Lemniscal Corticothalamic Feedback in Auditory Scene Analysis.

Sound information is transmitted from the ear to central auditory stations of the brain via several nuclei. In addition to these ascending pathways there exist descending projections that can influence the information processing at each of these nuclei. A major descending pathway in the auditory system is the feedback projection from layer VI of the primary auditory cortex (A1) to the ventral division of medial geniculate body (MGBv) in the thalamus. The corticothalamic axons have small glutamatergic terminals that can modulate thalamic processing and thalamocortical information transmission. Corticothalamic neurons also provide input to GABAergic neurons of the thalamic reticular nucleus (TRN) that receives collaterals from the ascending thalamic axons. The balance of corticothalamic and TRN inputs has been shown to refine frequency tuning, firing patterns, and gating of MGBv neurons. Therefore, the thalamus is not merely a relay stage in the chain of auditory nuclei but does participate in complex aspects of sound processing that include top-down modulations. In this review, we aim (i) to examine how lemniscal corticothalamic feedback modulates responses in MGBv neurons, and (ii) to explore how the feedback contributes to auditory scene analysis, particularly on frequency and harmonic perception. Finally, we will discuss potential implications of the role of corticothalamic feedback in music and speech perception, where precise spectral and temporal processing is essential.

Plasticity of Multidimensional Receptive Fields in Core Rat Auditory Cortex Directed by Sound Statistics.

Sensory cortical neurons can nonlinearly integrate a wide range of inputs. The outcome of this nonlinear process can be approximated by more than one receptive field component or filter to characterize the ensuing stimulus preference. The functional properties of multidimensional filters are, however, not well understood. Here we estimated two spectrotemporal receptive fields (STRFs) per neuron using maximally informative dimension analysis. We compared their temporal and spectral modulation properties and determined the stimulus information captured by the two STRFs in core rat auditory cortical fields, primary auditory cortex (A1) and ventral auditory field (VAF). The first STRF is the dominant filter and acts as a sound feature detector in both fields. The second STRF is less feature specific, preferred lower modulations, and had less spike information compared to the first STRF. The information jointly captured by the two STRFs was larger than that captured by the sum of the individual STRFs, reflecting nonlinear interactions of two filters. This information gain was larger in A1. We next determined how the acoustic environment affects the structure and relationship of these two STRFs. Rats were exposed to moderate levels of spectrotemporally modulated noise during development. Noise exposure strongly altered the spectrotemporal preference of the first STRF in both cortical fields. The interaction between the two STRFs was reduced by noise exposure in A1 but not in VAF. The results reveal new functional distinctions between A1 and VAF indicating that (i) A1 has stronger interactions of the two STRFs than VAF, (ii) noise exposure diminishes modulation parameter representation contained in the noise more strongly for the first STRF in both fields, and (iii) plasticity induced by noise exposure can affect the strength of filter interactions in A1. Taken together, ascertaining two STRFs per neuron enhances the understanding of cortical information processing and plasticity effects in core auditory cortex.

Information diversity in individual auditory cortical neurons is associated with functionally distinct coordinated neuronal ensembles.

Neuronal activity in auditory cortex is often highly synchronous between neighboring neurons. Such coordinated activity is thought to be crucial for information processing. We determined the functional properties of coordinated neuronal ensembles (cNEs) within primary auditory cortical (AI) columns relative to the contributing neurons. Nearly half of AI cNEs showed robust spectro-temporal receptive fields whereas the remaining cNEs showed little or no acoustic feature selectivity. cNEs can therefore capture either specific, time-locked information of spectro-temporal stimulus features or reflect stimulus-unspecific, less-time specific processing aspects. By contrast, we show that individual neurons can represent both of those aspects through membership in multiple cNEs with either high or absent feature selectivity. These associations produce functionally heterogeneous spikes identifiable by instantaneous association with different cNEs. This demonstrates that single neuron spike trains can sequentially convey multiple aspects that contribute to cortical processing, including stimulus-specific and unspecific information.

Auditory Cortical Plasticity Dependent on Environmental Noise Statistics.

During critical periods, neural circuits develop to form receptive fields that adapt to the sensory environment and enable optimal performance of relevant tasks. We hypothesized that early exposure to background noise can improve signal-in-noise processing, and the resulting receptive field plasticity in the primary auditory cortex can reveal functional principles guiding that important task. We raised rat pups in different spectro-temporal noise statistics during their auditory critical period. As adults, they showed enhanced behavioral performance in detecting vocalizations in noise. Concomitantly, encoding of vocalizations in noise in the primary auditory cortex improves with noise-rearing. Significantly, spectro-temporal modulation plasticity shifts cortical preferences away from the exposed noise statistics, thus reducing noise interference with the foreground sound representation. Auditory cortical plasticity shapes receptive field preferences to optimally extract foreground information in noisy environments during noise-rearing. Early noise exposure induces cortical circuits to implement efficient coding in the joint spectral and temporal modulation domain.

Detachment of Chain-Forming Neuroblasts by Fyn-Mediated Control of cell-cell Adhesion in the Postnatal Brain.

