Electrophysiology publications

Anticipating positive outcomes is a core cognitive function in the process of reward prediction. However, no neurophysiological method objectively assesses reward prediction in basic medical research. In the present study, we established a physiological paradigm using cortical direct current (DC) potential responses in rats to assess reward prediction. This paradigm consisted of five daily 1-h sessions with two tones, wherein the rewarded tone was followed by electrical stimulation of the medial forebrain bundle (MFB) scheduled at 1000 ms later, whereas the unrewarded tone was not. On day 1, both tones induced a negative DC shift immediately after auditory responses, persisting up to MFB stimulation. This negative shift progressively increased and peaked on day 4. Starting from day 3, the negative shift from 600 to 1000 ms was significantly larger following the rewarded tone than that following the unrewarded tone. This negative DC shift was particularly prominent in the frontal cortex, suggesting its crucial role in discriminative reward prediction. During the extinction sessions, the shift diminished significantly on extinction day 1. These findings suggest that cortical DC potential is related to reward prediction and could be a valuable tool for evaluating animal models of depression, providing a testing system for anhedonia.

Loss of cochlear hair cells (HCs) leads to permanent hearing loss in mammals, and regenerative medicine is regarded as an ideal strategy for hearing recovery. Limited genetic and pharmaceutical approaches for HC regeneration have been established, and the existing strategies cannot achieve recovery of auditory function. A promising target to promote HC regeneration is MEK/ERK signaling because dynamic shifts in its activity during the critical stages of inner ear development have been observed. Here, we first showed that MEK/ERK signaling is activated specifically in supporting cells (SCs) after aminoglycoside-induced HC injury. We then selected 4 MEK/ERK signaling inhibitors, and PD0325901 (PD03) was found to induce the transdifferentiation of functional supernumerary HCs from SCs in the neonatal mammalian cochlear epithelium. We next found that PD03 facilitated the generation of HCs in inner ear organoids. Through genome-wide high-throughput RNA sequencing and verification, we found that the Notch pathway is the downstream target of MEK/ERK signaling. Importantly, delivery of PD03 into the inner ear induced mild HC regeneration in vivo. Our study thus reveals the importance of MEK/ERK signaling in cell fate determination and suggests that PD03 might serve as a new approach for HC regeneration.

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.

Social interactions in primates require social cognition abilities such as anticipating the partner's future choices as well as pure cognitive skills involving processing task-relevant information. The medial prefrontal cortex (mPFC) has been implicated in these cognitive processes. Here, we investigated the neural oscillations underlying the complex social behaviors involving the interplay of social roles (Actor vs. Observer) and interaction types (whether working with a "Good" or "Bad" partner). We found opposite power modulations of the beta and gamma bands by social roles, indicating dedicated processing for task-related information. Concurrently, the interaction type was conveyed by lower frequencies, which are commonly associated with neural circuits linked to performance and reward monitoring. Thus, the mPFC exhibits parallel coding of both "cold" processes (purely cognitive) and "hot" processes (reward and social-related). This allocation of neural resources gives the mPFC a key neural node, flexibly integrating multiple sources of information during social interactions.

The P2 component of the auditory evoked potential has previously been shown to depend on the acoustic stimulus properties and prior exposure to the materials. Here, we show that it is also affected by acoustic changes, as P2 amplitudes were strongly enhanced in response to voice pitch changes with a stepwise pattern compared to dynamic pitch changes typical for natural speech, and also reflected the magnitude of these pitch changes. Furthermore, it is demonstrated that neither the P2 nor any other component is affected by the harmonicity of the materials. Despite no prior exposure and a weaker pitch, artificially created inharmonic versions of the materials elicited similar activity throughout the auditory cortex. This suggests that so-called harmonic template neurons observed in animal studies are either absent or do not exist in sufficient number in the human auditory cortex to detect their activity extracranially. Crucially, morphology as well as scalp maps and source reconstructions of the EEG data showed that the P2 appears to consist of two separate subcomponents. While the “P2a” was localised to the auditory cortex, the subsequent “P2b” included generators spread across the auditory cortex and association areas. The two subcomponents thus likely reflect processing at different stages of the auditory pathway.

