Electrophysiology publications

Sensory hypersensitivity, especially in the auditory system, is a common symptom in Fragile X syndrome (FXS), the most common monogenic form of intellectual disability. However, linking phenotypes across genetic background strains of mouse models has been a challenge and could underly some of the issues with translatability of drug studies to the human condition. This study is the first to characterize the auditory brain stem response (ABR), a minimally invasive physiological readout of early auditory processing that is also used in humans, in a commonly used mouse background strain model of FXS, C57BL/6J. We measured morphological features of pinna and head and used ABR to measure the hearing range, and monaural and binaural auditory responses in hemizygous males, homozygous females, and heterozygous females compared with those in wild-type mice. Consistent with previous study, we showed no difference in morphological parameters across genotypes or sexes. There was no significant difference in hearing range between the sexes or genotypes, however there was a trend towards high frequency hearing loss in male FXS mice. In contrast, female mice with homozygous FXS had a decreased amplitude of wave IV of the monaural ABR, while there was no difference in males for amplitudes and no change in latency of ABR waveforms across sexes and genotypes. Finally, males with FXS had an increased latency of the binaural interaction component (BIC) at 0 interaural timing difference compared with that in wild-type males. These findings further clarify auditory brain stem processing in FXS by adding more information across genetic background strains allowing for a better understanding of shared phenotypes.

Neuropeptides are contained in nearly every neuron in the central nervous system and can be released from somatodendritic sites as well as from nerve terminals. Cholecystokinin (CCK), among the most abundant neuropeptides in the brain, is expressed in the majority of midbrain dopamine neurons. Here we report that ventral tegmental area (VTA) dopamine neurons release CCK from somatodendritic regions, where it triggers long-term potentiation of GABAergic synapses. The somatodendritic release occurs with trains of action potentials or prolonged but modest depolarization and is dependent on synaptotagmin 7 and T-type Ca 2+ channels. Depolarization-induced LTP is blocked by the CCK2R antagonist, LY225910, and mimicked by exogenously added CCK. To test the behavioral role of CCK, we infused it into the mouse VTA. Ca 2+ imaging in vivo demonstrated that infused CCK reduced dopamine cell signals during fasted food consumption. Moreover, local infusion of CCK also inhibited food consumption and decreased distance traveled in an open field test. Together our experiments introduce somatodendritic neuropeptide release as a previously unknown feedback regulator of VTA dopamine cell excitability and dopamine-related behaviors.

During conversation, people take turns speaking by rapidly responding to their partners while simultaneously avoiding interruption1,2. Such interactions display a remarkable degree of coordination, as gaps between turns are typically about 200 milliseconds3-approximately the duration of an eyeblink4. These latencies are considerably shorter than those observed in simple word-production tasks, which indicates that speakers often plan their responses while listening to their partners2. Although a distributed network of brain regions has been implicated in speech planning5-9, the neural dynamics underlying the specific preparatory processes that enable rapid turn-taking are poorly understood. Here we use intracranial electrocorticography to precisely measure neural activity as participants perform interactive tasks, and we observe a functionally and anatomically distinct class of planning-related cortical dynamics. We localize these responses to a frontotemporal circuit centred on the language-critical caudal inferior frontal cortex10 (Broca's region) and the caudal middle frontal gyrus-a region not normally implicated in speech planning11-13. Using a series of motor tasks, we then show that this planning network is more active when preparing speech as opposed to non-linguistic actions. Finally, we delineate planning-related circuitry during natural conversation that is nearly identical to the network mapped with our interactive tasks, and we find this circuit to be most active before participant speech during unconstrained turn-taking. Therefore, we have identified a speech planning network that is central to natural language generation during social interaction.

