Single Unit publications

Interpersonal coordination is fundamental to social evolution. We investigate its phenomenology and neural underpinnings in humans and macaques, examining the behavioral adaptations required for mutual coordination during motor interactions and the extent to which the underlying brain mechanisms are shared across species. Using a common interpersonal coordination paradigm, we conducted functional magnetic resonance imaging (fMRI) in humans and intracranial local field potential (LFP) recordings in macaques. Despite between-species behavioral discrepancies, both monkeys and humans coordinate through adjustments that proved to be based on proactive adaptation of motor planning and execution. Evidence from fMRI and time-resolved decoding analysis of LFPs converged to show modulation of premotor brain activity associated with interpersonal coordination and its effectiveness. Moreover, a dynamic sequential coding emerged, whereby the action context is represented early during planning, and coordination features near movement onset. Our findings reveal an evolutionarily conserved cortical architecture across primates that supports cooperative motor behavior.

This work presents three open datasets featuring various levels of processing, containing neural recordings from the auditory cortex of rats. These recordings were obtained during experiments using the auditory oddball paradigm before, during and after the local microiontophoretic application of acetylcholine. The primary objective of these datasets is to investigate how the brain processes predictable versus unexpected auditory stimuli, and the role of cholinergic inputs during such processing. The data include multi-unit recordings of neuronal activity during the presentation of standard and deviant tones, classified by stimulus type and cortical sub-region. These resources enable quantitative investigations of deviance detection, stimulus-specific adaptation, cholinergic modulation and predictive-coding mechanisms at multiple temporal scales.

The hippocampus is classically linked to memory, yet increasing evidence points to a broader role in perceptual inference and deviance detection. Predictive coding theories propose that perception minimizes mismatches between expected and actual sensory input, expressed in neural signatures such as mismatch negativity (MMN) and P300. Although MMN arises mainly from sensory and prefrontal cortices, the hippocampus is anatomically interconnected with both and may also contribute to prediction error processing. We recorded single- and multi-unit activity and local field potentials (LFPs) from DG and CA1 in urethane-anesthetized rats during an auditory oddball paradigm and a no-repetition control sequence to dissociate prediction error from repetition suppression. Approximately 20% of hippocampal neurons were sound responsive, and a subset showed deviant selectivity. Spiking activity predominantly reflected prediction errors, while LFPs revealed complementary contributions from repetition suppression and prediction error. Early LFP components were enhanced for randomly presented deviants, whereas later components within the P300 latency range were stronger for predictable deviants, indicating temporally distinct phases of error signaling and top-down modulation. These findings identify the hippocampus as an active contributor to auditory deviance detection and support a hierarchical model in which hippocampal circuits participate in predictive sensory processing beyond memory.

Impulsivity is a core pathological feature of various psychiatric disorders including obsessive‐compulsive disorder, attention‐deficit/hyperactivity disorder, and schizophrenia, which is conceptualized as dysregulated motivational and inhibitory processes. However, the underlying neural mechanism is poorly known. Using an olfactory cued Go/No‐Go task, this work finds increased false alarm rate, shortened licking onset latency, elevated licking frequency and reduced inter‐trial consistency in mice treated by the NMDAR antagonist (MK‐801). Fiber optic recordings reveal MK‐801 enhanced cue‐evoked neuronal responses in the olfactory bulb (OB), orbitofrontal cortex (OFC), ventral tegmental area (VTA), and nucleus accumbens (NAc), while reducing reward‐predictive cue selectivity and increasing NAc dopamine release. Additionally, in vivo electrophysiological recordings demonstrate that theta oscillation power in the NAc and its coherence with OB, OFC, and VTA are also amplified. MK‐801 treatment enhances the correlation between firing rates of NAc neurons and cue, decreases the association with reward, strengthens the correlation with licking and increases the probability of firing peak preceding lick onset. Furthermore, this work confirms that the application of the trace amine‐associated receptor 1 agonist SEP‐363856 could correct the abnormal responses of NAc neurons and behavioral deficits. These findings elucidate the neural basis of impulsivity and support the potential therapeutic effect of SEP.

Long-term robust intracortical microelectrode (IME) neural recording quality is negatively affected by the neuroinflammatory response following microelectrode insertion. This adversely impacts brain-machine interface (BMI) performance for patients with neurological disorders or amputations. Recent studies suggest that the leakage of blood-brain barrier (BBB) and microhemorrhage caused by IME insertions contribute to increased neuroinflammation and reduced neural recording performance. Here, we evaluated dexamethasone sodium phosphate-loaded platelet-inspired nanoparticles (DEXSPPIN) to simultaneously augment local hemostasis and serve as an implant-site targeted drug-delivery vehicle. Weekly systemic treatment or control therapy was provided to rats for 8 weeks following IME implantation, while evaluating extracellular single-unit recording performance. End-point immunohistochemistry was performed to further assess the local tissue response to the IMEs. Treatment with DEXSPPIN significantly increased the recording capabilities of IMEs compared to controls over the 8-week observation period. Immunohistochemical analyses of neuron density, activated microglia/macrophage density, astrocyte density, and BBB permeability suggested that the improved neural recording performance may be attributed to reduced neuron degeneration and neuroinflammation. Overall, we found that DEXSPPIN treatment promoted an anti-inflammatory environment that improved neuronal density and enhanced IME recording performance.

