Electrophysiology publications

The lateral hypothalamus (LH) is involved in feeding behavior and defense responses by interacting with different brain structures, including the Ventral Tegmental Area (VTA). Emerging evidence indicates that LH-glutamatergic neurons infrequently synapse on VTA-dopamine neurons but preferentially establish multiple synapses on VTA-glutamatergic neurons. Here, we demonstrated that LH-glutamatergic inputs to VTA promoted active avoidance, long-term aversion, and escape attempts. By testing feeding in the presence of a predator, we observed that ongoing feeding was decreased, and that this predator-induced decrease in feeding was abolished by photoinhibition of the LH-glutamatergic inputs to VTA. By VTA specific neuronal ablation, we established that predator-induced decreases in feeding were mediated by VTA-glutamatergic neurons but not by dopamine or GABA neurons. Thus, we provided evidence for an unanticipated neuronal circuitry between LH-glutamatergic inputs to VTA-glutamatergic neurons that plays a role in prioritizing escape, and in the switch from feeding to escape in mice.

Most people can conjure images and sounds that they experience in their minds. There are, however, marked individual differences. Some people report that they cannot generate imagined sensory experiences at all (aphantasics) and others report that they have unusually intense imagined experiences (hyper-phantasics). These individual differences have been linked to activity in sensory brain regions, driven by feedback. We would therefore expect imagined experiences to be associated with specific frequencies of oscillatory brain activity, as these can be a hallmark of neural interactions within and across regions of the brain. Replicating a number of other studies, relative to a Resting-State we find that the act of engaging in auditory or in visual imagery is linked to reductions in the power of oscillatory brain activity across a broad range of frequencies, with prominent peaks in the alpha band (8–12 Hz). This oscillatory activity, however, did not predict individual differences in the subjective intensity of imagined experiences. For audio imagery, these were rather predicted by reductions within the theta (6–9 Hz) and gamma (33–38 Hz) bands, and by increases in beta (15–17 Hz) band activity. For visual imagery these were predicted by reductions in lower (14–16 Hz) and upper (29–32 Hz) beta band activity, and by an increase in mid-beta band (24–26 Hz) activity. Our data suggest that there is sufficient ground truth in the subjective reports people use to describe the intensity of their imagined sensory experiences to allow these to be linked to the power of distinct rhythms of brain activity. In future, we hope to combine this approach with better measures of the subjective intensity of imagined sensory experiences to provide a clearer picture of individual differences in the subjective intensity of imagined experiences, and of why these eventuate.

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.

Background Redox imbalance and inflammation have been proposed as the principal mechanisms of damage in the auditory system, resulting in functional alterations and hearing loss. Microglia and astrocytes play a crucial role in mediating oxidative/inflammatory injury in the central nervous system; however, the role of glial cells in the auditory damage is still elusive. Objectives Here we investigated glial-mediated responses to toxic injury in peripheral and central structures of the auditory pathway, i.e., the cochlea and the auditory cortex (ACx), in rats exposed to styrene, a volatile compound with well-known oto/neurotoxic properties. Methods Male adult Wistar rats were treated with styrene (400 mg/kg daily for 3 weeks, 5/days a week). Electrophysiological, morphological, immunofluorescence and molecular analyses were performed in both the cochlea and the ACx to evaluate the mechanisms underlying styrene-induced oto/neurotoxicity in the auditory system. Results We showed that the oto/neurotoxic insult induced by styrene increases oxidative stress in both cochlea and ACx. This was associated with macrophages and glial cell activation, increased expression of inflammatory markers (i.e., pro-inflammatory cytokines and chemokine receptors) and alterations in connexin (Cxs) and pannexin (Panx) expression, likely responsible for dysregulation of the microglia/astrocyte network. Specifically, we found downregulation of Cx26 and Cx30 in the cochlea, and high level of Cx43 and Panx1 in the ACx. Conclusions Collectively, our results provide novel evidence on the role of immune and glial cell activation in the oxidative/inflammatory damage induced by styrene in the auditory system at both peripheral and central levels, also involving alterations of gap junction networks. Our data suggest that targeting glial cells and connexin/pannexin expression might be useful to attenuate oxidative/inflammatory damage in the auditory system.