Listeners with sensorineural hearing loss (SNHL) struggle to understand speech, especially in noise, despite audibility compensation. These real-world suprathreshold deficits are hypothesized to arise from degraded frequency tuning and reduced temporal-coding precision; however, peripheral neurophysiological studies testing these hypotheses have been largely limited to in-quiet artificial vowels. Here, we measured single auditory-nerve-fiber responses to a connected speech sentence in noise from anesthetized male chinchillas with normal hearing (NH) or noise-induced hearing loss (NIHL). Our results demonstrated that temporal precision was not degraded following acoustic trauma, and furthermore that sharpness of cochlear frequency tuning was not the major factor affecting impaired peripheral coding of connected speech in noise. Rather, the loss of cochlear tonotopy, a hallmark of NH, contributed the most to both consonant-coding and vowel-coding degradations. Because distorted tonotopy varies in degree across etiologies (e.g., noise exposure, age), these results have important implications for understanding and treating individual differences in speech perception for people suffering from SNHL. SIGNIFICANCE STATEMENT Difficulty understanding speech in noise is the primary complaint in audiology clinics and can leave people with sensorineural hearing loss (SNHL) suffering from communication difficulties that affect their professional, social, and family lives, as well as their mental health. We measured single-neuron responses from a preclinical SNHL animal model to characterize salient neural-coding deficits for naturally spoken speech in noise. We found the major mechanism affecting neural coding was not a commonly assumed factor, but rather a disruption of tonotopicity, the systematic mapping of acoustic frequency to cochlear place that is a hallmark of normal hearing. Because the degree of distorted tonotopy varies across hearing-loss etiologies, these results have important implications for precision audiology approaches to diagnosis and treatment of SNHL.

Dopamine degeneration in Parkinson's disease (PD) dysregulates the striatal neural network and causes motor deficits. However, it is unclear how altered striatal circuits relate to dopamine-acetylcholine chemical imbalance and abnormal local field potential (LFP) oscillations observed in PD. We perform a multimodal analysis of the dorsal striatum using cell-type-specific calcium imaging and LFP recording. We reveal that dopamine depletion selectively enhances LFP beta oscillations during impaired locomotion, supporting beta oscillations as a biomarker for PD. We further demonstrate that dynamic cholinergic interneuron activity during locomotion remains unaltered, even though cholinergic tone is implicated in PD. Instead, dysfunctional striatal output arises from elevated coordination within striatal output neurons, which is accompanied by reduced locomotor encoding of parvalbumin interneurons and transient pathological LFP high-gamma oscillations. These results identify a pathological striatal circuit state following dopamine depletion where distinct striatal neuron subtypes are selectively coordinated with LFP oscillations during locomotion.

We report on the ensemble organization of interneuronal activity in the spinal cord during locomotor movements and show that lumbar intermediate zone interneurons organize in two groups related to the two major phases of walking: stance and swing. Ensemble organization is also shown to better correlate with muscular output than single-cell activity, although ensemble membership does not appear to be somatotopically organized within the spinal cord.

The human hand is unique in the animal kingdom for unparalleled dexterity, ranging from complex prehension to fine finger individuation. How does the brain represent such a diverse repertoire of movements? We evaluated mesoscale neural dynamics across the human "grasp network," using electrocorticography and dimensionality reduction methods, for a repertoire of hand movements. Strikingly, we found that the grasp network represented both finger and grasping movements alike. Specifically, the manifold characterizing the multi-areal neural covariance structure was preserved during all movements across this distributed network. In contrast, latent neural dynamics within this manifold were surprisingly specific to movement type. Aligning latent activity to kinematics further uncovered distinct submanifolds despite similarities in synergistic coupling of joints between movements. We thus find that despite preserved neural covariance at the distributed network level, mesoscale dynamics are compartmentalized into movement-specific submanifolds; this mesoscale organization may allow flexible switching between a repertoire of hand movements.

Novelty detection is a primitive subcomponent of cognitive control that can be deficient in Parkinson's disease (PD) patients. Here, we studied the corticostriatal mechanisms underlying novelty-response deficits. In participants with PD, we recorded from cortical circuits with scalp-based electroencephalography (EEG) and from subcortical circuits using intraoperative neurophysiology during surgeries for implantation of deep brain stimulation (DBS) electrodes. We report three major results. First, novel auditory stimuli triggered midfrontal low-frequency rhythms; of these, 1-4 Hz "delta" rhythms were linked to novelty-associated slowing, whereas 4-7 Hz "theta" rhythms were specifically attenuated in PD. Second, 32% of subthalamic nucleus (STN) neurons were response-modulated; nearly all (94%) of these were also modulated by novel stimuli. Third, response-modulated STN neurons were coherent with midfrontal 1-4 Hz activity. These findings link scalp-based measurements of neural activity with neuronal activity in the STN. Our results provide insight into midfrontal cognitive control mechanisms and how purported hyperdirect frontobasal ganglia circuits evaluate new information.