Diverse biological factors, such as sex and age, confer heterogeneity on sensory processing challenges in autism. These factors result in major difficulties in the processing of contextual information in social and non-social situations. To assess divergence in autistic traits, it is critical to consider sex- and age-related variability. Nevertheless, these differences remain largely elusive. Animal models of autism offer the possibility to examine contextual processing at the single-neuron level. Here, we investigated predictive processing of contextual auditory cues in the auditory midbrain of control and prenatally valproic acid-induced rats, a well-established animal model of autism. The rats were prepubertal and adult female and male animals. We performed single-unit recordings in the inferior colliculus of control and prenatally, or in utero , exposed rats under the classical oddball paradigm and non-repetitive cascade control sequences to study neuronal mismatch. This is the neuronal correlate of mismatch negativity, the brain’s automatic response to interruptions in environmental regularity. When comparing control and exposed rats, our results demonstrated a reduction in neuronal mismatch in rats exposed to valproic acid. However, exposed adult females exhibited an increased neuronal mismatch compared to their control counterparts. With respect to sex distinctions, valproic acid induced sex differences in neuronal mismatch of prepubertal and adult rats that are not observable in control animals. Moreover, we detected an age-dependent refinement in prediction error that is not affected by the drug. But valproic acid altered typical developmental trajectory of neuronal mismatch in both sexes. Such observations support sex- and age-related effects of in utero valproic acid exposure in contextual auditory processing at the neural level of the inferior colliculus. In autism, atypical predictive processing of environmental regularities underlies unusual responses to novel experiences. The present study highlights the importance of sex and age, that confer heterogeneity to these challenges.

Intracortical microelectrodes are used for recording activity from individual neurons, providing both a valuable neuroscience tool and an enabling medical technology for individuals with motor disabilities. Standard neural probes carrying the microelectrodes are rigid silicon-based structures that can penetrate the brain parenchyma to interface with the targeted neurons. Unfortunately, within weeks after implantation, neural recording quality from microelectrodes degrades, owing largely to a neuroinflammatory response. Key contributors to the neuroinflammatory response include mechanical mismatch at the device-tissue interface and oxidative stress. We developed a mechanically-adaptive, resveratrol-eluting (MARE) neural probe to mitigate both mechanical mismatch and oxidative stress and thereby promote improved neural recording quality and longevity. In this work, we demonstrate that compared to rigid silicon controls, highly-flexible MARE probes exhibit improved recording performance, more stable impedance, and a healing tissue response. With further optimization, MARE probes can serve as long-term, robust neural probes for brain-machine interface applications.

Atypical sensory processing, particularly in the auditory domain, is one of the most common and quality-of-life affecting symptoms seen in autism spectrum disorders (ASD). Fragile X Syndrome (FXS) is a leading inherited cause of ASD and a majority of FXS individuals present with auditory processing alterations. While auditory hypersensitivity is a common phenotype observed in FXS and Fmr1 knockout (KO) rodent models, it is important to consider other auditory coding impairments that could contribute to sound processing difficulties and disrupted language comprehension in FXS. We have shown previously that a Fmr1 KO rat model of FXS exhibits heightened sound sensitivity that coincided with abnormal perceptual integration of stimulus bandwidth, indicative of altered spectral processing. Frequency discrimination is a fundamental aspect of sound encoding that is important for a range of auditory processes, such as source segregation and speech comprehension, and disrupted frequency coding could thus contribute to a range of auditory issues in FXS and ASD. Here we explicitly characterized spectral processing deficits in male Fmr1 KO rats using an operant conditioning tone discrimination assay and in vivo electrophysiological recordings from the auditory cortex and inferior colliculus. We found that Fmr1 KO rats exhibited poorer frequency resolution, which corresponded with neuronal hyperactivity and broader frequency tuning in auditory cortical but not collicular neurons. Using an experimentally informed population model, we show that these cortical physiological differences can recapitulate the observed behavior discrimination deficits, with decoder performance being tightly linked to differences in cortical tuning width and signal-to-noise ratios. Together, these findings indicate that cortical hyperexcitability in Fmr1 KO rats may act to preserve signal-to-noise ratios and signal detection threshold at the expense of sound sensitivity and fine feature discrimination, highlighting a potential mechanistic locus for a range of auditory behavioral phenotypes in FXS.

