Record Neural Activity Research Articles

Stimulus-Specific Prediction Error Neurons in Mouse Auditory Cortex.

Comparing expectation with experience is an important neural computation performed throughout the brain and is a hallmark of predictive processing. Experiments that alter the sensory outcome of an animal's behavior reveal enhanced neural responses to unexpected self-generated stimuli, indicating that populations of neurons in sensory cortex may reflect prediction errors (PEs), mismatches between expectation and experience. However, enhanced neural responses to self-generated stimuli could also arise through nonpredictive mechanisms, such as the movement-based facilitation of a neuron's inherent sound responses. If sensory prediction error neurons exist in sensory cortex, it is unknown whether they manifest as general error responses, or respond with specificity to errors in distinct stimulus dimensions. To answer these questions, we trained mice of either sex to expect the outcome of a simple sound-generating behavior and recorded auditory cortex activity as mice heard either the expected sound or sounds that deviated from expectation in one of multiple distinct dimensions. Our data reveal that the auditory cortex learns to suppress responses to self-generated sounds along multiple acoustic dimensions simultaneously. We identify a distinct population of auditory cortex neurons that are not responsive to passive sounds or to the expected sound but that encode prediction errors. These prediction error neurons are abundant only in animals with a learned motor-sensory expectation, and encode one or two specific violations rather than a generic error signal. Together, these findings reveal that cortical predictions about self-generated sounds have specificity in multiple simultaneous dimensions and that cortical prediction error neurons encode specific violations from expectation.SIGNIFICANCE STATEMENT Audette et. al record neural activity in the auditory cortex while mice perform a sound-generating forelimb movement and measure neural responses to sounds that violate an animal's expectation in different ways. They find that predictions about self-generated sounds are highly specific across multiple stimulus dimensions and that a population of typically nonsound-responsive neurons respond to sounds that violate an animal's expectation in a specific way. These results identify specific prediction error (PE) signals in the mouse auditory cortex and suggest that errors may be calculated early in sensory processing.

A Novel Head-Fixed Assay for Social Touch in Mice Uncovers Aversive Responses in Two Autism Models.

Social touch, an important aspect of social interaction and communication, is essential to kinship across animal species. How animals experience and respond to social touch has not been thoroughly investigated, in part because of the lack of appropriate assays. Previous studies that examined social touch in freely moving rodents lacked the necessary temporal and spatial control over individual touch interactions. We designed a novel head-fixed assay for social touch in mice, in which the experimenter has complete control to elicit highly stereotyped bouts of social touch between two animals. The user determines the number, duration, context, and type of social touch interactions, while monitoring an array of complex behavioral responses with high resolution cameras. We focused on social touch to the face because of its high translational relevance to humans. We validated this assay in two different models of autism spectrum disorder (ASD), the Fmr1 knock-out (KO) model of Fragile X syndrome (FXS) and maternal immune activation (MIA) mice. We observed higher rates of avoidance running, hyperarousal, and aversive facial expressions (AFEs) to social touch than to object touch, in both ASD models compared with controls. Fmr1 KO mice showed more AFEs to mice of the same sex but whether they were stranger or familiar mice mattered less. Because this new social touch assay for head-fixed mice can be used to record neural activity during repeated bouts of social touch it could be used to uncover underlying circuit differences.SIGNIFICANCE STATEMENT Social touch is important for communication in animals and humans. However, it has not been extensively studied and current assays to measure animals' responses to social touch have limitations. We present a novel head-fixed assay to quantify how mice respond to social facial touch with another mouse. We validated this assay in autism mouse models since autistic individuals exhibit differences in social interaction and touch sensitivity. We find that mouse models of autism exhibit more avoidance, hyperarousal, and aversive facial expressions (AFEs) to social touch compared with controls. Thus, this novel assay can be used to investigate behavioral responses to social touch and the underlying brain mechanisms in rodent models of neurodevelopmental conditions, and to evaluate therapeutic responses in preclinical studies.

