Single Unit publications

Platinum electrodes are used in many bionic devices; however, they have limited charge injection capacity (CIC) and signal‐to‐noise ratio (SNR), restricting performance. Iridium oxide has substantially larger CIC and reduced impedance compared to platinum. While these types of electrochemical measurements are typically used to infer improved electrophysiological performance, there are no studies demonstrating this correlation. This article compares the electrochemical and acute electrophysiological recording performance of iridium and electrochemically activated IrOx. Increased iridium activation reduced total impedance at low‐intermediate frequencies and steady‐state electroactive area but had no impact on linear diffusion electroactive area. The total impedance had a poor correlation with background noise, SNR and spike count. The results contribute to the previous literature indicating linear diffusion electroactive area determines the number of neurons within recording distance of the electrode, impacting SNR and spike count. Measurements of impedance are mainly of benefit as an indirect measure of linear diffusion electroactive area, in which case the measurement and analysis must be performed appropriately. A wide range of IrOx activation states can be produced with increased CIC, without concern of neural recording performance impacts. However, higher oxidation states resulting in electrode dissolution or increase in electrode resistance may limit IrOx chronic performance.

Stimulus-specific adaptation is a key feature of sensory systems, where the repeated presentation of a stimulus results in diminishing neuronal responses specifically to that stimulus, but not to a different stimulus. Cortical neurons display varying degrees of stimulus-specific adaptation, with cortical circuits shaping the dynamics of these responses. Here, we use calcium imaging and optogenetic approaches to assess the contributions of SOM and PV neurons to stimulus-specific adaptation in the mouse auditory cortex. We find opposing and complementary effects of SOM and PV neurons on the adaptation of principal neurons which manifest as context-dependent SOM neuron-mediated enhancement and PV-neuron mediated suppression of responses that depend on the temporal repetition rate of the sounds. Our results suggest that SOM and PV neurons can engage in multiple operating regimes that exist in a continuum during sensory processing.

How neuronal firing within a circuit encodes behavioural intensity, like running speed, is largely unknown. Projections from temporal association cortex (TeA) and superior colliculus (SC) to dorsal periaqueductal grey (dPAG) circuit can both trigger running behaviour. Using in vivo loose-patch recordings with circuit manipulations in mice, we quantified a firing - speed relationship and established its encoding model. Here, we report two behavioural patterns induced by circuit activation: backing away and rebound running. Mechanistically, dPAG CaMKIIα neurons receiving inputs from either TeA or SC, function as distinct “behavioural units”, controlling two “unit behaviours” of running and backing away, respectively. The unidirectional inhibition from the backing away unit to the running unit is mediated by somatostatin (SOM) neurons in dPAG, enabling transitions among four behavioural states: running, backing away, stopping, and rebound running. Both running and backing away behaviours follow a unified motor encoding model, quantified by a single-phase association equation.

A central goal in neuroscience is to clarify how neural circuits translate sensory input into adaptive behaviours. Although unisensory evoked escape circuits in mice are well defined, it remains unclear whether a single nucleus contains specialized sensory, sensory‒motor decision, and motor command neurons for escapes driven by distinct sensory cues, and how these neurons form functional microcircuits. Using multiple sensory stimuli in mice, we identified the temporal association cortex (TeA) as a critical escape hub. Combining in vivo electrophysiology, optogenetics and chemogenetics, we characterized three distinct neuron subtypes within TeA layer 5 (L5) CaMKII neurons that correspond to these three functional classes. Intratelencephalic (IT) neurons serve as sensory‒motor decision neurons, while layer matched pyramidal tract (PT) neurons projecting to the dorsal periaqueductal grey (dPAG) act as motor command neurons. We reveal a laminar IT–PT microcircuit that converts sensory input into sensory-motor decisions and commands for escape locomotion.