Introduction The mechanisms underlying tinnitus perception are still under research. One of the proposed hypotheses involves an alteration in top-down processing of auditory activity. Low-frequency oscillations in the delta and theta bands have been recently described in brain and cochlear infrasonic signals during selective attention paradigms in normal hearing controls. Here, we propose that the top-down oscillatory activity observed in brain and cochlear signals during auditory and visual selective attention in normal subjects, is altered in tinnitus patients, reflecting an abnormal functioning of the corticofugal pathways that connect brain circuits with the cochlear receptor. Methods To test this hypothesis, we used a behavioral task that alternates between auditory and visual top-down attention while we simultaneously measured electroencephalogram (EEG) and distortion-product otoacoustic emissions (DPOAE) signals in 14 tinnitus and 14 control subjects. Results We found oscillatory activity in the delta and theta bands in cortical and cochlear channels in control and tinnitus patients. There were significant decreases in the DPOAE oscillatory amplitude during the visual attention period as compared to the auditory attention period in tinnitus and control groups. We did not find significant differences when using a between-subjects statistical approach comparing tinnitus and control groups. On the other hand, we found a significant cluster in the delta band in tinnitus when using within-group statistics to compare the difference between auditory and visual DPOAE oscillatory power. Conclusion These results confirm the presence of top-down infrasonic low-frequency cochlear oscillatory activity in the delta and theta bands in tinnitus patients, showing that the corticofugal suppression of cochlear oscillations during visual and auditory attention in tinnitus patients is preserved.

Background Individuals with autism spectrum disorders (ASD) often exhibit altered sensory processing and deficits in language development. Prenatal exposure to valproic acid (VPA) increases the risk for ASD and impairs both receptive and expressive language. Like individuals with ASD, rodents prenatally exposed to VPA exhibit degraded auditory cortical processing and abnormal neural activity to sounds. Disrupted neuronal morphology has been documented in earlier processing areas of the auditory pathway in VPA-exposed rodents, but there are no studies documenting early auditory pathway physiology. Therefore, the objective of this study is to characterize inferior colliculus (IC) responses to different sounds in rats prenatally exposed to VPA compared to saline-exposed rats. Methods In vivo extracellular multiunit recordings from the inferior colliculus were collected in response to tones, speech sounds, and noise burst trains. Results Our results indicate that the overall response to speech sounds was degraded in VPA-exposed rats compared to saline-exposed controls, but responses to tones and noise burst trains were unaltered. Conclusions These results are consistent with observations in individuals with autism that neural responses to complex sounds, like speech, are often altered, and lays the foundation for future studies of potential therapeutics to improve auditory processing in the VPA rat model of ASD.

The hearing abilities of mammals are impacted by factors such as social cues, habitat, and physical characteristics. Despite being used commonly to study social behaviors, hearing of the monogamous prairie vole (Microtus ochrogaster) has never been characterized. In this study, anatomical features are measured and auditory brainstem responses (ABRs) are used to measure auditory capabilities of prairie voles, characterizing monaural and binaural hearing and hearing range. Sexually naive male and female voles were measured to characterize differences due to sex. It was found that prairie voles show a hearing range with greatest sensitivity between 8 and 32 kHz, binaural hearing across interaural time difference ranges appropriate for their head sizes. No differences are shown between the sexes in binaural hearing or hearing range (except at 1 kHz), however, female voles have increased amplitude of peripheral ABR waves I and II and longer latency of waves III and IV compared to males. The results confirm that prairie voles have a broad hearing range, binaural hearing consistent with rodents of similar size, and differences in amplitudes and thresholds of monaural physiological measures between the sexes. These data further highlight the necessity to understand sex-specific differences in neural processing that may underly variability in responses between sexes.