Rapid eye movement (REM) sleep is known to facilitate fear extinction and play a protective role against fearful memories.1,2 Consequently, disruption of REM sleep after a traumatic event may increase the risk for developing PTSD.3,4 However, the underlying mechanisms by which REM sleep promotes extinction of aversive memories remain largely unknown. The infralimbic cortex (IL) is a key brain structure for the consolidation of extinction memory.5 Using calcium imaging, we found in mice that most IL pyramidal neurons are intensively activated during REM sleep. Optogenetically suppressing the IL specifically during REM sleep within a 4-h window after auditory-cued fear conditioning impaired extinction memory consolidation. In contrast, REM-specific IL inhibition after extinction learning did not affect the extinction memory. Whole-cell patch-clamp recordings demonstrated that inactivating IL neurons during REM sleep depresses their excitability. Together, our findings suggest that REM sleep after fear conditioning facilitates fear extinction by enhancing IL excitability and highlight the importance of REM sleep in the aftermath of traumatic events for protecting against traumatic memories.

Aims The hippocampus has been reported to be morphologically and neurochemically altered in schizophrenia (SZ). Hyperlocomotion is a characteristic SZ‐associated behavioral phenotype, which is associated with dysregulated dopamine system function induced by hippocampal hyperactivity. However, the neural mechanism of hippocampus underlying hyperlocomotion remains largely unclear. Methods Mouse pups were injected with N ‐methyl‐ D ‐aspartate receptor antagonist (MK‐801) or vehicle twice daily on postnatal days (PND) 7–11. In the adulthood phase, one cohort of mice underwent electrode implantation in field CA1 of the hippocampus for the recording local field potentials and spike activity. A separate cohort of mice underwent surgery to allow for calcium imaging of the hippocampus while monitoring the locomotion. Lastly, the effects of atypical antipsychotic (aripiprazole, ARI) were evaluated on hippocampal neural activity. Results We found that the hippocampal theta oscillations were enhanced in MK‐801‐treated mice, but the correlation coefficient between the hippocampal spiking activity and theta oscillation was reduced. Consistently, although the rate and amplitude of calcium transients of hippocampal neurons were increased, their synchrony and correlation to locomotion speed were disrupted. ARI ameliorated perturbations produced by the postnatal MK‐801 treatment. Conclusions These results suggest that the disruption of neural coordination may underly the neuropathological mechanism for hyperlocomotion of SZ.

Having two ears enables us to localize sound sources by exploiting interaural time differences (ITDs) in sound arrival. Principal neurons of the medial superior olive (MSO) are sensitive to ITD, and each MSO neuron responds optimally to a best ITD (bITD). In many cells, especially those tuned to low sound frequencies, these bITDs correspond to ITDs for which the contralateral ear leads, and are often larger than the ecologically relevant range, defined by the ratio of the interaural distance and the speed of sound. Using in vivo recordings in gerbils, we found that shortly after hearing onset the bITDs were even more contralaterally leading than found in adult gerbils, and travel latencies for contralateral sound-evoked activity clearly exceeded those for ipsilateral sounds. During the following weeks, both these latencies and their interaural difference decreased. A computational model indicated that spike timing-dependent plasticity can underlie this fine-tuning. Our results suggest that MSO neurons start out with a strong predisposition toward contralateral sounds due to their longer neural travel latencies, but that, especially in high-frequency neurons, this predisposition is subsequently mitigated by differential developmental fine-tuning of the travel latencies.