Harmonicity is a property of complex sounds such as vocalizations or music, but it remains unclear how harmonicity is processed in the auditory cortex (ACtx). Subregions of ACtx are thought to process harmonic stimuli differently. Selective responses to sound features in ACtx emerge hierarchically from primary ACtx (A1) L4 and secondary ACtx (A2) layer (L)2/3, which is believed to be the most responsive to harmonic sounds. Since harmonic stacks can range from 2 to >10 components, being more similar to naturalistic vocalizations, harmonic sensitivity might also arise hierarchically across layers and areas. We studied responses to harmonic stacks of 2–10 frequencies across A1 L4, A1 L2/3, and A2 L2/3 in adult male and female mice using in vivo two-photon microscopy. We found harmonic-sensitive neurons (HNs) responding only to harmonic stacks but not to individual frequencies in all areas at similar proportions. HNs showed highly nonlinear spectral integration of harmonic frequencies that decreased as the harmonic stacks became more complex. Specifically, onset-biased HNs showed greater nonlinearity than offset-biased HNs only in A1 L4. Moreover, HNs in A1 L4 exhibited higher signal correlation than A2 L2/3. Sound-responsive neurons in A1 L4 have the weakest noise correlation compared with A1 L2/3 and A2 L2/3. Together, harmonic sensitivity is not a unique feature of A2 L2/3 but is already established in A1 L4, where neurons robustly encode harmonic sounds through sparse connections.

Habituation is a crucial sensory filtering mechanism whose dysregulation can lead to a continuously intense world in disorders with hypersensitivity. Although habituation is often termed the simplest form of learning, its circuit mechanisms remain elusive. Conventional peripheral explanations fail to fully account for long-term habituation in complex sensory environments, leading to theories proposing top-down regulation. Here we evaluated two competing top-down mechanistic explanations for habituation in mice (growth in predictive filtering and waning of novelty-driven amplification) and identified an unexpected role for the orbitofrontal cortex (OFC) in predictive filtering. After daily sound exposure, neural habituation in the primary auditory cortex (A1) was reversed by inactivating the OFC. Top-down projections from the OFC, but not other frontal areas, carried predictive signals that grew with daily sound experience and suppressed A1 via somatostatin-expressing inhibitory neurons. Thus, prediction signals from the OFC cancel out anticipated stimuli by generating their 'negative images' in sensory cortices.

Adolescence is a developmental period characterized by heightened plasticity. Yet, how ongoing development affects sensory processing and cognitive function is unclear. We investigated how adolescent (postnatal day 20–42) and adult (postnatal day 60–82) mice differ in performance on a pure tone Go/No-Go auditory discrimination task of varying difficulty. Using dense electrophysiological recordings, we measured spiking activity at single neuron resolution in the auditory cortex while mice were engaged in the task. As compared to adults, adolescent mice showed lower auditory discrimination performance in a difficult task. This difference in performance was due to higher response variability and weaker cognitive control expressed as higher lick bias. Adolescent and adult neuronal responses differed only slightly in representations of pure tones when measured outside the context of learning and the task. However, cortical representations after learning within the context of the task were markedly different. We found differences in stimulus- and choice-related activity at the single neuron level representations, as well as lower population-level decoding of the difficult task in adolescents. Overall, cortical decoding in adolescents was lower and slower, especially for difficult sound discrimination, reflecting immature cortical representations of sounds and choices. Notably, we found age-related differences, which were more pronounced after learning, reflecting the combined impact of age and learning. Our findings highlight distinct neurophysiological and behavioral profiles in adolescence, underscoring the ongoing development of cognitive control mechanisms and cortical plasticity during this sensitive developmental period.

Cross-modal responses are common in primary sensory cortex, yet a recent study showed that signals in primary visual cortex (V1) once labeled multisensory were instead more closely related to face movements. To what extent can multisensory processing in other modalities also be explained by face movements? We measured face movements and neural activity in awake mouse primary auditory cortex (A1) and V1 in response to visual and auditory stimulation as well as during spontaneous activity. We find that visual stimuli rarely evoke face movements, A1 responses to visual input remain robust even in the absence of face movement, and optogenetic silencing of V1 reduces A1 visual responses. Taken together, these results confirm that cross-modal responses in the auditory system are primarily sensory, not state driven, in origin.