Fabrication and characterization of flexible microelectrode arrays for the long-term recording of mammalian brain slices

Abstract A profound understanding of brain disorders is essential for developing more effective treatments, targeted therapies, and reliable diagnoses. Electrical in vitro long-term and repetitive measurements give insight to neural activity of more complex neural circuits and, thus, into malfunctioning caused by illness. Flexible microelectrode arrays (flexMEAs) enable the recording of neural activity with promising spatial and temporal resolution over longer durations. The present study aims to combine the long-term recording by flexMEAs with the cultivation of brain slices inside an incubator. An 8 μm-thin flexMEA with up to 256 electrodes with 30 μm in diameter and interelectrode spacing of 200 μm was fabricated. Characterization showed uniform and reproducible electronic characteristics. Coating with PEDOT:PSS by electropolymerization formed stable low-impedance spectra. The platform is ready for future experiments with brain slices inside an incubator.

Exploring retinal ganglion cells encoding to multi-modal stimulation using 3D microelectrodes arrays.

Microelectrode arrays (MEA) are extensively utilized in encoding studies of retinal ganglion cells (RGCs) due to their capacity for simultaneous recording of neural activity across multiple channels. However, conventional planar MEAs face limitations in studying RGCs due to poor coupling between electrodes and RGCs, resulting in low signal-to-noise ratio (SNR) and limited recording sensitivity. To overcome these challenges, we employed photolithography, electroplating, and other processes to fabricate a 3D MEA based on the planar MEA platform. The 3D MEA exhibited several improvements compared to planar MEA, including lower impedance (8.73 ± 1.66kΩ) and phase delay (-15.11° ± 1.27°), as well as higher charge storage capacity (CSC = 10.16 ± 0.81mC/cm2), cathodic charge storage capacity (CSCc = 7.10 ± 0.55mC/cm2), and SNR (SNR = 8.91 ± 0.57). Leveraging the advanced 3D MEA, we investigated the encoding characteristics of RGCs under multi-modal stimulation. Optical, electrical, and chemical stimulation were applied as sensory inputs, and distinct response patterns and response times of RGCs were detected, as well as variations in rate encoding and temporal encoding. Specifically, electrical stimulation elicited more effective RGC firing, while optical stimulation enhanced RGC synchrony. These findings hold promise for advancing the field of neural encoding.

Improving Fast Ripples Recording with Model-Guided Design of Microelectrodes.

Microelectrodes allow for the recording of neural activities with a high spatial resolution. However, their small sizes result in high impedance causing high thermal noise and poor signal-to-noise ratio. In drug-resistant epilepsy, the accurate detection of Fast Ripples (FRs; 250-600 Hz) can help in the identification of epileptogenic networks and Seizure Onset Zone (SOZ). Consequently, good-quality recordings are instrumental to improve surgical outcome. In this work, we propose a novel model-based approach for the design of microelectrodes optimized for FRs recording. A 3D microscale computational model was developed to simulate FRs generated in the hippocampus (CA1 subfield). It was coupled with a model of the Electrode-Tissue Interface (ETI) that accounts for the biophysical properties of the intracortical microelectrode. This hybrid model was used to analyze the microelectrode geometrical (diameter, position, and direction) and physical (materials, coating) characteristics and their impact on recorded FRs. For model validation, experimental signals (local field potentials, LFPs) were recorded from CA1 using different electrode materials: stainless steel (SS), gold (Au) and Au coated with poly(3,4-ethylene dioxythiophene) /Poly(styrene sulfonate) (Au:PEDOT/PSS). results indicated that a radius between 65 and 120 μm for a wire microelectrode is the most optimal for recording FRs. In addition, in silico and in vivo quantified results showed a possible improvement in FRs observability using PEDOT/PSS coated microelectrodes. the optimization of the design of microelectrodes for FRs recording can improve the observability and detectability of FRs which are a recognized marker of epileptogenicity. This model-based approach can assist in the design of hybrid electrodes (micro, macro) that can be used in the presurgical evaluation of epileptic patients with drug-resistant epilepsy.