Cortical electro-encephalography (EEG) served as the clinical reference for monitoring unconsciousness during general anesthesia. The existing EEG-based monitors classified general anesthesia states as underdosed, adequate, or overdosed, lacking predictive power due to the absence of transition phases among these states. In response to this limitation, we undertook an analysis of the EEG signal during isoflurane-induced general anesthesia in mice. Adopting a data-driven approach, we applied signal processing techniques to track θ- and δ-band dynamics, along with iso-electric suppressions. Combining this approach with machine learning, we successfully developed an automated algorithm. The findings of our study revealed that the dampening of the δ-band occurred several minutes before the onset of significant iso-electric suppression episodes. Furthermore, a distinct γ-frequency oscillation was observed, persisting for several minutes during the recovery phase subsequent to isoflurane-induced overdose. As a result of our research, we generated a map summarizing multiple brain states and their transitions, offering a tool for predicting and preventing overdose during general anesthesia. The transition phases identified, along with the developed algorithm, have the potential to be generalized, enabling clinicians to prevent inadequate anesthesia and, consequently, tailor anesthetic regimens to individual patients.

Sleep disturbances are detrimental to our behavioral and emotional well-being. Stressful events disrupt sleep, in particular by inducing brief awakenings (microarousals, MAs), resulting in sleep fragmentation. The preoptic area of the hypothalamus (POA) is crucial for sleep control. However, how POA neurons contribute to the regulation of MAs and thereby impact sleep quality is unknown. Using fiber photometry in mice, we examine the activity of genetically defined POA subpopulations during sleep. We find that POA glutamatergic neurons are rhythmically activated in synchrony with an infraslow rhythm in the spindle band of the electroencephalogram during non-rapid eye movement sleep (NREMs) and are transiently activated during MAs. Optogenetic stimulation of these neurons promotes MAs and wakefulness. Exposure to acute social defeat stress fragments NREMs and significantly increases the number of transients in the calcium activity of POA glutamatergic neurons during NREMs. By reducing MAs, optogenetic inhibition during spontaneous sleep and after stress consolidates NREMs. Monosynaptically restricted rabies tracing reveals that POA glutamatergic neurons are innervated by brain regions regulating stress and sleep. In particular, presynaptic glutamatergic neurons in the lateral hypothalamus become activated after stress, and stimulating their projections to the POA promotes MAs and wakefulness. Our findings uncover a novel circuit mechanism by which POA excitatory neurons regulate sleep quality after stress.

Among the myriad of complications associated with traumatic brain injury (TBI), impairments in social behaviors and cognition have emerged as a significant area of concern. Animal models of social behavior are necessary to explore the underlying brain mechanisms contributing to chronic social impairments following brain injury. Here, we utilize large-scale brain recordings of local field potentials to identify neural signatures linked with social preference deficits following frontal brain injury. We used a controlled cortical impact model of TBI to create a severe bilateral injury centered on the prefrontal cortex. Behavior (social preference and locomotion) and brain activity (power and coherence) during a three-chamber social preference task were compared between sham and injured animals. Sham rats preferred to spend time with a social conspecific over an inanimate object. An analysis of local field oscillations showed that social preference was associated with a significant increase in coherence in gamma frequency band across widespread brain regions in these animals. Animals with a frontal TBI showed a significant reduction in this social preference, visiting an inanimate object more frequently and for more time. Reflecting these changes in social behavior, these animals also showed a significant reduction in gamma frequency (25–60 Hz) coherence associated with social preference.

Research using the model organism nematode C. elegans has greatly facilitated our understanding of sensory biology, including touch, olfaction, taste, vision and proprioception. While hearing had long been considered to be restricted to vertebrates and some arthropods, we recently discovered that C. elegans is capable of sensing and responding to airborne sound in a frequency and sound source-size-dependent manner. C. elegans auditory sensation occurs when airborne sound physically vibrates their external cuticle (skin) to activate the sound-sensitive mechanosensory FLP/PVD neurons via nicotinic acetylcholine receptors (nAChRs), triggering aversive phonotaxis behavior. Here, we report stepwise methods to characterize these three features of C. elegans auditory sensation, including sound-evoked skin vibration, neuronal activation, and behavior. This approach provides an accessible platform to investigate the cellular and molecular mechanisms underlying auditory sensation and mechanotransduction mechanisms in C. elegans.

