Electrophysiology publications

Haptic feedback elicits sensations of touch to communicate information to the user. Recent developments in virtual reality and sensory prostheses have demonstrated the need for systems that can provide more information than the simple vibrotactor in your phone. A novel multidimensional encoding approach allows for percepts of signal intensity and flutter frequency in a single distal location using transcutaneous neural stimulation. In this study we aimed to determine if these percepts are able to convey useful information to participants performing motor control tasks and if they perform better than a typical intensity-only modulation approach. Eleven participants performed three types of tasks to assess the efficacy of multidimensional stimulation. The first set included discrete matching tasks, where participants had to differentiate between thirteen combinations of flutter frequency and intensity. In the other two sets, participants had to differentiate between simultaneous changes in the percepts. Participants in this study could correctly identify all discrete percept combinations and follow the changes in the percepts better than chance. Performance in the discrete task using a multidimensional approach showed increased information transfer compared to the individual modulation of intensity or flutter frequency. These results suggest that multidimensional encoding is a promising approach for increasing information throughput in sensory feedback systems. Hence, such an approach might improve upon conventional methods of providing graded percepts, creating more informative tactile percepts for haptic feedback through peripheral nerve stimulation.

Recent studies suggest some hippocampal (HC) neurons respond to passively presented sounds in naive subjects, but the specificity and prevalence of these responses remain unclear. We used Neuropixels probes to record unit activity across layers in mid-ventral HC and auditory cortex (ACtx) of awake, untrained mice (male and female) while presenting diverse sounds at typical environmental levels (65–70 dB SPL). A subset of HC neurons exhibited reliable, short latency responses to passive sounds, including tones and broadband noise. HC units showed evidence of tuning for tone frequency but not spectrotemporal features in continuous dynamic moving ripples. Across sound types, HC responses overwhelmingly occurred at stimulus onset; they quickly adapted to continuous sounds and did not respond at sound offset. Among all sounds tested, broadband noise was most effective at driving HC activity. Spectral manipulations indicated response prevalence scaled with increasing spectral bandwidth and density. Similar responses were also observed for visual flash and contrast-modulated noise movies, although these were less common than for broadband noise. Sound-evoked face movements, quantified by total face motion energy (FME), correlated with population-level HC activity. However, many individual units responded regardless of FME strength, suggesting both auditory and motor-correlated inputs. Together, our results show that abrupt sound onsets are sufficient to activate many HC neurons in the absence of learning or behavioral engagement. This supports a role for HC in detecting salient environmental changes and supports the idea that auditory inputs contribute directly to HC function.

The cochlear implant is a widely available hearing restoration technology that can provide speech understanding in quiet environments. This technology struggles however, in noisy settings or situations involving multiple speakers. The primary cause of these performance limitations is a poor neural interface, in which the bony wall of the cochlea separates the electrode surface from the auditory nerve fibers, thus causing unwanted current spread and non-specific frequency activation. This study utilizes an alternative auditory prosthetic technology (auditory nerve implant, ANI) that enables direct auditory nerve stimulation, which provides a potentially superior neural interface and enables more precise targeting of auditory nerve fibers than traditional cochlear implants. As auditory nerve implants progress towards clinical translation, new implant designs and stimulation strategies will be created. Animal models to efficiently test and iterate through these new designs will be useful for the continued development of ANI technology. We present a viable surgical approach in the non-human primate (rhesus macaque) along with electrophysiological results that demonstrate robust activation of the auditory system at low current levels via intraneural stimulation. Our findings indicate that the rhesus macaque, which possesses an inner ear anatomy more similar to the human compared to other animal models used in the hearing field (e.g., rodents, felines and ferrets), has strong potential as a useful preclinical testbed involving an upright head model for future ANI prototypes and stimulation strategy development.

Stories, Chirps, And Noisy Sentences (MEG-SCANS) is a dataset that provides raw magnetoencephalography (MEG) recordings from 24 German-speaking subjects. Each subject listened to approximately one hour of stimuli, including two audiobooks, sentences from the Oldenburger Matrix Sentence Test (OLSA) for Speech Reception Threshold (SRT) assessment, and short up-chirps used to assess MEG signal quality. The dataset includes MEG data, structural MRI (Magnetic Resonance Imaging) scans of the head, corresponding audio material (audiobooks, OLSA envelopes, and chirp stimuli), and behavioral audiogram and SRT results from hearing screenings. Organized according to the Brain Imaging Data Structure (BIDS), this resource offers a robust benchmark for large-scale encoding/decoding analyses of temporally-resolved brain responses to speech. Comprehensive Matlab and Python code are included to replicate key data validations, ensuring transparency and reproducibility.