Mast cells link immune sensing to antigen-avoidance behaviour

The physiological functions of mast cells remain largely an enigma. In the context of barrier damage, mast cells are integrated in type 2 immunity and, together with immunoglobulin E (IgE), promote allergic diseases. Allergic symptoms may, however, facilitate expulsion of allergens, toxins and parasites and trigger future antigen avoidance1–3. Here, we show that antigen-specific avoidance behaviour in inbred mice4,5 is critically dependent on mast cells; hence, we identify the immunological sensor cell linking antigen recognition to avoidance behaviour. Avoidance prevented antigen-driven adaptive, innate and mucosal immune activation and inflammation in the stomach and small intestine. Avoidance was IgE dependent, promoted by Th2 cytokines in the immunization phase and by IgE in the execution phase. Mucosal mast cells lining the stomach and small intestine rapidly sensed antigen ingestion. We interrogated potential signalling routes between mast cells and the brain using mutant mice, pharmacological inhibition, neural activity recordings and vagotomy. Inhibition of leukotriene synthesis impaired avoidance, but overall no single pathway interruption completely abrogated avoidance, indicating complex regulation. Collectively, the stage for antigen avoidance is set when adaptive immunity equips mast cells with IgE as a telltale of past immune responses. On subsequent antigen ingestion, mast cells signal termination of antigen intake. Prevention of immunopathology-causing, continuous and futile responses against per se innocuous antigens or of repeated ingestion of toxins through mast-cell-mediated antigen-avoidance behaviour may be an important arm of immunity.

The mode is the message

In this issue of Neuron, Khazali etal.1 record neural activity during coordinated reaches and saccades. They find that excitatory neurons link arm and eye movement regions of parietal cortex, creating a multiregional mode that predicts movement timing and direction.

Omission responses in local field potentials in rat auditory cortex

BackgroundNon-invasive recordings of gross neural activity in humans often show responses to omitted stimuli in steady trains of identical stimuli. This has been taken as evidence for the neural coding of prediction or prediction error. However, evidence for such omission responses from invasive recordings of cellular-scale responses in animal models is scarce. Here, we sought to characterise omission responses using extracellular recordings in the auditory cortex of anaesthetised rats. We profiled omission responses across local field potentials (LFP), analogue multiunit activity (AMUA), and single/multi-unit spiking activity, using stimuli that were fixed-rate trains of acoustic noise bursts where 5% of bursts were randomly omitted.ResultsSignificant omission responses were observed in LFP and AMUA signals, but not in spiking activity. These omission responses had a lower amplitude and longer latency than burst-evoked sensory responses, and omission response amplitude increased as a function of the number of preceding bursts.ConclusionsTogether, our findings show that omission responses are most robustly observed in LFP and AMUA signals (relative to spiking activity). This has implications for models of cortical processing that require many neurons to encode prediction errors in their spike output.

Self-assembled ultraflexible probes for long-term neural recordings and neuromodulation.

Ultraflexible microelectrode arrays (MEAs) that can stably record from a large number of neurons after their chronic implantation offer opportunities for understanding neural circuit mechanisms and developing next-generation brain-computer interfaces. The implementation of ultraflexible MEAs requires their reliable implantation into deep brain tissues in a minimally invasive manner, as well as their precise integration with optogenetic tools to enable the simultaneous recording of neural activity and neuromodulation. Here, we describe the process for the preparation of elastocapillary self-assembled ultraflexible MEAs, their use in combination with adeno-associated virus vectors carrying opsin genes and promoters to form an optrode probe and their in vivo experimental use in the brains of rodents, enabling electrophysiological recordings and optical modulation of neuronal activity over long periods of time (on the order of weeks to months). The procedures, including device fabrication, probe assembly and implantation, can be completed within 3 weeks. The protocol is intended to facilitate the applications of ultraflexible MEAs for long-term neuronal activity recording and combined electrophysiology and optogenetics. The protocol requires users with expertise in clean room facilities for the fabrication of ultraflexible MEAs.

