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

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 and even later in the primary auditory cortex (A1). We found this maturation process to be experience-dependent in A1 but not in thalamus and to be related to alterations in deep but not input layers of A1. We also identified corticothalamic projections to be implicated in thalamic 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.

Soluble amyloid-ß precursor peptide does not regulate GABAB receptor activity.

Amyloid-ß precursor protein (APP) regulates neuronal activity through the release of secreted APP (sAPP) acting at cell surface receptors. APP and sAPP were reported to bind to the extracellular sushi domain 1 (SD1) of GABAB receptors (GBRs). A 17 amino acid peptide (APP17) derived from APP was sufficient for SD1 binding and shown to mimic the inhibitory effect of sAPP on neurotransmitter release and neuronal activity. The functional effects of APP17 and sAPP were similar to those of the GBR agonist baclofen and blocked by a GBR antagonist. These experiments led to the proposal that sAPP activates GBRs to exert its neuronal effects. However, whether APP17 and sAPP influence classical GBR signaling pathways in heterologous cells was not analyzed. Here, we confirm that APP17 binds to GBRs with nanomolar affinity. However, biochemical and electrophysiological experiments indicate that APP17 does not influence GBR activity in heterologous cells. Moreover, APP17 did not regulate synaptic GBR localization, GBR-activated K+ currents, neurotransmitter release, or neuronal activity in vitro or in vivo. Our results show that APP17 is not a functional GBR ligand and indicate that sAPP exerts its neuronal effects through receptors other than GBRs.

Distinct integration of spectrally complex sounds in mouse primary auditory cortices.

The standard hierarchical signal transmission along the lemniscal auditory pathway in mice changes in the cortex, where two tonotopically organized auditory regions receive thalamic inputs in parallel: the primary auditory cortex (A1) and the anterior auditory field (AAF). These fields show distinct properties of sound-evoked responses, where A1 responds robustly to sound onset and AAF exhibits faster and more transient responses following both sound onset and offset. Previous reports showed a strong involvement of AAF in temporal processing, revealing its particular role in encoding temporal information. A more regular tonotopy, narrower frequency response areas, and more robust direction selectivity to frequency modulated sweeps led to the speculation that A1 codes better the spectral composition of a sound than AAF. However, potential mechanisms explaining why A1 favors spectral processing have not been previously described. Using in vivo electrophysiological recordings in the mouse auditory cortex, we found that A1 neurons, unlike AAF neurons, respond stronger and faster to spectrally complex tones than to pure tones. Next, we show that both regular and putative fast-spiking neurons in A1, but not in AAF, display larger responses to spectrally complex tones than to pure tones. Finally, we use a laminar analysis to demonstrate that A1 neurons in layer 2/3 respond stronger to spectrally complex tones than neurons in layer 4, indicating an important transformation of the neural representation of spectral complexity between thalamo-recipient and supragranular layers in A1, but not in AAF. Our study reveals circuit features contributing to distinct processing of spectrally simple and complex sounds in the two primary auditory cortices and supports a dual-stream processing in the core auditory cortex.

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.

Emergence and function of cortical offset responses in sound termination detection.

Offset responses in auditory processing appear after a sound terminates. They arise in neuronal circuits within the peripheral auditory system, but their role in the central auditory system remains unknown. Here, we ask what the behavioral relevance of cortical offset responses is and what circuit mechanisms drive them. At the perceptual level, our results reveal that experimentally minimizing auditory cortical offset responses decreases the mouse performance to detect sound termination, assigning a behavioral role to offset responses. By combining in vivo electrophysiology in the auditory cortex and thalamus of awake mice, we also demonstrate that cortical offset responses are not only inherited from the periphery but also amplified and generated de novo. Finally, we show that offset responses code more than silence, including relevant changes in sound trajectories. Together, our results reveal the importance of cortical offset responses in encoding sound termination and detecting changes within temporally discontinuous sounds crucial for speech and vocalization.

Task-induced modulations of neuronal activity along the auditory pathway.

Sensory processing varies depending on behavioral context. Here, we ask how task engagement modulates neurons in the auditory system. We train mice in a simple tone-detection task and compare their neuronal activity during passive hearing and active listening. Electrophysiological extracellular recordings in the inferior colliculus, medial geniculate body, primary auditory cortex, and anterior auditory field reveal widespread modulations across all regions and cortical layers and in both putative regular- and fast-spiking cortical neurons. Clustering analysis unveils ten distinct modulation patterns that can either enhance or suppress neuronal activity. Task engagement changes the tone-onset response in most neurons. Such modulations first emerge in subcortical areas, ruling out cortical feedback as the only mechanism underlying subcortical modulations. Half the neurons additionally display late modulations associated with licking, arousal, or reward. Our results reveal the presence of functionally distinct subclasses of neurons, differentially sensitive to specific task-related variables but anatomically distributed along the auditory pathway.

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 Organization of Critical Periods in the Mouse Auditory System.