The ability to associate environmental stimuli with positive outcomes is a fundamental form of learning. While extensive research has focused on midbrain dopamine neurons during associative learning, less is known about learning-mediated changes in the afferents that shape dopamine neuron responses. We demonstrate in rats that during critical phases of learning, anion homeostasis in midbrain inhibitory GABA neurons - a primary source of input to dopamine neurons - is disrupted due to downregulation of the potassium chloride cotransporter KCC2. This alteration in GABA neurons preferentially impacted lateral mesoaccumbal dopamine pathways and was not observed after learning was established. At the network level, learning-mediated KCC2 downregulation was associated with enhanced synchronization between individual GABA neurons and increased dopamine responses to rewards and reward-related stimuli. Conversely, enhancing KCC2 function during learning reduced GABA synchronization, diminished relevant dopamine signaling, and prevented cue-reward associations. Thus, circuit-specific adaptations in midbrain GABA neurons are crucial for forming new reward-related behaviors.

The CCKBR agonists induce neocortical long-term potentiation of excitatory synaptic transmission and enhance memory formation, while its antagonists weaken the potentiation in the amygdala and alleviate depression-like behaviors. However, the mechanism that drives CCKBR dependent long-term potentiation remains elusive. There is also no signaling pathway-biased CCKBR agonist to modulate the potentiation. Here, we discover a β-arrestin biased CCKBR agonist MF-8 with IC50 = 0.9 nM. The activation of CCKBR with MF-8 fails to induce the potentiation but efficiently induces CCKBR endocytosis. Multi-Electrode Array results demonstrate that the potentiation is dependent on Gαq/11-Ca2+ and Gαs-cAMP signaling pathways. The potentiation is entirely blocked by MF-8 through β-arrestin signaling. Furthermore, MF-8 effectively inhibits the formation of cue-to-cue associative fear memory. These results reveal the signal pathway preference of the CCKBR long-term potentiation and identify a blocker of the potentiation, which provides us with broader insights into developing drugs targeting CCKBR.

The hypothalamus is critical for regulating behaviors essential for survival and locomotion, but how it integrates internal needs and transmits locomotion commands to the spinal cord (SC) remains unclear. We found that glutamatergic neurons in lateral hypothalamic area (LHA) are essential for regulating motivated locomotor activity. Using single-neuron projectome analysis, trans-synaptic tracing, and optogenetic manipulation, we showed that LHA facilitates motivated locomotion during food seeking via pontine reticular nucleus, oral part (PnO) projection neurons, rather than direct SC projections or indirect stress signaling via medial septum and diagonal band. Activating PnO-SC projection neurons also initiated locomotion. Importantly, LHA-PnO projection neurons were crucial for regulating locomotor recovery following mouse spinal cord injury (SCI). Motor cortex signals gated LHA deep brain stimulation treatment markedly promoted long-term restoration of hindlimb motor functions after severe SCI. Thus, we have identified a hypothalamic-pontine-spinal pathway and the stimulation paradigm for potential therapeutic intervention after SCI.

Memory consolidation enables animals to draw on past experiences to guide future behavior. This process involves system- and synaptic-level changes and predominantly occurs during sleep. While hippocampal-cortical circuits are well studied in this context, the contributions of other systems, including dopaminergic circuits—key players in learning-related processes—remain poorly understood. Ventral tegmental area dopaminergic (VTA DA ) neurons are active during sleep and suggested to participate in memory consolidation processes; however, causal evidence for this is lacking. Using calcium-dependent fiber photometry, electrophysiology, and chemogenetic and optogenetic manipulations across learning paradigms, we explore the functions of VTA DA neuronal activity during sleep. We show that VTA DA activity during nonrapid eye movement sleep is experience dependent, is enhanced by motor skill and associative learning, facilitates motor skill memory consolidation, and exhibits a motor learning–dependent increase in temporal coordination with cortical spindle oscillations. Our findings uncover a previously unidentified function for VTA DA neurons in consolidating memories during sleep, advancing understanding of this central neuromodulator’s functions in regulating fundamental biological processes.

The insula is critical for integrating sensory information from the body with that arising from the environment. Although previous studies suggested that posterior insula is sensitive to sounds, these studies usually involved behaviorally relevant stimuli. Further, auditory response properties of the human insula have not previously been studied on the single neuron level. Here, we provide the first report of a population of human single neuron data from both anterior and posterior insula and provide comparative data from the primary auditory cortex, recorded intracranially from human participants during passive listening. In each condition, more than 340 single neurons were recorded in 12 participants of either sex. Almost a third of neurons in posterior insula and a smaller subset in anterior insula responded to simple tones and clicks. Responsive neurons were distributed throughout posterior and anterior insula and showed preferred frequency tuning. Onset latencies in insula were short, but response durations were significantly shorter than primary auditory cortex. Overall, these data show that insula neurons respond to auditory stimuli even in nonbehaviorally relevant contexts and change our understanding of this brain region, suggesting that processing basic auditory stimuli is an important integrative function of insular cortex.