Social Interaction Elicits Activity in Glutamatergic Neurons in the Posterior Intralaminar Complex of the Thalamus

BackgroundThe posterior intralaminar complex of the thalamus (PIL) is a multimodal nucleus that has been implicated in maternal behaviors and conspecific social behaviors in male and female rodents. Glutamatergic neurons are a major component of the PIL; however, their specific activity and role during social interactions has not yet been assessed. MethodsWe used immunohistochemistry for the immediate early gene c-fos as a proxy for neuronal activity in the PIL of mice exposed to a novel social stimulus, a novel object stimulus, or no stimulus. We then used fiber photometry to record neural activity of glutamatergic neurons in the PIL in real time during social and nonsocial interactions. Finally, we used inhibitory DREADDs (designer receptors exclusively activated by designer drugs) in glutamatergic PIL neurons and tested social preference and social habituation-dishabituation. ResultsWe observed significantly more c-fos–positive cells in the PIL of mice exposed to a social stimulus versus an object stimulus or no stimulus. Neural activity of PIL glutamatergic neurons was increased when male and female mice were engaged in social interaction with a same-sex juvenile or opposite-sex adult, but not a toy mouse. Neural activity was positively correlated with social investigation bout length and negatively correlated with chronological order of bouts. Social preference was unaffected by inhibition; however, inhibiting activity of glutamatergic neurons in the PIL delayed the time that it took for female mice to form social habituation. ConclusionsTogether, these findings suggest that glutamatergic PIL neurons respond to social stimuli in both male and female mice and may regulate perceptual encoding of social information to facilitate recognition of social stimuli.

Glutamatergic and GABAergic neurons in the vLGN mediate the nociceptive effects of green and red light on neuropathic pain

Phototherapy is an emerging non-pharmacological treatment for depression, circadian rhythm disruptions, and neurodegeneration, as well as pain conditions including migraine and fibromyalgia. However, the mechanism of phototherapy-induced antinociception is not well understood. Here, using fiber photometry recordings of population-level neural activity combined with chemogenetics, we found that phototherapy elicits antinociception via regulation of the ventral lateral geniculate body (vLGN) located in the visual system. Specifically, both green and red lights caused an increase of c-fos in vLGN, with red light increased more. In vLGN, green light causes a large increase in glutamatergic neurons, whereas red light causes a large increase in GABAergic neurons. Green light preconditioning increases the sensitivity of glutamatergic neurons to noxious stimuli in vLGN of PSL mice. Green light produces antinociception by activating glutamatergic neurons in vLGN, and red light promotes nociception by activating GABAergic neurons in vLGN. Together, these results demonstrate that different colors of light exert different pain modulation effects by regulating glutamatergic and GABAergic subpopulations in the vLGN. This may provide potential new therapeutic strategies and new therapeutic targets for the precise clinical treatment of neuropathic pain.

A History of Low-Dose Ethanol Shifts the Role of Ventral Hippocampus during Reward Seeking in Male Mice.

Although casual drinkers are a majority of the alcohol drinking population, understanding of the long-term effects of chronic exposure to lower levels of alcohol is limited. Chronic exposure to lower doses of ethanol may facilitate the development of alcohol use disorders, potentially because of ethanol effects on reward learning and motivation. Indeed, our previously published findings showed that chronic low-dose ethanol exposure enhanced motivation for sucrose in male, but not female, mice. As the ventral hippocampus (vHPC) is sensitive to disruption by higher doses of chronic ethanol and tracks reward-related information, we hypothesized that this region is impacted by low-dose ethanol and, further, that manipulating vHPC activity would alter reward motivation. In vivo electrophysiological recordings of vHPC population neural activity during progressive ratio testing revealed that vHPC activity was suppressed in the period immediately after reward seeking (lever press) in ethanol-naive controls, whereas suppression of vHPC activity anticipated reward seeking in ethanol-exposed mice. In both ethanol-naive and exposed mice, vHPC activity was suppressed before a reward magazine entry. Temporally selective inhibition of vHPC using optogenetics increased motivation for sucrose in ethanol-naive controls, but not in ethanol-exposed mice. Further, regardless of exposure history, vHPC inhibition promoted checking of the reward magazine, indicating a role for vHPC in reward tracking. There was no effect of chemogenetic inhibition of the vHPC either during training or testing on sucrose reward motivation. These results reveal novel ethanol-induced alterations in vHPC neural activity that shift how vHPC activity is able to regulate reward seeking.

Do you like it or not? Identifying preference using an electroencephalogram during the viewing of short videos.