The mediodorsal thalamic nucleus (MD) forms neural circuits with various brain regions, including the prefrontal cortex (PFC), the reticular thalamic nucleus (TRN), and the midbrain reticular nucleus (MRN). However, the specific roles and underlying mechanisms in auditory information processing remain unclear. Here, we perform multi-channel electrophysiological recordings in awake mice to investigate the response patterns of the MD to auditory stimuli, as well as the regulatory effects of PFC, MRN, and TRN inputs. We identify two distinct types of sound-evoked responses. The Phasic-response features a transient burst firing to the stimulus with short latency, rapidly adapting to baseline and corresponding to the onset fluctuation of the local field potential. The Sustained-response is marked by prolonged firing with longer latency and is accompanied by persistent enhancement of oscillatory power following stimulus offset. The response patterns of MD neurons remain consistent across different types of auditory stimuli. Optogenetic inactivation of the MRN suppresses both response types in the MD. The Sustained-response is attenuated by PFC inactivation but enhanced by TRN inactivation, while the Phasic-response remains unaffected by inactivation of either the PFC or TRN. Our findings expand the understanding of the MD's role in sound information integration and auditory cognitive regulation.

Closed-loop neural control is a powerful tool for both the scientific exploration of neural function and for mitigating deficiencies found in open-loop deep brain stimulation (DBS). Here, we present a protocol for artificial intelligence-guided neural control in rats using deep reinforcement learning (RL) and infrared neural stimulation (INS). We describe steps for integrating RL closed-loop control into neuroscience and neuromodulation studies. We then detail procedures for using and deploying infrared INS in chronic DBS applications. For complete details on the use and execution of this protocol, please refer to Coventry et al.1 and Coventry and Bartlett.2.

Noise exposure is one of the most common causes of hearing loss and hyperacusis. Studies have shown that noise exposure can induce a cortical gain to compensate for reduced input of the cochlea, which may contribute to the increased sound sensitivity. However, many people with hyperacusis have no measurable cochlear lesion after being exposed to loud sound. In this experiment, we studied the neurological alterations in the cortical and subcortical areas following a prolonged moderate level of noise exposure (84 dB SPL, 8 h/day for 4 weeks) in the laboratory mice. The cochlear function was monitored by auditory brainstem responses (ABRs). The behavioral auditory sensitivity and temporal processing were evaluated using the acoustic startle response (ASR) and gap‐induced prepulse inhibition (gap‐PPI). The central auditory functions were determined by electrophysiological recordings of the inferior colliculus (IC) and the auditory cortex (AC). Our results showed that although there was no significant difference in the ABR thresholds, the noise group showed enhanced ASR and gap‐PPI compared to the control group. Increased neural activity in both the IC and the AC was recorded in the noise‐exposed mice compared to the control group, suggesting a central gain in both the subcortical and cortical regions. The current source density (CSD) analysis of the AC response revealed an increased columnar excitation and reduced corticocortical projection in the noise group, different from the central gain model of noise‐induced hearing loss. Our results suggest that chronic “nondestructive” noise can increase the gain of the central auditory system by altering the balance of auditory thalamocortical and intracortical inputs, which may contribute to the increased sound sensitivity in people with normal hearing.

Tinnitus has been identified as a potential contributor to anxiety. Thalamo-cortical pathway plays a crucial role in the transmission of auditory and emotional information, but its casual link to tinnitus-associated anxiety remains unclear. In this study, we explore the neural activities in the thalamus and cortex of the sodium salicylate (NaSal)-treated mice, which exhibit both hyperacusis and anxiety-like behaviors. We find an increase in gamma band oscillations (GBO) in both auditory cortex (AC) and prefrontal cortex (PFC), as well as phase-locking between cortical GBO and thalamic neural activity. These changes are attributable to a suppression of GABAergic neuron activity in thalamic reticular nucleus (TRN), and optogenetic activation of TRN reduces NaSal-induced hyperacusis and anxiety-like behaviors. The elevation of endocannabinoid (eCB)/ cannabinoid receptor 1 (CB1R) transmission in TRN contributes to the NaSal-induced abnormalities. Our results highlight the regulative role of TRN in the auditory and limbic thalamic-cortical pathways.