Brain-wide communication supporting flexible behavior requires coordination between sensory and associative regions but how brain networks route sensory information at fast timescales to guide action remains unclear. Using human intracranial electrophysiology and spiking neural networks during spatial attention tasks, where participants detected targets at cued locations, we show that high-frequency activity bursts (HFAbs) mark temporal windows of elevated population firing that enable fast, long-range communications. HFAbs were evoked by sensory cues and targets, dynamically coupled to low-frequency rhythms. Notably, both the strength of cue-evoked HFAbs and their decoupling from slow rhythms predicted behavioral accuracy. HFAbs synchronized across the brain, revealing distinct cue- and target-activated subnetworks. These subnetworks exhibited lead-lag dynamics following target onset, with cue-activated subnetworks preceding target-activated subnetworks when cues were informative. Computational modeling suggested that HFAbs reflect transitions to population spiking, denoting temporal windows for network communications supporting attentional performance. These findings establish HFAbs as signatures of population state transitions, supporting information routing across distributed brain networks.

Damage to inner hair cells (IHCs) is a leading cause of hearing loss, typically initiating at the base region of the basilar membrane. However, the mechanisms and preventative strategies for IHC damage remain to be elucidated. This study revealed that IHCs in the low-frequency region exhibit a significantly faster calcium clearance rate than high-frequency IHCs. This difference is associated with different PMCA1 expression. We then generated an IHC-specific Pmca1 knockout mouse model ( Pmca1 CKO) exhibiting profound hearing loss and IHC death. Using single-cell RNA-seq analysis, we found that the differentially expressed genes (DEGs) were related to tetrahydrofolate biosynthesis, DNA damage, and DNA repair dysfunction. We therefore treated Pmca1 CKO mice with folic acid and found that it protected IHCs by reducing γ-H2A.X levels. In addition, we found that folic acid protected IHCs from noise-induced damage. Overall, our findings suggest that disrupted calcium homeostasis plays a role in IHC damage and that folic acid may be a promising therapeutic agent for protecting hair cells.

Spatial disorientation is emerging as an early cognitive biomarker of dementia, but the underlying neural mechanisms remain undefined. The anterodorsal nucleus of the thalamus (ADn) exhibits early and selective vulnerability to pathological misfolded forms of tau, a major hallmark of Alzheimer's disease. As the ADn contains a high density of head direction (HD) cells, we hypothesized that ptau disrupts HD cell activity, promoting spatial disorientation. To test this, we virally expressed human mutant tau in the ADn of adult wild-type and C1ql2-Cre mice. ADn-tau mice were defined by phosphorylated and oligomeric forms of tau in ADn somata and axon terminals. During initial spatial learning, ADn-tau mice exhibited increased looping behavior, indicative of spatial disorientation. Using in vivo extracellular recordings, we found that ADn cells had reduced directionality, lower directional coherence, and altered burst firing. These findings suggest that early alterations in HD signaling are predictive of future cognitive decline.

Exposure to acute intermittent hypoxia (AIH) induced sustained increases in phrenic nerve activity (phrenic long-term facilitation, pLTF) that were associated with increased nucleus tractus solitarii (nTS) neuronal Ca 2+ and action potential discharge. nTS CaMKII activity was critical for pLTF development and AIH-induced increases in neuronal discharge. In contrast, nTS NMDA receptor (NMDAR) activation, but not CaMKII activity, was required for maintaining AIH-induced pLTF. Increased nTS neuronal activity, NMDAR activation, and CaMKII are critical for AIH-induced neuroplasticity in central cardiorespiratory output.

Hearing loss is the most common sensory disorder, with a substantial proportion caused by genetic mutations. KCNQ4, a voltage-gated potassium channel highly expressed in cochlear outer hair cells, is a common genetic etiology implicated in autosomal dominant progressive hearing loss (DFNA2). The dominant-negative KCNQ4 p.W276S (c.827G>C) mutation represents a mutational hotspot in DFNA2, yet no effective treatments exist. Here, we developed allele-preferential antisense oligonucleotides (ASOs) targeting this dominant-negative KCNQ4 mutation. In a systemic in vitro screen, ASO-123 demonstrated a knockdown of mutant Kcnq4 while preserving wild-type transcripts. In a Kcnq4 p.W277S knockin mouse model mimicking DFNA2, ASO-123 preferentially suppressed mutant transcripts, attenuated progressive hearing loss, and improved outer hair cell survival while enhancing their electrophysiologic function. Comprehensive transcriptomic analyses further validated the efficacy of ASO-123. Thus, our findings establish ASO-based therapy as a promising strategy for treating hereditary hearing loss caused by dominant-negative KCNQ4 mutations.