Accurately predicting whether a short video will be liked by viewers is a topic of interest to media researchers. This study used an electroencephalogram (EEG) to record neural activity in 109 participants as they watched short videos (16 clips per person) to see which neural signals reflected viewers' preferences. The results showed that, compared with the short videos they disliked, individuals would experience positive emotions [indexed by a higher theta power, lower (beta - theta)/(beta + theta) score], more relaxed states (indexed by a lower beta power), lower levels of mental engagement and alertness [indexed by a lower beta/(alpha + theta) score], and devote more attention (indexed by lower alpha/theta) when watching short videos they liked. We further used artificial neural networks to classify the neural signals of different preferences induced by short videos. The classification accuracy was the highest when using data from bands over the whole brain, which was 75.78%. These results may indicate the potential of EEG measurement to evaluate the subjective preferences of individuals for short videos.

Anatomical organization of temporally correlated neural calcium activity in the hippocampal CA1 region

Hippocampal CA1 neuronal ensembles generate sequential patterns of firing activity that contribute to episodic memory formation and spatial cognition. Here we used invivo calcium imaging to record neural ensemble activities in mouse hippocampal CA1 and identified CA1 excitatory neuron sub-populations whose members are active across the same second-long period of time. We identified groups of hippocampal neurons sharing temporally correlated neural calcium activity during behavioral exploration and found that they also organized as clusters in anatomical space. Such clusters vary in membership and activity dynamics with respect to movement in different environments, but also appear during immobility in the dark suggesting an internal dynamic. The strong covariance between dynamics and anatomical location within the CA1 sub-region reveals a previously unrecognized form of topographic representation in hippocampus that may guide generation of hippocampal sequences across time and therefore organize the content of episodic memory.

Recording central nervous system responses of freely-swimming marine and freshwater fishes with a customizable, implantable AC differential amplifier

BackgroundFish have adapted to a diversity of environments but the neural mechanisms underlying natural aquatic behaviors are not well known. New methodWe have developed a small, customizable AC differential amplifier and surgical procedures for recording multi-unit extracellular signals in the CNS of marine and freshwater fishes. ResultsOur minimally invasive amplifier allowed fish to orient to flow and respond to hydrodynamic and visual stimuli. We recorded activity in the cerebellum and optic tectum during these behaviors. Comparison with existing methodsOur system is very low-cost, hydrodynamically streamlined, and capable of high-gain in order to allow for recordings from freely behaving, fast fishes in complex fluid environments. ConclusionsOur tethered approach allows access to record neural activity in a diversity of adult fishes in the lab, but can also be modified for data logging in the field.

Co-variations of cerebral blood volume and single neurons discharge during resting state and visual cognitive tasks in non-human primates

To better understand how the brain allows primates to perform various sets of tasks, the ability to simultaneously record neural activity at multiple spatiotemporal scales is challenging but necessary. However, the contribution of single-unit activities (SUAs) to neurovascular activity remains to be fully understood. Here, we combine functional ultrasound imaging of cerebral blood volume (CBV) and SUA recordings in visual and fronto-medial cortices of behaving macaques. We show that SUA provides a significant estimate of the neurovascular response below the typical fMRI spatial resolution of 2mm3. Furthermore, our results also show that SUAs and CBV activities are statistically uncorrelated during the resting state but correlate during tasks. These results have important implications for interpreting functional imaging findings while one constructs inferences of SUA during resting state or tasks.

Synchrony in parent-offspring social interactions across development: A cross-species review of rodents and humans.

In humans, parent-child neural synchrony has been shown to support early communication, social attunement and learning. Further, some animal species (including rodents and bats) are now known to share neural synchrony during certain forms of social behaviour. However, very little is known about the developmental origins and sequelae of neural synchrony, and whether this neural mechanism might play a causal role in the control of social and communicative behaviour across species. Rodent models are optimal for exploring such questions of causality, with a plethora of tools available for both disruption/induction (optogenetics) and even mechanistic dissection of synchrony-induction pathways (in vivo electrical or optical recording of neural activity). However, before the benefits of rodent models for advancing research on parent-infant synchrony can be realised, it is first important to address a gap in understanding the forms of parent-pup synchrony that occur during rodent development, and how these social relationships evolve over time. Accordingly, this review seeks to identify parent-pup social behaviours that could potentially drive or facilitate synchrony and to discuss key differences or limitations when comparing mouse to human models of parent-infant synchrony. Uniquely, our review will focus on parent-pup dyadic social behaviours that have particular analogies to the human context, including instrumental, social interactive and vocal communicative behaviours. This review is intended to serve as a primer on the study of neurobehavioral synchrony across human and rodent dyadic developmental models.

