and brainstem activity is reflected in behavioral responses to sound, including phonetic discrimination, and in evoked brainstem and early middle latency responses. The perinatal period is also the time of peak development of brainstem input to the cortex through the marginal layer, and of the long latency cortical potentials, the N(2) and mismatch negativity. In early childhood, from the sixth post-natal month to age five, there is progressive maturation of the thalamic projections to the cortex and of the longer latency Pa and P(1) evoked potentials. Later childhood, from six to twelve years, is the time of maturation of the superficial cortical layers and their intracortical connections, accompanied by appearance of the N(1) potential and improved linguistic discriminative abilities. Some consideration is given to the potential negative effects of deafness-induced sound deprivation during the perinatal period and childhood.

Large-scale reorganization of the tonotopic map in mouse auditory midbrain revealed by MRI.

The cortex is thought to be the primary site of sensory plasticity, particularly during development. Here, we report that large-scale reorganization of the mouse auditory midbrain tonotopic map is induced by a specific sound-rearing environment consisting of paired low- (16 kHz) and high-frequency (40 kHz) tones. To determine the potential for plasticity in the mouse auditory midbrain, we used manganese-enhanced MRI to analyze the midbrain tonotopic maps of control mice during normal development and mice reared in the two-tone (16 + 40 kHz) environment. We found that the tonotopic map emerged during the third postnatal week in normal mice. Before 3 weeks, a larger percentage of auditory midbrain responded to each of the suprathreshold test frequencies, despite the fact that the primary afferent projections are in place even before hearing onset. By 3 weeks, the midbrain tonotopic map of control mice was established, and manganese-enhanced MRI showed a clear separation between the 16- and 40-kHz responses. Two-tone rearing dramatically altered the appearance of these discrete frequency-specific responses. A significant volume of the auditory midbrain became responsive to both rearing frequencies, resulting in a large-scale reorganization of the tonotopic map. These results indicate that developmental plasticity occurs on a much greater scale than previously appreciated in the mammalian auditory midbrain.

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.

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.

Maturation and plasticity of the central auditory system.

Studies across mammalian species have indicated that the ontogeny of the central auditory system relies on the utilization of both genetic and environmental instructions. Both types of instructions are relevant for the development of cortical as well as subcortical systems and are apparently used for the establishment of a wide range of functions from cochleotopic representation to language-specific filters in humans. To show this, the pre- and postnatal development of the mammalian central auditory system are briefly considered on seven levels of neuronal organization: neurogenesis, axonal growth, axonal maturation, synaptic maturation, cochleotopy, the descending auditory system, and adult plasticity.

Tonotopic gradients of Eph family proteins in the chick nucleus laminaris during synaptogenesis.

Topographically precise projections are established early in neural development. One such topographically organized network is the auditory brainstem. In the chick, the auditory nerve transmits auditory information from the cochlea to nucleus magnocellularis (NM). NM in turn innervates nucleus laminaris (NL) bilaterally. These projections preserve the tonotopy established at the level of the cochlea. We have begun to examine the expression of Eph family proteins during the formation of these connections. Optical density measurements were used to describe gradients of Eph proteins along the tonotopic axis of NL in the neuropil, the somata, and the NM axons innervating NL at embryonic day 10, when synaptic connections from NM to NL are established. At E10-11, NL dorsal neuropil expresses EphA4 at a higher concentration in regions encoding high frequency sounds, decreasing in concentration monotonically toward the low frequency (caudolateral) end. In the somata, both EphA4 and ephrin-B2 are concentrated at the high frequency end of the nucleus. These tonotopic gradients disappear between E13 and E15, and expression of these molecules is completely downregulated by hatching. The E10-11 patterns run counter to an apparent gradient in dendrite density, as indicated by microtubule associated protein 2 (MAP2) immunolabeling. Finally, ephrin-B2 is also expressed in a gradient in tissue ventral to the NL neuropil. Our findings thus suggest a possible conserved mechanism for establishing topographic projections in diverse sensory systems. These results of this study provide a basis for the functional examination of the role of Eph proteins in the formation of tonotopic maps in the brainstem.

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. .

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.

Expression of the P2X7 receptor subunit of the adenosine 5'-triphosphate-gated ion channel in the developing and adult rat cochlea.

ATP-gated ion channels assembled from P2X(7) subunits have been implicated in ontogeny and cellular pathology. Here, the expression of the P2X(7) receptor subunit was studied in the embryonic (E14-E18 days) and postnatal (P0-adult) rat cochlea using immunohistochemistry. Strong P2X(7) immunolabelling was observed in the primary auditory neurons of the spiral ganglion from E18 to adult and in the fibres innervating the sensory inner and outer hair cells from birth to adult. Strong immunolabelling of P2X(7) receptor protein was also observed in the inner and outer hair cells over a limited developmental period, from birth to P6. Weak expression was observed in cochlear duct epithelium on E18 and in the supporting cells (footplates of pillar cells in adult and in Böttcher's cells after birth). The immunolocalisation of P2X(7) receptors further implicates extracellular ATP in signalling process in cochlear ontogeny and in establishment and function of auditory neurotransmission. The P2X(7) receptors may be involved in signal transduction and modulation as well as in regulating cell death during development and in pathological conditions.