Outer hair cells (OHCs) in the cochlea contain specialized stereociliary structures essential for auditory function. These include horizontal top connectors (HTCs), linking adjacent stereocilia and tectorial membrane (TM)-attachment crowns (ACs), anchoring the tallest stereocilia to the TM. The known molecular components of these structures, such as stereocilin, otogelin, otogelin-like, and tubby, lack transmembrane domains, suggesting the existence of anchoring proteins. This study identifies TMEM145, a transmembrane protein with a Golgi dynamics domain, as a crucial OHC stereocilia component. TMEM145 is expressed in both OHCs and spiral ganglion neurons, with specific localization to TM-ACs and HTCs in OHCs. Tmem145 knockout (KO) mice exhibit profound hearing impairment at 3 weeks of age, with complete loss of distortion product otoacoustic emissions, indicating OHC dysfunction. Immunostaining and scanning electron microscopy reveal the absence of TM-ACs and HTCs in Tmem145 KO mice. In heterologous cell systems, TMEM145 interacts with stereocilin and tubby, facilitating their extracellular secretion. TMEM145 is undetectable in Stereocilin KO and tubby mutant mice, indicating interdependence among these proteins. These findings establish TMEM145 as an essential membrane protein for the structural integrity of OHC stereocilia, providing insights into the molecular architecture of cochlear hair cells and their role in auditory function.

The anterior-lateral motor cortex (ALM) has been extensively studied as a model for understanding the cortical mechanisms involved in planning directional movements. ALM neurons show preparatory activity that predict whether the mouse will produce a left- or right-directed lick. While the neural mechanisms underlying ALM dynamics and their links to behavior are beginning to be elucidated, the sources of this directional activity remain unclear. Here, we examined the role of ALM dopaminergic circuits in mice performing a directional licking task. We report that dopamine (DA) signals and the activity of neurons expressing D1 receptors (D1R + ) tracked the preparation and execution of licking and demonstrated a bias for planning of licks aimed at the direction contralateral to the recording site. Unilateral optogenetic manipulations of D1R + neurons or DA afferents affected lateral licking in a way consistent with their role in planning contralateral movements. Together, these results show that cortical DA modulation plays an important role in the motor preparation of directional movements.

The lateral habenula (LHb) integrates cortical and basal forebrain (BF) input to control monoaminergic outflow and is implicated in depression, anxiety, impulsivity, and aversion. Although cannabis withdrawal is associated with negative affect and heightened anxiety, LHb involvement is not established. Here, effects of withdrawal from the psychoactive cannabis constituent Δ 9 -tetrahydrocannabinol (Δ 9 -THC) on LHb neurons were assessed with photometric calcium measurement during fear conditioning and in vitro electrophysiology. LHb calcium signals were larger during footshock, and presentation of a tone paired with footshock in Δ 9 -THC withdrawn rats. Fear-induced freezing to the tone was also larger during Δ 9 -THC withdrawal. Electrophysiology revealed larger LHb excitatory-inhibitory (E-I) ratios during Δ 9 -THC withdrawal, resulting from impaired synaptic GABA release. Moreover, GABA release via optogenetic activation of BF-LHb inputs was impaired during Δ 9 -THC withdrawal, whereas no changes occurred at ventral tegmental area-LHb inputs. Recovery of BF-LHb GABA release and cannabinoid CB1 receptor desensitization were incomplete at 30 days of Δ 9 -THC withdrawal. The data show that LHb responsivity to primary aversive and conditioned stimuli are increased during Δ 9 -THC withdrawal, and that this is likely mediated by altered E-I balance. We propose negative affect experienced during cannabis withdrawal is related to LHb hypersensitivity to aversive stimuli and this facilitates encoding of associated environmental cues.