Questionnaires based on natural language processing elicit immersive ruminative thinking in ruminators: Evidence from behavioral responses and EEG data.

Rumination is closely related to mental disorders and can thus be used as a marker of their presence or a predictor of their development. The presence of masking and fabrication in psychological selection can lead to inaccurate detection of psychological disorders. Human language is considered crucial in eliciting specific conscious activities, and the use of natural language processing (NLP) in the development of questionnaires for psychological tests has the potential to elicit immersive ruminative thinking, leading to changes in neural activity. Electroencephalography (EEG) is commonly used to detect and record neural activity in the human brain and is sensitive to changes in brain activity. In this study, we used NLP to develop a questionnaire to induce ruminative thinking and then recorded the EEG signals in response to the questionnaire. The behavioral results revealed that ruminators exhibited higher arousal rates and longer reaction times, specifically in response to the ruminative items of the questionnaire. The EEG results showed no significant difference between the ruminators and the control group during the resting state; however, a significant alteration in the coherence of the entire brain of the ruminators existed while they were answering the ruminative items. No differences were found in the control participants while answering the two items. These behavioral and EEG results indicate that the questionnaire elicited immersive ruminative thinking, specifically in the ruminators. Therefore, the questionnaire designed using NLP is capable of eliciting ruminative thinking in ruminators, offering a promising approach for the early detection of mental disorders in psychological selection.

Using an appetitive operant conditioning paradigm to screen rats for tinnitus induced by intense sound exposure: Experimental considerations and interpretation.

In an effort to help elucidate the neural mechanisms underlying tinnitus in humans, researchers have often relied on animal models; a preclinical approach which ultimately required that behavioral paradigms be designed to reliably screen animals for tinnitus. Previously, we developed a two-alternative forced-choice (2AFC) paradigm for rats that allowed for the simultaneous recording of neural activity at the very moments when they were reporting the presence/absence of tinnitus. Because we first validated our paradigm in rats experiencing transient tinnitus following a high-dose of sodium salicylate, the present study now sought to evaluate its utility to screen for tinnitus caused by intense sound exposure; a common tinnitus-inducer in humans. More specifically, through a series of experimental protocols, we aimed to (1) conduct sham experiments to ensure that the paradigm was able to correctly classify control rats as not having tinnitus, (2) confirm the time course over which the behavioral testing could reliably be performed post-exposure to assess chronic tinnitus, and (3) determine if the paradigm was sensitive to the variable outcomes often observed after intense sound exposure (e.g., hearing loss with our without tinnitus). Ultimately, in accordance with our predictions, the 2AFC paradigm was indeed resistant to false-positive screening of rats for intense sound-induced tinnitus, and it was able to reveal variable tinnitus and hearing loss profiles in individual rats following intense sound exposure. Taken together, the present study documents the utility of our appetitive operant conditioning paradigm to assess acute and chronic sound-induced tinnitus in rats. Finally, based on our findings, we discuss important experimental considerations that will help ensure that our paradigm is able to provide a suitable platform for future investigations into the neural basis of tinnitus.

Activity in developing prefrontal cortex is shaped by sleep and sensory experience.

In developing rats, behavioral state exerts a profound modulatory influence on neural activity throughout the sensorimotor system, including primary motor cortex (M1). We hypothesized that similar state-dependent modulation occurs in prefrontal cortical areas with which M1 forms functional connections. Here, using 8- and 12-day-old rats cycling freely between sleep and wake, we record neural activity in M1, secondary motor cortex (M2), and medial prefrontal cortex (mPFC). At both ages in all three areas, neural activity increased during active sleep (AS) compared with wake. Also, regardless of behavioral state, neural activity in all three areas increased during periods when limbs were moving. The movement-related activity in M2 and mPFC, like that in M1, is driven by sensory feedback. Our results, which diverge from those of previous studies using anesthetized pups, demonstrate that AS-dependent modulation and sensory responsivity extend to prefrontal cortex. These findings expand the range of possible factors shaping the activity-dependent development of higher-order cortical areas.