The neural representations of acoustic features that differ in the location or timbre of the emitter elicit similar perceptions, suggesting the existence of a robust stimulus‐response function between complex sounds and the activity of neural populations at all stages of the auditory system. This hypothesis is tested by decoding a random sound stream, using spike trains from a biophysical model of the auditory nerve and from large‐scale recordings in the inferior colliculus, the auditory thalamus, and the auditory cortex of awake mice. At the level of individual neurons, the reliability of temporal and rate codes is found to decrease along the ascending auditory pathways. Rate coding is progressively favored with increasing independence of neuron frequency tuning. Firing in the auditory cortex is found to be synergistic, whereas that in subcortical areas is more redundant. Finally, combinatorial codes involving neural firing and neural silence within neuron pairs are shown to efficiently encode sound information, particularly in the auditory cortex. Overall, these findings reveal a progressive transformation of the neural code from an individual, redundant, and temporal code at the periphery to a more distributed rate‐based code in the auditory cortex.

The insular cortex is involved in a wide range of auditory functions in the mammalian brain. We studied the organization and basic response properties of auditory neurons in the insular cortex and adjacent areas by recording responses to sound stimuli in anesthetized female rats. Auditory neurons were present in an insulo-parietal auditory field that spans the boundary between the posterior insula, particularly in the granular insular cortex, and the ventral part of the adjacent nonprimary somatosensory fields. Confirming previous reports, neurons in this field had narrow tuning and were preferentially tuned to relatively low frequencies (<16 kHz). Intriguingly, auditory units in this field displayed shorter minimal latencies than units in the primary auditory cortex, as well as weaker sensitivity to deviance. These results establish the existence of a rapid auditory information stream with distinct properties through the insulo-parietal cortex that may parallel the pathway through the primary and anterior auditory fields.

Auditory processing in the cerebral cortex is considered to begin with thalamocortical inputs to layer 4 (L4) of the primary auditory cortex (A1). In this canonical model, A1 L4 inputs initiate a hierarchical cascade that propagates to higher-order cortices for slower integration of complex sounds. Here, we identify parallel ascending pathways in mice that bypass A1 and directly reach the secondary auditory cortex (A2), alongside the canonical hierarchical route. We found that layer 6 (L6) of both A1 and A2 receive short-latency (<10 ms) sound inputs via higher-order thalamic nuclei. Additionally, A2 L4 is innervated by a caudal subdivision of the traditionally defined primary thalamus, which we now re-classify as non-primary. Notably, both identified thalamic regions receive projections from distinct subdivisions of the higher-order inferior colliculus, which in turn receive direct projections from cochlear nucleus neurons. Thus, higher-order auditory cortex integrates both slower, pre-processed information and rapid, direct sensory inputs, enabling parallel processing of fast sensory information across cortical areas.

Electroanalytical methods are used to understand, modify, and control bionic devices. Bionic devices can record or stimulate cells to understand and/or control normal or abnormal biological processes. These devices contain electrodes that transduce electrical current within the electrical circuit into ionic current within a tissue. Despite the similarity between electroanalysis and electrophysiology, there remains a poor understanding of the relationship between the two techniques, including their methodology and theory. This paper investigates the electrochemical and acute electrophysiological recording performance of neural electrodes. A range of behaviors is achieved by modifying electrodes with the conducting polymer poly(3,4‐ethylenedioxythiophene) (PEDOT) doped with chondroitin sulfate, dextran sulfate, or para ‐toluene sulfonate. The results support previous studies showing that increased electrode area reduced total impedance below the Maxwell–Wagner relaxation frequency and thermal noise while increasing the signal‐to‐noise ratio and neural spike count. The results allowed novel investigation of relative contributions of biological and electrode properties to electrophysiological performance, with increased electrode area having a larger impact on neural population within recording range rather than reducing thermal noise. The utility of measuring electrode impedance for predicting electrophysiological performance is mainly for an indirect measure of electrode area. The results provide insight into noise sources from electrophysiological recordings and limitations in cable theory in neuroscience.