Species recognition is essential for reproductive isolation and plays a central role in the evolution of mating signals. In acoustically communicating species, temporal features of calls are critical for distinguishing conspecific from heterospecific signals. Anurans rely heavily on the precise timing of pulse trains for mate recognition. Females of Hyla chrysoscelis use the species-specific temporal structure of male advertisement (Adv) calls-specifically pulse rate (PR)-to select mates. For stimuli with the Adv call PR (40-60 pulses/s), females require at least ~ 6-7 pulses to approach a sound source, implicating interval-counting neurons (ICNs) in call recognition. To test this model and further investigate the neural basis of this temporal selectivity, we used behavioral and neurophysiological approaches. We lengthened interpulse intervals (IPIs) in pulse trains either at a single midpoint or in an alternating fashion while holding pulse number and, thus, stimulus energy constant. In phonotaxis assays, females showed sharply reduced responses when even one IPI was lengthened twofold or more, revealing high sensitivity to temporal irregularity. Single-unit in vivo extracellular recordings from the auditory midbrain revealed that ICNs exhibited a progressive decline in activity with increasing IPI length, closely mirroring behavioral trends. In contrast, long-interval neurons (LINs) responded more strongly to temporally irregular stimuli. These results support the hypothesis that ICNs mediate behavioral selectivity for conspecific Adv call temporal patterns, whereas LINs may contribute to processing other call types. Our study directly links a defined neuronal population to natural behavior, underscoring how midbrain temporal computations underlie species-specific recognition in Hyla chrysoscelis.

Objective. Infrared neural stimulation (INS) has emerged as a potent neuromodulation technology, offering safe and focal stimulation with superior spatial recruitment profiles compared to conventional electrical methods. However, the neural dynamics induced by INS stimulation remain poorly understood. Elucidating these dynamics will help develop new INS stimulation paradigms and advance its clinical application. Approach. In this study, we assessed the local network dynamics of INS entrainment in the auditory thalamocortical circuit using the chronically implanted rat model. Our approach focused on measuring INS energy-based local field potential (LFP) recruitment induced by focal thalamocortical stimulation. We further characterized linear and nonlinear oscillatory LFP activity in response to single-pulse and periodic INS and performed spectral decomposition to uncover specific LFP band entrainment to INS. Finally, we examined spike-field transformations across the thalamocortical synapse using spike-LFP coherence coupling measures. Main results. We found that INS significantly increases LFP amplitude as a log-linear function of INS energy per pulse, primarily entraining to LFP β and γ bands with synchrony extending to 200 Hz in some cases. A subset of neurons demonstrated nonlinear, chaotic oscillations linked to information transfer across cortical circuits. Finally, we utilized spike-field coherences to correlate spike coupling to LFP frequency band activity and suggest an energy-dependent model of network activation resulting from INS stimulation. Significance. We show that INS reliably drives robust network activity and can potently modulate cortical field potentials across a wide range of frequencies in a stimulus parameter-dependent manner. Based on these results, we propose design principles for developing full coverage, all-optical thalamocortical auditory neuroprostheses.

Obective. Bipolar re-referencing (BPRR), in which one electrode’s signal is subtracted from a neighboring electrode to produce a differential signal, can improve signal readability and refine localization for intracranial electroencephalography. There is wide variation in manufactured electrode array spacing, yet how BPRR affects specific frequencies at precise inter-electrode distances has not been systematically evaluated. Approach. Intracranial recordings with uniquely large numbers of electrodes were obtained for sixteen patients with drug-resistant epilepsy. We evaluated combinations of high-density subdural grid, depth, and strip electrodes ( n = 3,664, 742, and 336) with manufactured linear inter-electrode distances of 4, 5, and 10 mm, respectively. BPRR was performed using all possible electrode pairs ( n = 445 305 grid, 16 004 depth, 3278 strip) spanning distances from 2–60 mm. Multi-taper power spectra were generated separately for grid, depth, and strip contacts. Distances were consolidated across patients and anatomical areas for generalizability, and distance-related influences on task-related brain activity and quantitative interictal epileptiform discharge localization were evaluated. Main results. We identified 8 mm as a consistent reversal point for BPRR, below which low-frequency signals (<30 Hz) had consistently decreased power, and higher frequencies had increased power. Larger distances increased all broadband (2–200 Hz) signals. Task-related increases in superior temporal gyrus 50–200 Hz activity were consistently enhanced across 4–40 mm bipolar distances. There were non-significant difference trends between 4 and 8 mm re-referencing on epileptiform discharge detection. Significance. BPRR distance imposed specific transition points for distance and frequency (roughly 8 mm and ∼30 Hz, respectively) that produced differential effects on measurements of signal power. The consistency across brain regions and electrode types (depth, subdural) suggests these influences are physical brain bio-signal properties, potentially related to spatial wavelength of periodic oscillations in lower frequencies in contrast to more aperiodic activity in higher frequencies. A distance-frequency relation map is provided to help optimize neural signal biomarker quality for intracranial applications by guiding strategic re-referencing distance selection.