Recent studies have established significant anatomical and functional connections between visual areas and primary auditory cortex (A1), which may be important for cognitive processes such as communication and spatial perception. These studies have raised two important questions: First, which cell populations in A1 respond to visual input and/or are influenced by visual context? Second, which aspects of sound encoding are affected by visual context? To address these questions, we recorded single-unit activity across cortical layers in awake mice during exposure to auditory and visual stimuli. Neurons responsive to visual stimuli were most prevalent in the deep cortical layers and included both excitatory and inhibitory cells. The overwhelming majority of these neurons also responded to sound, indicating unimodal visual neurons are rare in A1. Other neurons for which sound-evoked responses were modulated by visual context were similarly excitatory or inhibitory but more evenly distributed across cortical layers. These modulatory influences almost exclusively affected sustained sound-evoked firing rate (FR) responses or spectrotemporal receptive fields (STRFs); transient FR changes at stimulus onset were rarely modified by visual context. Neuron populations with visually modulated STRFs and sustained FR responses were mostly non-overlapping, suggesting spectrotemporal feature selectivity and overall excitability may be differentially sensitive to visual context. The effects of visual modulation were heterogeneous, increasing and decreasing STRF gain in roughly equal proportions of neurons. Our results indicate visual influences are surprisingly common and diversely expressed throughout layers and cell types in A1, affecting nearly one in five neurons overall.

Dysregulated homeostasis of neural activity has been hypothesized to drive Alzheimer's disease (AD) pathogenesis. AD begins with a decades-long presymptomatic phase, but whether homeostatic mechanisms already begin failing during this silent phase is unknown. We show that before the onset of memory decline and sleep disturbances, familial AD (fAD) model mice display no deficits in CA1 mean firing rate (MFR) during active wakefulness. However, homeostatic down-regulation of CA1 MFR is disrupted during non-rapid eye movement (NREM) sleep and general anesthesia in fAD mouse models. The resultant hyperexcitability is attenuated by the mitochondrial dihydroorotate dehydrogenase (DHODH) enzyme inhibitor, which tunes MFR toward lower set-point values. Ex vivo fAD mutations impair downward MFR homeostasis, resulting in pathological MFR set points in response to anesthetic drug and inhibition blockade. Thus, firing rate dyshomeostasis of hippocampal circuits is masked during active wakefulness but surfaces during low-arousal brain states, representing an early failure of the silent disease stage.

How we distinguish multiple simultaneous stimuli is uncertain, particularly given that such stimuli sometimes recruit largely overlapping populations of neurons. One commonly proposed hypothesis is that the sharpness of tuning curves might change to limit the number of stimuli driving any given neuron when multiple stimuli are present. To test this hypothesis, we recorded the activity of neurons in the inferior colliculus while monkeys made saccades to either one or two simultaneous sounds differing in frequency and spatial location. Although monkeys easily distinguished simultaneous sounds (~90% correct performance), the frequency selectivity of inferior colliculus neurons on dual‐sound trials did not improve in any obvious way. Frequency selectivity was degraded on dual‐sound trials compared to single‐sound trials: neural response functions broadened and frequency accounted for less of the variance in firing rate. These changes in neural firing led a maximum‐likelihood decoder to perform worse on dual‐sound trials than on single‐sound trials. These results fail to support the hypothesis that changes in frequency response functions serve to reduce the overlap in the representation of simultaneous sounds. Instead, these results suggest that alternative possibilities, such as recent evidence of alternations in firing rate between the rates corresponding to each of the two stimuli, offer a more promising approach.

Causal perturbations suggest that the primate dorsal pulvinar (dPul) plays a crucial role in target selection and saccade planning, but its basic visuomotor neuronal properties are unclear. While some functional aspects of dPul and interconnected frontoparietal areas – e.g. ipsilesional choice bias after inactivation – are similar, it is unknown if dPul shares oculomotor properties of the cortical circuitry, in particular the delay and choice-related activity. We investigated such properties in macaque dPul during instructed and free-choice memory saccades. Most recorded units showed visual (16%), visuomotor (29%) or motor-related (35%) responses. Visual responses were mainly contralateral; motor-related responses were predominantly post-saccadic (64%) and showed weak contralateral bias. Pre-saccadic enhancement was infrequent (9-15%) – instead, activity was often suppressed during saccade planning (30%) and execution (19%). Surprisingly, only few units exhibited classical visuomotor patterns combining cue and continuous delay activity until the saccade or pre-saccadic ramping, and most spatially-selective neurons did not encode the upcoming decision during free-choice delay. Thus, in absence of a visible goal, the dorsal pulvinar has a limited role in prospective saccade planning, with patterns partially complementing its frontoparietal partners. Conversely, prevalent cue and post-saccadic responses imply the participation in integrating spatial goals with processing across saccades.