The natural environment challenges the brain to prioritize the processing of salient stimuli. The barn owl, a sound localization specialist, exhibits a circuit called the midbrain stimulus selection network, dedicated to representing locations of the most salient stimulus in circumstances of concurrent stimuli. Previous competition studies using unimodal (visual) and bimodal (visual and auditory) stimuli have shown that relative strength is encoded in spike response rates. However, open questions remain concerning auditory–auditory competition on coding. To this end, we present diverse auditory competitors (concurrent flat noise and amplitude-modulated noise) and record neural responses of awake barn owls of both sexes in subsequent midbrain space maps, the external nucleus of the inferior colliculus (ICx) and optic tectum (OT). While both ICx and OT exhibit a topographic map of auditory space, OT also integrates visual input and is part of the global-inhibitory midbrain stimulus selection network. Through comparative investigation of these regions, we show that while increasing strength of a competitor sound decreases spike response rates of spatially distant neurons in both regions, relative strength determines spike train synchrony of nearby units only in the OT. Furthermore, changes in synchrony by sound competition in the OT are correlated to gamma range oscillations of local field potentials associated with input from the midbrain stimulus selection network. The results of this investigation suggest that modulations in spiking synchrony between units by gamma oscillations are an emergent coding scheme representing relative strength of concurrent stimuli, which may have relevant implications for downstream readout.

The feedback projections from cortical layer 6 (L6CT) to the sensory thalamus have long been implicated in playing a primary role in gating sensory signaling but remain poorly understood. To causally elucidate the full range of effects of these projections, we targeted silicon probe recordings to the whisker thalamocortical circuit of awake mice selectively expressing Channelrhodopsin-2 in L6CT neurons. Through optogenetic manipulation of L6CT neurons, multi-site electrophysiological recordings, and modeling of L6CT circuitry, we establish L6CT neurons as dynamic modulators of ongoing spiking in the ventral posteromedial nucleus of the thalamus (VPm), either suppressing or enhancing VPm spiking depending on L6CT neurons’ firing rate and synchrony. Differential effects across the cortical excitatory and inhibitory sub-populations point to an overall influence of L6CT feedback on cortical excitability that could have profound implications for regulating sensory signaling across a range of ethologically relevant conditions.

Advancements in cochlear implants (CIs) have led to a significant increase in bilateral CI users, especially among children. Yet, most bilateral CI users do not fully achieve the intended binaural benefit due to potential limitations in signal processing and/or surgical implant positioning. One crucial auditory cue that normal hearing (NH) listeners can benefit from is the interaural time difference (ITD), i.e ., the time difference between the arrival of a sound at two ears. The ITD sensitivity is thought to be heavily relying on the effective utilization of temporal fine structure (very rapid oscillations in sound). Unfortunately, most current CIs do not transmit such true fine structure. Nevertheless, bilateral CI users have demonstrated sensitivity to ITD cues delivered through envelope or interaural pulse time differences, i.e ., the time gap between the pulses delivered to the two implants. However, their ITD sensitivity is significantly poorer compared to NH individuals, and it further degrades at higher CI stimulation rates, especially when the rate exceeds 300 pulse per second. The overall purpose of this research thread is to improve spatial hearing abilities in bilateral CI users. This study aims to develop electroencephalography (EEG) paradigms that can be used with clinical settings to assess and optimize the delivery of ITD cues, which are crucial for spatial hearing in everyday life. The research objective of this article was to determine the effect of CI stimulation pulse rate on the ITD sensitivity, and to characterize the rate-dependent degradation in ITD perception using EEG measures. To develop protocols for bilateral CI studies, EEG responses were obtained from NH listeners using sinusoidal-amplitude-modulated (SAM) tones and filtered clicks with changes in either fine structure ITD (ITD FS ) or envelope ITD (ITD ENV ). Multiple EEG responses were analyzed, which included the subcortical auditory steady-state responses (ASSRs) and cortical auditory evoked potentials (CAEPs) elicited by stimuli onset, offset, and changes. Results indicated that acoustic change complex (ACC) responses elicited by ITD ENV changes were significantly smaller or absent compared to those elicited by ITD FS changes. The ACC morphologies evoked by ITD FS changes were similar to onset and offset CAEPs, although the peak latencies were longest for ACC responses and shortest for offset CAEPs. The high-frequency stimuli clearly elicited subcortical ASSRs, but smaller than those evoked by lower carrier frequency SAM tones. The 40-Hz ASSRs decreased with increasing carrier frequencies. Filtered clicks elicited larger ASSRs compared to high-frequency SAM tones, with the order being 40 > 160 > 80> 320 Hz ASSR for both stimulus types. Wavelet analysis revealed a clear interaction between detectable transient CAEPs and 40-Hz ASSRs in the time-frequency domain for SAM tones with a low carrier frequency.