Tinnitus is a phantom auditory sensation often accompanied by hearing loss, cognitive impairments, and psychological disturbances in various populations. Dysfunction of KCNQ2 and KCNQ3 channels—voltage-dependent potassium ion channels—in the cochlear nucleus can cause tinnitus. Despite the recognized significance of KCNQ2 and KCNQ3 channels in the auditory cortex, their precise relationship and implications in the pathogenesis of tinnitus remain areas of scientific inquiry. This study aimed to elucidate the pathological roles of KCNQ2 and KCNQ3 channels within the auditory cortex in tinnitus development and examine the therapeutic potential of mid-infrared photons for tinnitus treatment. We utilized a noise-induced tinnitus model combined with immunofluorescence, electrophysiological recording, and molecular dynamic simulation to investigate the morphological and physiological alterations after inducing tinnitus. Moreover, in vivo irradiation was administered to verify the treatment effects of infrared photons. Tinnitus was verified by deficits of the gap ratio with similar prepulse inhibition ratio and auditory brainstem response threshold. We observed an important enhancement in neuronal excitability in the auditory cortex using patch-clamp recordings, which correlated with KCNQ2 and KCNQ3 channel dysfunction. After irradiation with infrared photons, excitatory neuron firing was inhibited owing to increased KCNQ2 current resulting from structural alterations in the filter region. Meanwhile, deficits of the acoustic startle response in tinnitus animals were alleviated by infrared photons. Furthermore, infrared photons reversed the abnormal hyperexcitability of excitatory neurons in the tinnitus group. This study provided a novel method for modulating neuron excitability in the auditory cortex using KCNQ2 channels through a nonthermal effect. Infrared photons effectively mitigated tinnitus-related behaviors by suppressing abnormal neural excitability, potentially laying the groundwork for innovative therapeutic approaches for tinnitus treatment.

Recent studies have explored functional and effective neural networks in animal models; however, the dynamics of information propagation among functional modules under cognitive control remain largely unknown. Here, we addressed the issue using transfer entropy and graph theory methods on mesoscopic neural activities recorded in the dorsal premotor cortex of rhesus monkeys. We focused our study on the decision time of a Stop-signal task, looking for patterns in the network configuration that could influence motor plan maturation when the Stop signal is provided. When comparing trials with successful inhibition to those with generated movement, the nodes of the network resulted organized into four clusters, hierarchically arranged, and distinctly involved in information transfer. Interestingly, the hierarchies and the strength of information transmission between clusters varied throughout the task, distinguishing between generated movements and canceled ones and corresponding to measurable levels of network complexity. Our results suggest a putative mechanism for motor inhibition in premotor cortex: a topological reshuffle of the information exchanged among ensembles of neurons.

Chondroitin sulfate-based bioactive coating improves neuronal density and decreases biofouling and acute inflammation of neural interface devices.

Tonotopic organization of the auditory cortex has been extensively studied in many mammalian species using various methodologies and physiological preparations. Tonotopy mapping in primates, however, is more limited due to constraints such as cortical folding, use of anesthetized subjects, and mapping methodology. Here we applied a combination of through-skull and through-window intrinsic optical signal imaging, wide-field calcium imaging, and neural probe recording techniques in awake marmosets (Callithrix jacchus), a New World monkey with most of its auditory cortex located on a flat brain surface. Coarse tonotopic gradients, including a recently described rostral-temporal (RT) to parabelt gradient, were revealed by the through-skull imaging of intrinsic optical signals and were subsequently validated by single-unit recording. Furthermore, these tonotopic gradients were observed with more detail through chronically implanted cranial windows with additional verifications on the experimental design. Moreover, the tonotopy mapped by the intrinsic-signal imaging methods was verified by wide-field calcium imaging in an AAV-GCaMP labeled subject. After these validations and with further effort to expand the field of view more rostrally in both windowed and through-skull subjects, an additional putative tonotopic gradient was observed more rostrally to the area RT, which has not been previously described by the standard model of tonotopic organization of the primate auditory cortex. Together, these results provide the most comprehensive data of tonotopy mapping in an awake primate species with unprecedented coverage and details in the rostral proportion and support a caudal-rostrally arranged mesoscale organization of at least three repeats of functional gradients in the primate auditory cortex, similar to the ventral stream of primate visual cortex.