Significance The human voice contains information about a speaker's identity and emotional state. How the brain processes the human voice remains largely unknown. We recorded electrocorticographic signals from intracranial electrodes implanted in epilepsy patients while they listened to different categories of voice and nonvoice sounds. We identified several spatially distinct “voice patches” in the temporal lobe that exhibited preferences for human voices. Further analyses suggested that the voice patches are functionally connected, and form a dual-directional hierarchical network for voice processing. This study provides clear evidence to demonstrate the existence of an interconnected “voice patch system” in the human brain, which is analogous to the face patch system of primate visual cortex, suggesting similar cortical architectures for processing faces and voices.

Significance Impulsive overeating is a common, disabling feature of eating disorders. Calcium imaging using fiber photometry has emerged as an in vivo methodology to measure neuronal population activity immune to electrical stimulation artifact from deep brain stimulation (DBS). Thus, when used simultaneously, calcium imaging can elucidate poorly understood DBS mechanisms. We show that nucleus accumbens D1 medial spiny calcium signaling increases in preparation of hedonic feeding of high-fat food. Further, responsive, over continuous, DBS strategies effectively disrupt this activity leading to decreased consumption. Implementation of this methodology to better understand mechanisms of these and other forms of neuromodulation for various indications may help advance the field to identify novel therapeutic targets with applications extending beyond obesity.

Mutations in a number of genes encoding mitochondrial aminoacyl-tRNA synthetases lead to non-syndromic and/or syndromic sensorineural hearing loss in humans, while their cellular and physiological pathology in cochlea has rarely been investigated in vivo . In this study, we showed that histidyl-tRNA synthetase HARS2, whose deficiency is associated with Perrault syndrome 2 (PRLTS2), is robustly expressed in postnatal mouse cochlea including the outer and inner hair cells. Targeted knockout of Hars2 in mouse hair cells resulted in delayed onset (P30), rapidly progressive hearing loss similar to the PRLTS2 hearing phenotype. Significant hair cell loss was observed starting from P45 following elevated reactive oxygen species (ROS) level and activated mitochondrial apoptotic pathway. Despite of normal ribbon synapse formation, whole-cell patch clamp of the inner hair cells revealed reduced calcium influx and compromised sustained synaptic exocytosis prior to the hair cell loss at P30, consistent with the decreased supra-threshold wave I amplitudes of the auditory brainstem response. Starting from P14, increasing proportion of morphologically abnormal mitochondria was observed by transmission electron microscope, exhibiting swelling, deformation, loss of cristae and emergence of large intrinsic vacuoles that are associated with mitochondrial dysfunction. Though the mitochondrial abnormalities are more prominent in inner hair cells, it is the outer hair cells suffering more severe cell loss. Taken together, our results suggest that conditional knockout of Hars2 in mouse cochlear hair cells leads to accumulating mitochondrial dysfunction and ROS stress, triggers progressive hearing loss highlighted by hair cell synaptopathy and apoptosis, and is differentially perceived by inner and outer hair cells.