While evolutionary cortical expansion is thought to underlie the evolution of human cognitive capabilities, excessive developmental expansion can lead to megalencephaly, often found in neurodevelopmental disorders. Still, little is known about how the overproduction of cortical neurons during development affects cortical processing and behavior in later life. Here we show that developmental overproduction of cortical superficial neurons impairs auditory processing in adult mice. We applied XAV939 to overproduce cortical superficial excitatory neurons during development. XAV939-treated adult mice exhibited auditory behavioral deficits and abnormal auditory cortical processing. Furthermore, we found fewer functional monosynaptic connections between cortical putative excitatory neurons. Altogether, our results suggest that abnormal auditory cortical processing contributes to the atypical auditory detectability in XAV939-treated mice. Although the expansion of cortical size is evolutionarily advantageous, an abnormal expansion during development can result in detrimental effects on cortical processing and perceptual behavior in adulthood.

Molecular profiling of inner ear neurons has broadened the classification of the primary afferents that support neural coding for hearing and balance. To extend spatiotemporal characterization of auditory and vestibular neuron diversity, we established a transgenic reporter mouse model (Prphp-mCherry), where elements of the peripherin promoter (Prphp) drive expression of the mCherry fluorescent reporter. Type III intermediate filament protein peripherin expression is a marker for type II spiral ganglion neurons (SGN) that innervate the cochlear outer hair cells, and the small diameter 'bouton' vestibular ganglion neurons (VGN) innervating the type II vestibular hair cells. Using Nanopore genome sequencing, the integration site of the transgene construct was identified within the class III metabotropic glutamate receptor 8 gene (Grm8, chromosome 6). Use of CUBIC / PEGASOS clearing of early postnatal to adult inner ear tissues enabled in situ 3D spatial localization of a dispersed population of cochlear mCherry + ve SGN, with highest expression and density in the hook (high frequency encoding) basal region. Of these mCherry + ve SGN, type II SGN (peripherin-immunopositive) were all co-labeled in the basal region, but the majority of the overall mCherry-delineated SGN auditory subpopulation were type I SGN innervating inner hair cells. In the VGN, mCherry + ve neurons represented ~ 15% of the adult population, dispersed as a small diameter subpopulation throughout both the inferior and superior VGN regions. These findings resolve heterogeneous type I and type II cochlear SGN subpopulations, particularly in the structurally complex hook region, and further differentiate vestibular primary afferents across postnatal development.

Sound location coding has been extensively studied at the central nucleus of the mammalian inferior colliculus (CNIC), supporting a population code. However, this population code has not been extensively characterized on the single-trial level with simultaneous recordings or at other anatomical regions like the dorsal cortex of inferior colliculus (DCIC), which is relevant for learning-induced experience dependent plasticity. To address these knowledge gaps, here we made in two complementary ways large-scale recordings of DCIC populations from awake mice in response to sounds delivered from 13 different frontal horizontal locations (azimuths): volumetric two-photon calcium imaging with ~700 cells simultaneously recorded at a relatively low temporal resolution, and high-density single-unit extracellular recordings with ~20 cells simultaneously recorded at a high temporal resolution. Independent of the method, the recorded DCIC population responses revealed substantial trial-to-trial variation (neuronal noise) which was significantly correlated across pairs of neurons (noise correlations) in the passively listening condition. Nevertheless, decoding analysis supported that these noisy response patterns encode sound location on the single-trial basis, reaching errors that match the discrimination ability of mice. The detected noise correlations contributed to minimize the error of the DCIC population code of sound azimuth. Altogether these findings point out that DCIC can encode sound location in a similar format to what has been proposed for CNIC, opening exciting questions about how noise correlations could shape this code in the context of cortico-collicular input and experience-dependent plasticity.