Critical periods-time windows of heightened plasticity in postnatal development-are specific to sensory features and are asynchronous. Whether they are timed by a temporally precise developmental program or are sequentially organized is not known. We use electrophysiology and molecular or sensory manipulations to elucidate the biological constraints on critical period timing. Passive sound exposure shows that the cortical representations of two sound features, pure tone and frequency-modulated sweep (FMS), are not influencing each other. Enhancing inhibition before the critical period for pure tone accelerates it without changing the critical period for FMS. Similarly, delaying the critical period for pure tone with white noise exposure has no effect on the critical period for FMS. However, the critical period for FMS starts only if the one for pure tone has occurred. Together, these results indicate that distinct critical periods, although sequentially organized, can be temporally shifted independently of each other.

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.

White Noise Background Improves Tone Discrimination by Suppressing Cortical Tuning Curves.

The brain faces the difficult task of maintaining a stable representation of key features of the outside world in noisy sensory surroundings. How does the sensory representation change with noise, and how does the brain make sense of it? We investigated the effect of background white noise (WN) on tuning properties of neurons in mouse A1 and its impact on discrimination performance in a go/no-go task. We find that WN suppresses the activity of A1 neurons, which surprisingly increases the discriminability of tones spectrally close to each other. To confirm the involvement of A1, we optogenetically excited parvalbumin-positive (PV+) neurons in A1, which have similar effects as WN on both tuning properties and frequency discrimination. A population model suggests that the suppression of A1 tuning curves increases frequency selectivity and thereby improves discrimination. Our findings demonstrate that the cortical representation of pure tones adapts during noise to improve sensory acuity.

Distinct processing of tone offset in two primary auditory cortices.

In the rodent auditory system, the primary cortex is subdivided into two regions, both receiving direct inputs from the auditory thalamus: the primary auditory cortex (A1) and the anterior auditory field (AAF). Although neurons in the two regions display different response properties, like response latency, firing threshold or tuning bandwidth, it is still not clear whether they process sound in a distinct way. Using in vivo electrophysiological recordings in the mouse auditory cortex, we found that AAF neurons have significantly stronger responses to tone offset than A1 neurons. AAF neurons also display faster and more transient responses than A1 neurons. Additionally, offset responses in AAF - unlike in A1, increase with sound duration. Local field potential (LFP) and laminar analyses suggest that the differences in sound responses between these two primary cortices are both of subcortical and intracortical origin. These results emphasize the potentially critical role of AAF for temporal processing. Our study reveals a distinct role of two primary auditory cortices in tone processing and highlights the complexity of sound encoding at the cortical level.

Cochlear Implant Surgery and Electrically-evoked Auditory Brainstem Response Recordings in C57BL/6 Mice.

Cochlear implants (CIs) are neuroprosthetic devices that can provide a sense of hearing to deaf people. However, a CI cannot restore all aspects of hearing. Improvement of the implant technology is needed if CI users are to perceive music and perform in more natural environments, such as hearing out a voice with competing talkers, reflections, and other sounds. Such improvement requires experimental animals to better understand the mechanisms of electric stimulation in the cochlea and its responses in the whole auditory system. The mouse is an increasingly attractive model due to the many genetic models available. However, the limited use of this species as a CI model is mainly due to the difficulty of implanting small electrode arrays. More details about the surgical procedure are therefore of great interest to expand the use of mice in CI research. In this report, we describe in detail the protocol for acute deafening and cochlear implantation of an electrode array in the C57BL/6 mouse strain. We demonstrate the functional efficacy of this procedure with electrically-evoked auditory brainstem response (eABR) and show examples of facial nerve stimulation. Finally, we also discuss the importance of including a deafening procedure when using a normally hearing animal. This mouse model provides a powerful opportunity to study genetic and neurobiological mechanisms that would be of relevance for CI users.

A critical period for auditory thalamocortical connectivity.

Neural circuits are shaped by experience during periods of heightened brain plasticity in early postnatal life. Exposure to acoustic features produces age-dependent changes through largely unresolved cellular mechanisms and sites of origin. We isolated the refinement of auditory thalamocortical connectivity by in vivo recordings and day-by-day voltage-sensitive dye imaging in an acute brain slice preparation. Passive tone-rearing modified response strength and topography in mouse primary auditory cortex (A1) during a brief, 3-d window, but did not alter tonotopic maps in the thalamus. Gene-targeted deletion of a forebrain-specific cell-adhesion molecule (Icam5) accelerated plasticity in this critical period. Consistent with its normal role of slowing spinogenesis, loss of Icam5 induced precocious stubby spine maturation on pyramidal cell dendrites in neocortical layer 4 (L4), identifying a primary locus of change for the tonotopic plasticity. The evolving postnatal connectivity between thalamus and cortex in the days following hearing onset may therefore determine a critical period for auditory processing.

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 as well as in the ventral and medial divisions of the medial geniculate body (MGBv and MGBm, respectively). 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 with BF maps of neuronal spiking activity, the topographic order of subthreshold 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.