A critical period for auditory thalamocortical connectivity.

1 1 8 9 a r t I C l e S Neural circuits are shaped by experience during periods of heightened brain plasticity in early life 1,2 . Children raised in an English-speaking environment easily distinguish between the phonemes /la/ and /ra/, whereas those growing up in Japan find it increasingly difficult 3 . Passive exposure of young rodents to a variety of sound features reveals a cascading series of developmental windows that open and close shortly after hearing onset to define the persistent and specific influences of early experience on the functional organization of auditory cortex Motivated by the well known binocular interactions shaped by experience in developing visual cortex 7-9 , we used in vivo neurophysiological recordings to determine whether mouse A1 also exhibits a critical period for tonotopic map plasticity induced through passive tone exposure, and whether such plasticity is present in the auditory thalamus (ventral medial geniculate body, MGBv). We then isolated the connection between MGBv and primary auditory cortex (A1) (ref. 10) in an acute brain slice preparation 11 and used voltage-sensitive dye imaging (VSDI) techniques in vitro. We mapped A1 responses to electrical stimulation of discrete sites in MGBv across early postnatal days (P8-20), following tone-rearing or gene manipulation. Our results reveal a critical period for acoustically driven topographic plasticity at thalamocortical connections in mouse A1. RESULTS Tone exposure modifies tonotopic maps in A1, but not MGBv The auditory system is tonotopically organized 10 such that tones of similar frequency activate neighboring neurons at each station along the pathway. Given that rats show experience-dependent tonotopic map reorganization following passive tone exposure during the second postnatal week 2,12 , we first used high-density in vivo mapping to delineate A1 tonotopy in young adult mice 13 that were reared either in typical acoustic environments To determine whether remapping in A1 could be explained by a shifted frequency representation in the principal subcortical input source, we also examined best frequency distributions in the MGBv. We inserted a multichannel silicon probe at an angle that matched the plane of section used in subsequent thalamocortical slice experiment

Inhibition in the auditory cortex

The auditory system provides us with extremely rich and precise information about the outside world. Once a sound reaches our ears, the acoustic information it carries travels from the cochlea all the way to the auditory cortex, where its complexity and nuances are integrated. In the auditory cortex, functional circuits are formed by subpopulations of intermingled excitatory and inhibitory cells. In this review, we discuss recent evidence of the specific contributions of inhibitory neurons in sound processing and integration. We first examine intrinsic properties of three main classes of inhibitory interneurons in the auditory cortex. Then, we describe how inhibition shapes the responsiveness of the auditory cortex to sound. Finally, we discuss how inhibitory interneurons contribute to the sensation and perception of sounds. Altogether, this review points out the crucial role of cortical inhibitory interneurons in integrating information about the context, history, or meaning of a sound. It also highlights open questions to be addressed for increasing our understanding of the staggering complexity leading to the subtlest auditory perception

Ramped pulse shapes are more efficient for cochlear implant stimulation in an animal model

In all commercial cochlear implant (CI) devices, the electric stimulation is performed with a rectangular pulse that generally has two phases of opposite polarity. To date, developing new stimulation strategies has relied on the efficacy of this shape. Here, we investigate the potential of a novel stimulation paradigm that uses biophysically-inspired electrical ramped pulses. Using electrically-evoked auditory brainstem response (eABR) recordings in mice, we found that less charge, but higher current level amplitude, is needed to evoke responses with ramped shapes that are similar in amplitude to responses obtained with rectangular shapes. The most charge-efficient pulse shape had a rising ramp over both phases, supporting findings from previous in vitro studies. This was also true for longer phase durations. Our study presents the first physiological data on CI-stimulation with ramped pulse shapes. By reducing charge consumption ramped pulses have the potential to produce more battery-efficient CIs and may open new perspectives for designing other efficient neural implants in the future

The Perception of Ramped Pulse Shapes in Cochlear Implant Users

The electric stimulation provided by current cochlear implants (CI) is not power efficient. One underlying problem is the poor efficiency by which information from electric pulses is transformed into auditory nerve responses. A novel stimulation paradigm using ramped pulse shapes has recently been proposed to remedy this inefficiency. The primary motivation is a better biophysical fit to spiral ganglion neurons with ramped pulses compared to the rectangular pulses used in most contemporary CIs. Here, we tested the hypotheses that ramped pulses provide more efficient stimulation compared to rectangular pulses and that a rising ramp is more efficient than a declining ramp. Rectangular, rising ramped and declining ramped pulse shapes were compared in terms of charge efficiency and discriminability, and threshold variability in seven CI listeners. The tasks included single-channel threshold detection, loudness-balancing, discrimination of pulse shapes, and threshold measurement across the electrode array. Results showed that reduced charge, but increased peak current amplitudes, was required at threshold and most comfortable levels with ramped pulses relative to rectangular pulses. Furthermore, only one subject could reliably discriminate between equally-loud ramped and rectangular pulses, suggesting variations in neural activation patterns between pulse shapes in that participant. No significant difference was found between rising and declining ramped pulses across all tests. In summary, the present findings show some benefits of charge efficiency with ramped pulses relative to rectangular pulses, that the direction of a ramped slope is of less importance, and that most participants could not perceive a difference between pulse shapes