Photometry and electrophysiology are powerful tools for investigating brain-behavior relationships. Combining these techniques would allow us to ask previously un-addressable questions, such as how neuromodulators impact neuronal firing rates. Current options are highly limited—requiring a substantial loss in data-quality or severely restricting naturalistic-movement. These drawbacks arise from engineering-limits on devices that allow optically-tethered subjects to move freely. Here, we introduce a device that overcomes these challenges. Its automated orientation-tracking system allows subjects to move freely for multiple-hours with minimal supervision and without sacrificing data-quality. The device is modular and adaptable, being compatible with most recording systems and equipped for added functionality (e.g., optogenetics). To demonstrate its utility, we simultaneously tracked extracellular striatal dopamine and single-neuron firing as mice performed a reward-learning task. Mice showed excellent mobility, and we observed robust trial-by-trial correlations between striatal firing and dopamine signaling. This device provides a powerful tool that outperforms current commercial solutions.

This dataset was collected to study the functional consequences of age-related hearing loss for the auditory nerve, which carries acoustic information from the periphery to the central auditory system. Using high-impedance glass electrodes, raw voltage traces and spike times were recorded from more than one thousand single fibres of the auditory nerve of young-adult, middle-aged, and old Mongolian gerbils raised in a quiet environment. The dataset contains not only responses to simple acoustic stimuli to characterize the fibres, but also to more complex stimuli, such as speech logatomes in background noise and Schroeder-phase stimuli. A software toolbox is provided to search through the dataset, to plot various analysed outcomes, and to give insight into the analyses. This dataset may serve as a valuable resource to test further hypotheses about age-related hearing loss. Additionally, it can aid in optimizing available computational models of the auditory system, which can contribute to, or eventually even fully replace, animal experiments.

Sleep spindles appear to play an important role in learning new motor skills. Motor skill learning engages several brain regions with two important areas being the motor cortex (M1) and the cerebellum (CB). However, the neurophysiological processes in these areas during sleep, especially how spindle oscillations affect local and cross-region spiking, are not fully understood. We recorded an activity from the M1 and cerebellar cortex in eight rats during spontaneous activity to investigate how sleep spindles in these regions are related to local spiking as well as cross-region spiking. We found that M1 firing was significantly changed during both M1 and CB spindles, and this spiking occurred at a preferred phase of the spindle. On average, M1 and CB neurons showed most spiking at the M1 or CB spindle peaks. These neurons also developed a preferential phase locking to local or cross-area spindles with the greatest phase-locking value at spindle peaks; however, this preferential phase locking was not significant for cerebellar neurons when compared with CB spindles. Additionally, we found that the percentage of task-modulated cells in the M1 and CB that fired with nonuniform spike phase distribution during M1/CB spindle peaks were greater in the rats that learned a reach-to-grasp motor task robustly. Finally, we found that spindle band LFP coherence (for M1 and CB LFPs) showed a positive correlation with success rate in the motor task. These findings support the idea that sleep spindles in both the M1 and CB recruit neurons that participate in the awake task to support motor memory consolidation.