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

Prevailing theories of the neural basis of at least a subset of individuals with autism spectrum disorder (ASD) include an imbalance of excitatory and inhibitory neurotransmission. These circuitry imbalances are commonly probed in adults using auditory steady-state responses (ASSR, driven at 40 Hz) to elicit coherent electrophysiological responses (EEG/MEG) from intact circuitry. Challenges to the ASSR methodology occur during development, where the optimal ASSR driving frequency may be unknown. An alternative approach (more agnostic to driving frequency) is the amplitude-modulated (AM) sweep in which the amplitude of a tone (with carrier frequency 500 Hz) is modulated as a sweep from 10 to 100 Hz over the course of ∼15 s. Phase synchrony of evoked responses, measured via intra-trial coherence, is recorded (by EEG or MEG) as a function of frequency. We applied such AM sweep stimuli bilaterally to 40 typically developing and 80 children with ASD, aged 6–18 years. Diagnoses were confirmed by DSM-5 criteria as well as autism diagnostic observation schedule (ADOS) observational assessment. Stimuli were presented binaurally during MEG recording and consisted of 20 AM swept stimuli (500 Hz carrier; sweep 10–100 Hz up and down) with a duration of ∼30 s each. Peak intra-trial coherence values and peak response frequencies of source modeled responses (auditory cortex) were examined. First, the phase synchrony or inter-trial coherence (ITC) of the ASSR is diminished in ASD; second, hemispheric bias in the ASSR, observed in typical development (TD), is maintained in ASD, and third, that the frequency at which the peak response is obtained varies on an individual basis, in part dependent on age, and with altered developmental trajectories in ASD vs. TD. Finally, there appears an association between auditory steady-state phase synchrony (taken as a proxy of neuronal circuitry integrity) and clinical assessment of language ability/impairment. We concluded that (1) the AM sweep stimulus provides a mechanism for probing ASSR in an unbiased fashion, during developmental maturation of peak response frequency, (2) peak frequencies vary, in part due to developmental age, and importantly, (3) ITC at this peak frequency is diminished in ASD, with the degree of ITC disturbance related to clinically assessed language impairment.

Significance Our current understanding of how sleep is regulated is based upon the model of sleep homeostasis, which defines a variable called Process S as a measure of sleep need, and a so-called “flip-flop” model of state switching, which builds on a notion of a mutually antagonistic relationship between subcortical sleep-promoting and wake-promoting circuits. The neurobiological substrates of the interaction between the sleep switch and Process S are unknown. Our study identifies a previously unrecognized role of hypothalamic circuitry in tuning within-state brain activity or levels of arousal, which in turn determine the homeostatic drive for sleep.

Dominant neuroanatomical models hold that humans regulate their movements via loop-like cortico-subcortical networks, which include the subthalamic nucleus (STN), motor thalamus, and sensorimotor cortex (SMC). Inhibitory commands across these networks are purportedly sent via transient, burst-like signals in the β frequency (15–29 Hz). However, since human depth-recording studies are typically limited to one recording site, direct evidence for this proposition is hitherto lacking. Here, we present simultaneous multi-site recordings from SMC and either STN or motor thalamus in humans performing the stop-signal task. In line with their purported function as inhibitory signals, subcortical β-bursts were increased on successful stop-trials. STN bursts in particular were followed within 50 ms by increased β-bursting over SMC. Moreover, between-site comparisons (including in a patient with simultaneous recordings from SMC, thalamus, and STN) confirmed that β-bursts in STN temporally precede thalamic β-bursts. This highly unique set of recordings provides empirical evidence for the role of β-bursts in conveying inhibitory commands along long-proposed cortico-subcortical networks underlying movement regulation in humans.

Understanding communication signals, especially in noisy environments, is crucial to social interactions. Yet, as we age, acoustic signals can be disrupted by cochlear damage and the subsequent auditory nerve fibre degeneration. The most vulnerable medium‐ and high‐threshold‐auditory nerve fibres innervate various cell types in the cochlear nucleus, among which the small cells are unique in receiving this input exclusively. Furthermore, small cells project to medial olivocochlear (MOC) neurons, which in turn send branched collaterals back into the small cell cap. Here, we use single‐unit recordings to characterise small cell firing characteristics and demonstrate superior intensity coding in this cell class. We show converse effects when activating/blocking the MOC system, demonstrating that small‐cell unique coding properties are facilitated by direct cholinergic input from the MOC system. Small cells also maintain tone‐level coding in the presence of background noise. Finally, small cells precisely code low‐frequency modulation more accurately than other ventral cochlear nucleus cell types, demonstrating accurate envelope coding that may be important for vocalisation processing. These results highlight the small cell olivocochlear circuit as a key player in signal processing in noisy environments, which may be selectively degraded in ageing or after noise insult. Key points Cochlear nucleus small cells receive input from low/medium spontaneous rate auditory nerve fibres and medial olivocochlear neurons. Electrical stimulation of medial olivocochlear neurons in the ventral nucleus of the trapezoid body and blocking cholinergic input to small cells using atropine demonstrates an excitatory cholinergic input to small cells, which increases responses to suprathreshold sound. Unique inputs to small cells produce superior sound intensity coding. This coding of intensity is preserved in the presence of background noise, an effect exclusive to this cell type in the cochlear nucleus. These results suggest that small cells serve an essential function in the ascending auditory system, which may be relevant to disorders such as hidden hearing loss.