Multielectrode arrays for interfacing with neurons are of great interest for a wide range of medical applications. However, current electrodes cause damage over time. Ultra small carbon fibers help to address issues but controlling the electrode site geometry is difficult. Here we propose a methodology to create small, pointed fiber electrodes (SPFe). We compare the SPFe to previously made blowtorched fibers in characterization. The SPFe result in small site sizes [Formula: see text] with consistently sharp points (20.8 ± 7.64°). Additionally, these electrodes were able to record and/or stimulate neurons multiple animal models including rat cortex, mouse retina, Aplysia ganglia and octopus axial cord. In rat cortex, these electrodes recorded significantly higher peak amplitudes than the traditional blowtorched fibers. These SPFe may be applicable to a wide range of applications requiring a highly specific interface with individual neurons.

High‐density interconnect (HDI) technology for liquid metal (LM)‐based stretchable printed circuit boards is crucial for expanding their applicability. HDI technology provides high‐resolution multilayer circuits with a high density of components, as required for next generation of neuroprobes and ultrasonic and sensor arrays. This study presents a HDI technique utilizing laser engraved micro grooves in silicone with a protective lift‐off mask of polyvinyl alcohol (PVA) and subsequent microscale LM particle spray deposition. This approach achieves high‐resolution LM patterns and enables multilayer connectivity and high‐density integration of components simultaneously, that is, realizing HDI technology. It is demonstrated using a stretchable 0201 LED display with a density of six leads per mm 2 and a cochlear implant (CI) electrode array. The demonstrated manufacturing of the CI has the potential to enable fully automated printed circuit board manufacturing of such implants with increased precision and throughput. Implants in guinea pigs show that the CI is capable of activating the auditory neuron with electrical auditory brainstem response (eABR) and electrical compound action potential (eCAP) of high quality. Moreover, the U‐shaped cross section of the LM interconnects provides a higher mechanical shock resistance of the circuit than that of normal rectangular cross sections.

Recalling a salient experience provokes specific behaviors and changes in the physiology or internal state. Relatively little is known about how physiological memories are encoded. We examined the neural substrates of physiological memory by probing CRH PVN neurons of mice, which control the endocrine response to stress. Here we show these cells exhibit contextual memory following exposure to a stimulus with negative or positive valence. Specifically, a negative stimulus invokes a two-factor learning rule that favors an increase in the activity of weak cells during recall. In contrast, the contextual memory of positive valence relies on a one-factor rule to decrease activity of CRH PVN neurons. Finally, the aversive memory in CRH PVN neurons outlasts the behavioral response. These observations provide information about how specific physiological memories of aversive and appetitive experience are represented and demonstrate that behavioral readouts may not accurately reflect physiological changes invoked by the memory of salient experiences.

Bilateral vestibular deficiency (BVD) results in chronic dizziness, blurry vision when moving the head, and postural instability. Vestibular prostheses (VPs) show promise as a treatment, but the VP-restored vestibulo-ocular reflex (VOR) gain in human trials falls short of expectations. We hypothesize that the slope of the rising ramp in stimulation pulses plays an important role in the recruitment of vestibular afferent units. To test this hypothesis, we utilized customized programming to generate ramped pulses with different slopes, testing their efficacy in inducing electrically evoked compound action potentials (eCAPs) and current spread via bench tests and simulations in a virtual inner model created in this study. The results confirmed that the slope of the ramping pulses influenced the recruitment of vestibular afferent units. Subsequently, an optimized stimulation pulse train was identified using model simulations, exhibiting improved modulation of vestibular afferent activity. This optimized slope not only reduced the excitation spread within the semicircular canals (SCCs) but also expanded the neural dynamic range. While the model simulations exhibited promising results, in vitro and in vivo experiments are warranted to validate the findings of this study in future investigations.