According to the predictive processing framework, perception emerges from the reciprocal exchange of predictions and prediction errors (PEs) between hierarchically organized neural circuits. The nonlemniscal division of the inferior colliculus (IC) is the earliest source of auditory PE signals, but their neuronal generators, properties, and functional relevance have remained mostly undefined. We recorded single-unit mismatch responses to auditory oddball stimulation at different intensities, together with activity evoked by two sequences of alternating tones to control frequency-specific effects. Our results reveal a differential treatment of the unpredictable many-standards control and the predictable cascade control by lemniscal and nonlemniscal IC neurons that is not present in the auditory thalamus or cortex. Furthermore, we found that frequency response areas of nonlemniscal IC neurons reflect their role in subcortical predictive processing, distinguishing three hierarchical levels: (1) nonlemniscal neurons with sharply tuned receptive fields exhibit mild repetition suppression without signaling PEs, thereby constituting the input level of the local predictive processing circuitry. (2) Neurons with broadly tuned receptive fields form the main, spectral PE signaling system, which provides dynamic gain compensation to near-threshold unexpected sounds. This early enhancement of saliency reliant on spectral features was not observed in the auditory thalamus or cortex. (3) Untuned neurons form an accessory, nonspectral PE signaling system, which reports all surprising auditory deviances in a robust and consistent manner, resembling nonlemniscal neurons in the auditory cortex. These nonlemniscal IC neurons show unstructured and unstable receptive fields that could result from inhibitory input controlled by corticofugal projections conveying top-down predictions.

Autism spectrum disorder (ASD) is often associated with social communication impairments and specific sound processing deficits, for example, problems in following speech in noisy environments. To investigate underlying neuronal processing defects located in the auditory cortex (AC), we performed two-photon Ca 2+ imaging in FMR1 ( fragile X messenger ribonucleoprotein 1 ) knock-out (KO) mice, a model for fragile X syndrome (FXS), the most common cause of hereditary ASD in humans. For primary AC (A1) and the anterior auditory field (AAF), topographic frequency representation was less ordered compared with control animals. We additionally analyzed ensemble AC activity in response to various sounds and found subfield-specific differences. In A1, ensemble correlations were lower in general, while in secondary AC (A2), correlations were higher in response to complex sounds, but not to pure tones. Furthermore, sound specificity of ensemble activity was decreased in AAF. Repeating these experiments 1 week later revealed no major differences regarding representational drift. Nevertheless, we found subfield- and genotype-specific changes in ensemble correlation values between the two times points, hinting at alterations in network stability in FMR1 KO mice. These detailed insights into AC network activity and topography in FMR1 KO mice add to the understanding of auditory processing defects in FXS.

Infrared neural stimulation (INS) is a promising area of interest for the clinical application of a neuromodulation method. This is in part because of its low invasiveness, whereby INS modulates the activity of the neural tissue mainly through temperature changes. Additionally, INS may provide localized brain stimulation with less tissue damage. The inferior colliculus (IC) is a crucial auditory relay nucleus and a potential target for clinical application of INS to treat auditory diseases and develop artificial hearing devices. Here, using continuous INS with low to high-power density, we demonstrate the laminar modulation of neural activity in the mouse IC in the presence and absence of sound. We investigated stimulation parameters of INS to effectively modulate the neural activity in a facilitatory or inhibitory manner. A mathematical model of INS-driven brain tissue was first simulated, temperature distributions were numerically estimated, and stimulus parameters were selected from the simulation results. Subsequently, INS was administered to the IC of anesthetized mice, and the modulation effect on the neural activity was measured using an electrophysiological approach. We found that the modulatory effect of INS on the spontaneous neural activity was bidirectional between facilitatory and inhibitory effects. The modulatory effect on sound-evoked responses produced only an inhibitory effect to all examined stimulus intensities. Thus, this study provides important physiological evidence on the response properties of IC neurons to INS. Overall, INS can be used for the development of new therapies for neurological disorders and functional support devices for auditory central processing.