Cortical processing of auditory information can be affected by interspecies differences as well as brain states. Here we compare multifeature spectro-temporal receptive fields (STRFs) and associated input/output functions or nonlinearities (NLs) of neurons in primary auditory cortex (AC) of four mammalian species. Single-unit recordings were performed in awake animals (female squirrel monkeys, female, and male mice) and anesthetized animals (female squirrel monkeys, rats, and cats). Neuronal responses were modeled as consisting of two STRFs and their associated NLs. The NLs for the STRF with the highest information content show a broad distribution between linear and quadratic forms. In awake animals, we find a higher percentage of quadratic-like NLs as opposed to more linear NLs in anesthetized animals. Moderate sex differences of the shape of NLs were observed between male and female unanesthetized mice. This indicates that the core AC possesses a rich variety of potential computations, particularly in awake animals, suggesting that multiple computational algorithms are at play to enable the auditory system’s robust recognition of auditory events.

Sound is an important navigational cue for mammals. During spatial navigation, hippocampal place cells encode spatial representations of the environment based on visual information, but to what extent audiospatial information can enable reliable place cell mapping is largely unknown. We assessed this by recording from CA1 place cells in the dark, under circumstances where reliable visual, tactile, or olfactory information was unavailable. Male rats were exposed to auditory cues of different frequencies that were delivered from local or distal spatial locations. We observed that distal, but not local cue presentation, enables and supports stable place fields, regardless of the sound frequency used. Our data suggest that a context dependency exists regarding the relevance of auditory information for place field mapping: whereas locally available auditory cues do not serve as a salient spatial basis for the anchoring of place fields, auditory cue localization supports spatial representations by place cells when available in the form of distal information. Furthermore, our results demonstrate that CA1 neurons can effectively use auditory stimuli to generate place fields, and that hippocampal pyramidal neurons are not solely dependent on visual cues for the generation of place field representations based on allocentric reference frames.

The flow of neural activity across the neocortex during active sensory discrimination is constrained by task-specific cognitive demands, movements, and internal states. During behavior, the brain appears to sample from a broad repertoire of activation motifs. Understanding how these patterns of local and global activity are selected in relation to both spontaneous and task-dependent behavior requires in-depth study of densely sampled activity at single neuron resolution across large regions of cortex. In a significant advance toward this goal, we developed procedures to record mesoscale 2-photon Ca 2+ imaging data from two novel in vivo preparations that, between them, allow for simultaneous access to nearly all 0f the mouse dorsal and lateral neocortex. As a proof of principle, we aligned neural activity with both behavioral primitives and high-level motifs to reveal the existence of large populations of neurons that coordinated their activity across cortical areas with spontaneous changes in movement and/or arousal. The methods we detail here facilitate the identification and exploration of widespread, spatially heterogeneous neural ensembles whose activity is related to diverse aspects of behavior.

Salicylate is commonly used to induce tinnitus in animals, but its underlying mechanism of action is still debated. We therefore tested its effects on the firing properties of neurons in the mouse inferior colliculus (IC). Salicylate induced a large decrease in the spontaneous activity and an increase of ∼20 dB SPL in the minimum threshold of single units. In response to sinusoidally modulated noise (SAM noise) single units showed both an increase in phase locking and improved rate coding. Mice also became better at detecting amplitude modulations, and a simple threshold model based on the IC population response could reproduce this improvement. The responses to dynamic random chords (DRCs) suggested that the improved AM encoding was due to a linearization of the cochlear output, resulting in larger contrasts during SAM noise. These effects of salicylate are not consistent with the presence of tinnitus, but should be taken into account when studying hyperacusis.

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.