In the rodent olfactory system, neuroblasts produced in the ventricular-subventricular zone of the postnatal brain migrate tangentially in chain-like cell aggregates toward the olfactory bulb (OB) through the rostral migratory stream (RMS). After reaching the OB, the chains are dissociated and the neuroblasts migrate individually and radially toward their final destination. The cellular and molecular mechanisms controlling cell-cell adhesion during this detachment remain unclear. Here we report that Fyn, a nonreceptor tyrosine kinase, regulates the detachment of neuroblasts from chains in the male and female mouse OB. By performing chemical screening and in vivo loss-of-function and gain-of-function experiments, we found that Fyn promotes somal disengagement from the chains and is involved in neuronal migration from the RMS into the granule cell layer of the OB. Fyn knockdown or Dab1 (disabled-1) deficiency caused p120-catenin to accumulate and adherens junction-like structures to be sustained at the contact sites between neuroblasts. Moreover, a Fyn and N-cadherin double-knockdown experiment indicated that Fyn regulates the N-cadherin-mediated cell adhesion between neuroblasts. These results suggest that the Fyn-mediated control of cell-cell adhesion is critical for the detachment of chain-forming neuroblasts in the postnatal OB.SIGNIFICANCE STATEMENT In the postnatal brain, newly born neurons (neuroblasts) migrate in chain-like cell aggregates toward their destination, where they are dissociated into individual cells and mature. The cellular and molecular mechanisms controlling the detachment of neuroblasts from chains are not understood. Here we show that Fyn, a nonreceptor tyrosine kinase, promotes the somal detachment of neuroblasts from chains, and that this regulation is critical for the efficient migration of neuroblasts to their destination. We further show that Fyn and Dab1 (disabled-1) decrease the cell-cell adhesion between chain-forming neuroblasts, which involves adherens junction-like structures. Our results suggest that Fyn-mediated regulation of the cell-cell adhesion of neuroblasts is critical for their detachment from chains in the postnatal brain.

A Role for Auditory Corticothalamic Feedback in the Perception of Complex Sounds.

Feedback signals from the primary auditory cortex (A1) can shape the receptive field properties of neurons in the ventral division of the medial geniculate body (MGBv). However, the behavioral significance of corticothalamic modulation is unknown. The aim of this study was to elucidate the role of this descending pathway in the perception of complex sounds. We tested the ability of adult female ferrets to detect the presence of a mistuned harmonic in a complex tone using a positive conditioned go/no-go behavioral paradigm before and after the input from layer VI in A1 to MGBv was bilaterally and selectively eliminated using chromophore-targeted laser photolysis. MGBv neurons were identified by their short latencies and sharp tuning curves. They responded robustly to harmonic complex tones and exhibited an increase in firing rate and temporal pattern changes when one frequency component in the complex tone was mistuned. Injections of fluorescent microbeads conjugated with a light-sensitive chromophore were made in MGBv, and, following retrograde transport to the cortical cell bodies, apoptosis was induced by infrared laser illumination of A1. This resulted in a selective loss of ∼60% of layer VI A1-MGBv neurons. After the lesion, mistuning detection was impaired, as indicated by decreased d' values, a shift of the psychometric curves toward higher mistuning values, and increased thresholds, whereas discrimination performance was unaffected when level cues were also available. Our results suggest that A1-MGBv corticothalamic feedback contributes to the detection of harmonicity, one of the most important grouping cues in the perception of complex sounds.SIGNIFICANCE STATEMENT Perception of a complex auditory scene is based on the ability of the brain to group those sound components that belong to the same source and to segregate them from those belonging to different sources. Because two people talking simultaneously may differ in their voice pitch, perceiving the harmonic structure of sounds is very important for auditory scene analysis. Here we demonstrate mistuning sensitivity in the thalamus and that feedback from the primary auditory cortex is required for the normal ability of ferrets to detect a mistuned harmonic within a complex sound. These results provide novel insight into the function of descending sensory pathways in the brain and suggest that this corticothalamic circuit plays an important role in scene analysis.

Mistuning detection performance of ferrets in a go/no-go task.

The harmonic structure of sounds is an important grouping cue in auditory scene analysis. The ability of ferrets to detect mistuned harmonics was measured using a go/no-go task paradigm. Psychometric functions plotting sensitivity as a function of degree of mistuning were used to evaluate behavioral performance using signal detection theory. The mean (± standard error of the mean) threshold for mistuning detection was 0.8 ± 0.1 Hz, with sensitivity indices and reaction times depending on the degree of mistuning. These data provide a basis for investigation of the neural basis for the perception of complex sounds in ferrets, an increasingly used animal model in auditory research.

In vivo maturation of human embryonic stem cell-derived teratoma over time.

Transformation of human embryonic stem cells (hESC) is of interest to scientists who use them as a raw material for cell-processed therapeutic products. However, the WHO and ICH guidelines provide only study design advice and general principles for tumorigenicity tests. In this study, we performed in vivo tumorigenicity tests (teratoma formation) and genome-wide sequencing analysis of undifferentiated hESCs i.e. SEES-1, -2 and -3 cells. We followed up with teratoma formation histopathologically after subcutaneous injection of SEES cells into immunodeficient mice in a qualitative manner and investigated the transforming potential of the teratomas. Maturity of SEES-teratomas perceptibly increased after long-term implantation, while areas of each tissue component remained unchanged. We found neither atypical cells/structures nor cancer in the teratomas even after long-term implantation. The teratomas generated by SEES cells matured histologically over time and did not increase in size. We also analyzed genomic structures and sequences of SEES cells during cultivation by SNP bead arrays and next-generation sequencing, respectively. The nucleotide substitution rate was 3.1 × 10-9, 4.0 × 10-9, and 4.6 × 10-9 per each division in SEES-1, SEES-2, and SEES-3 cells, respectively. Heterozygous single-nucleotide variations were detected, but no significant homologous mutations were found. Taken together, these results imply that SEES-1, -2, and -3 cells do not exhibit in vivo transformation and in vitro genomic instability.