Excess oxygen (O 2 ) levels may have a stimulating effect, but in the long term, and at high concentrations of O 2 , it is harmful to the nervous system. The hippocampus is very sensitive to pathophysiological changes and altered O 2 concentrations can interfere with hippocampus-dependent learning and memory functions. In this study, we investigated the hyperoxia-induced changes in the rat hippocampus to evaluate the short-term effect of mild and severe hyperoxia. Wistar male rats were randomly divided into control (21% O 2 ), mild hyperoxia (30% O 2 ), and severe hyperoxia groups (100% O 2 ). The O 2 exposure lasted for 60 min. Multi-channel silicon probes were used to study network oscillations and firing properties of hippocampal putative inhibitory and excitatory neurons. Neural damage was assessed using the Gallyas silver impregnation method. Mild hyperoxia (30% O 2 ) led to the formation of moderate numbers of silver-impregnated “dark” neurons in the hippocampus. On the other hand, exposure to 100% O 2 was associated with a significant increase in the number of “dark” neurons located mostly in the hilus. The peak frequency of the delta oscillation decreased significantly in both mild and severe hyperoxia in urethane anesthetized rats. Compared to normoxia, the firing activity of pyramidal neurons under hyperoxia increased while it was more heterogeneous in putative interneurons in the cornu ammonis area 1 (CA1) and area 3 (CA3). These results indicate that short-term hyperoxia can change the firing properties of hippocampal neurons and network oscillations and damage neurons. Therefore, the use of elevated O 2 concentration inhalation in hospitals (i.e., COVID treatment and surgery) and in various non-medical scenarios (i.e., airplane emergency O 2 masks, fire-fighters, and high altitude trekkers) must be used with extreme caution.

Objective This study investigated the relationship between DBS evoked potentials (EPs) and diffusion tensor imaging (DTI) in a group of patients with dystonia who underwent DBS treatment. EPs and DTI are both useful methods for studying neural connectivity in the brain but measure different aspects of brain function. EPs provide information on electrical connectivity, while DTI provides information on anatomical pathways connecting regions. Methods This study focused on the pallidum and motor thalamus nuclei, which are common targets for DBS in dystonia. Prior to DBS implantation, DTI images were acquired for each patient, and were processed to obtain DTI coefficients such as length (L), volume (V), and fractional anisotropy (FA) of the fiber tracts. The relationship between the fiber tracts and electrophysiology was examined using a generalized linear model (GLM). Results We showed that the amplitude of EPs correlated with FA and tract volume, while delay correlated with tract length. These findings suggest that DBS signals travel across tracts to affect both local and distant brain regions, and the magnitude of the effect of DBS is determined by the integrity of the white matter tract, while DBS signal delay is affected by the tract length. Our results further suggest that the magnitude and delay of the spread of the DBS signal may be predicted by the DTI connectivity. This provides strong supporting evidence for other studies that have assumed, but have been unable to test, such a relationship. Conclusion Overall, this study suggests that the electrical effects of DBS can be at least partially predicted by noninvasive DTI imaging in patients with dystonia. By combining EPs with DTI, we could investigate the propagation of stimulation pulses through brain regions. While this relationship has been previously hypothesized by the neuroscience community, this is the first study in humans to demonstrate this relationship between DBS EPs and DTI, thereby advancing the field of human brain mapping and enhancing the precision of neurosurgical targeting.

Temporally coordinated neural activity is central to nervous system function and purposeful behavior. Still, there is a paucity of evidence demonstrating how this coordinated activity within cortical and subcortical regions governs behavior. We investigated this between the primary motor (M1) and contralateral cerebellar cortex as rats learned a neuroprosthetic/brain-machine interface (BMI) task. In neuroprosthetic task, actuator movements are causally linked to M1 “direct” neurons that drive the decoder for successful task execution. However, it is unknown how task-related M1 activity interacts with the cerebellum. We observed a notable 3 to 6 hertz coherence that emerged between these regions’ local field potentials (LFPs) with learning that also modulated task-related spiking. We identified robust task-related indirect modulation in the cerebellum, which developed a preferential relationship with M1 task–related activity. Inhibiting cerebellar cortical and deep nuclei activity through optogenetics led to performance impairments in M1-driven neuroprosthetic control. Together, these results demonstrate that cerebellar influence is necessary for M1-driven neuroprosthetic control.