Sequential maturation of stimulus-specific adaptation in the mouse lemniscal auditory system

<p>Stimulus-specific adaptation (SSA), the reduction of neural activity to a common stimulus that does not generalize to other, rare stimuli, is an essential property of our brain. Although well characterized in adults, it is still unknown how it develops during adolescence and what neuronal circuits are involved. Using in vivo electrophysiology and optogenetics in the lemniscal pathway of the mouse auditory system, we observed SSA to be stable from postnatal day 20 (P20) in the inferior colliculus, to develop until P30 in the auditory thalamus (MGV) and even later in the primary auditory cortex (A1). We found this maturation process to be experience-dependent in A1 but not in MGV, and to be related to alterations in deep but not input layers of A1. We also identified corticothalamic projections to be implicated in MGV SSA development. Together, our results reveal different circuits underlying the sequential SSA maturation and provide a unique perspective to understand predictive coding and surprise across sensory systems.</p><p>Funding provided by: Swiss National Science Foundation<br>Crossref Funder Registry ID: https://ror.org/00yjd3n13<br>Award Number: CRETP3-166735</p><p>Funding provided by: Swiss National Science Foundation<br>Crossref Funder Registry ID: https://ror.org/00yjd3n13<br>Award Number: 310030_19785</p><p><span>The data was collected using in vivo electrophysiological recordings in awake mice, using Neuronexus multishaft electrodes (A64 or A32). It was then processed for spike sorting using kilosort1, and curated manually using phy. Further details are described in the manuscript.<br></span></p&gt

General developmental health in the VPA-rat model of autism

Autism is a neurodevelopmental condition diagnosed by impaired social interaction, abnormal communication and, stereotyped behaviors. While post-mortem and imaging studies have provided good insights into the neurobiological symptomology of autism, animal models can be used to study the neuroanatomical, neurophysiological and molecular mediators in more detail and in a more controlled environment. The valproic acid (VPA) rat model is an environmentally triggered model with strong construct and clinical validity. It is based on VPA teratogenicity in humans, where mothers who are medicated with VPA during early pregnancy show an increased risk for giving birth to an autistic child. In rats, early embryonic exposure, around the time of neural tube closure, leads to autism-like anatomical and behavioral abnormalities in the offspring. Considering the increasing use of the VPA rat model, we present our observations of the general health of Wistar dams treated with a single intraperitoneal injection of 500 or, 600 mg/kg VPA on embryonic day E12.5, as well as their male and female offspring, in comparison to saline-exposed controls. We report increased rates of complete fetal reabsorption after both VPA doses. VPA 500 mg/kg showed no effect on dam body weight during pregnancy or, on litter size. Offspring exposed to VPA 500 mg/kg showed smaller brain mass on postnatal days 1 (P1) and 14 (P14), in addition to abnormal nest seeking behavior at P10 in the olfactory discrimination test, relative to controls. We also report increased rates of physical malformations in the offspring, rare occurrences of chromodacryorrhea and, developmentally similar body mass gain. Further documentation of developmental health may guide sub-grouping of individuals in a way to better predict core symptom severity

Linking topography to tonotopy in the mouse auditory thalamocortical circuit

The mouse sensory neocortex is reported to lack several hallmark features of topographic organization such as ocular dominance and orientation columns in primary visual cortex or fine-scale tonotopy in primary auditory cortex (AI). Here, we re-examined the question of auditory functional topography by aligning ultra-dense receptive field maps from the auditory cortex and thalamus of the mouse in vivo with the neural circuitry contained in the auditory thalamocortical slice in vitro. We observed precisely organized tonotopic maps of best frequency (BF) in the middle layers of AI and the anterior auditory field (AAF) as well as in ventral and medial divisions of the medial geniculate body (MGBv, MGBm). Tracer injections into distinct zones of the BF map in AI retrogradely labeled topographically organized MGBv projections and weaker, mixed projections from MGBm. Stimulating MGBv along the tonotopic axis in the slice produced an orderly shift of voltage-sensitive dye (VSD) signals along the AI tonotopic axis, demonstrating topography in the mouse thalamocortical circuit that is preserved in the slice. However, compared to BF maps of neuronal spiking activity, the topographic order of sub-threshold VSD maps was reduced in layer IV and even further degraded in layer II/III. Therefore, the precision of AI topography varies according to the source and layer of the mapping signal. Our findings further bridge the gap between in vivo and in vitro approaches for the detailed cellular study of auditory thalamocortical circuit organization and plasticity in the genetically tractable mouse model