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

Adaptive myelination is the emerging concept of tuning axonal conduction velocity to the activity within specific neural circuits over time. Sound processing circuits exhibit structural and functional specifications to process signals with microsecond precision: a time scale that is amenable to adjustment in length and thickness of myelin. Increasing activity of auditory axons by introducing sound-evoked responses during postnatal development enhances myelin thickness, while sensory deprivation prevents such radial growth during development. When deprivation occurs during adulthood, myelin thickness was reduced. However, it is unclear whether sensory stimulation adjusts myelination in a global fashion (whole fiber bundles) or whether such adaptation occurs at the level of individual fibers. Using temporary monaural deprivation in mice provided an internal control for a) differentially tracing structural changes in active and deprived fibers and b) for monitoring neural activity in response to acoustic stimulation of the control and the deprived ear within the same animal. The data show that sound-evoked activity increased the number of myelin layers around individual active axons, even when located in mixed bundles of active and deprived fibers. Thicker myelination correlated with faster axonal conduction velocity and caused shorter auditory brainstem response wave VI-I delays, providing a physiologically relevant readout. The lack of global compensation emphasizes the importance of balanced sensory experience in both ears throughout the lifespan of an individual.

Identifying different sleep stages in humans and other mammals has traditionally relied on electroencephalograms. Such an approach is not feasible in certain animals such as invertebrates, although these animals could also be sleeping in stages. Here, we perform long-term multichannel local field potential recordings in the brains of behaving flies undergoing spontaneous sleep bouts. We acquired consistent spatial recordings of local field potentials across multiple flies, allowing us to compare brain activity across awake and sleep periods. Using machine learning, we uncover distinct temporal stages of sleep and explore the associated spatial and spectral features across the fly brain. Further, we analyze the electrophysiological correlates of microbehaviors associated with certain sleep stages. We confirm the existence of a distinct sleep stage associated with rhythmic proboscis extensions and show that spectral features of this sleep-related behavior differ significantly from those associated with the same behavior during wakefulness, indicating a dissociation between behavior and the brain states wherein these behaviors reside.

A fundamental property of sensory systems is their ability to detect novel stimuli in the ambient environment. The auditory brain contains neurons that decrease their response to repetitive sounds but increase their firing rate to novel or deviant stimuli; the difference between both responses is known as stimulus-specific adaptation or neuronal mismatch (nMM). Here, we tested the effect of microiontophoretic applications of ACh on the neuronal responses in the auditory cortex (AC) of anesthetized rats during an auditory oddball paradigm, including cascade controls. Results indicate that ACh modulates the nMM, affecting prediction error responses but not repetition suppression, and this effect is manifested predominantly in infragranular cortical layers. The differential effect of ACh on responses to standards, relative to deviants (in terms of averages and variances), was consistent with the representational sharpening that accompanies an increase in the precision of prediction errors. These findings suggest that ACh plays an important role in modulating prediction error signaling in the AC and gating the access of these signals to higher cognitive levels.

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.

The auditory steady-state response (ASSR) is a cortical oscillation induced by trains of 40 Hz acoustic stimuli. While the ASSR has been widely used in clinic measurement, the underlying neural mechanism remains poorly understood. In this study, we investigated the contribution of different stages of auditory thalamocortical pathwaymedial geniculate body (MGB), thalamic reticular nucleus (TRN), and auditory cortex (AC)to the generation and regulation of 40 Hz ASSR in C57BL/6 mice of both sexes. We found that the neural response synchronizing to 40 Hz sound stimuli was most prominent in the GABAergic neurons in the granular layer of AC and the ventral division of MGB (MGBv), which were regulated by optogenetic manipulation of TRN neurons. Behavioral experiments confirmed that disrupting TRN activity has a detrimental effect on the ability of mice to discriminate 40 Hz sounds. These findings revealed a thalamocortical mechanism helpful to interpret the results of clinical ASSR examinations. Significance Statement Our study contributes to clarifying the thalamocortical mechanisms underlying the generation and regulation of the auditory steady-state response (ASSR), which is commonly used in both clinical and neuroscience research to assess the integrity of auditory function. Combining a series of electrophysiological and optogenetic experiments, we demonstrate that the generation of cortical ASSR is dependent on the lemniscal thalamocortical projections originating from the ventral division of medial geniculate body to the GABAergic interneurons in the granule layer of the auditory cortex. Furthermore, the thalamocortical process for ASSR is strictly regulated by the activity of thalamic reticular nucleus (TRN) neurons. Behavioral experiments confirmed that dysfunction of TRN would cause a disruption of mice's behavioral performance in the auditory discrimination task.

Intracortical microelectrode arrays (MEAs) can be used in a range of applications, from basic neuroscience research to providing an intimate interface with the brain as part of a brain-computer interface (BCI) system aimed at restoring function for people living with neurological disorders or injuries. Unfortunately, MEAs tend to fail prematurely, leading to a loss in functionality for many applications. An important contributing factor in MEA failure is oxidative stress resulting from chronically inflammatory-activated microglia and macrophages releasing reactive oxygen species (ROS) around the implant site. Antioxidants offer a means for mitigating oxidative stress and improving tissue health and MEA performance. Here, we investigate using the clinically available antioxidant dimethyl fumarate (DMF) to reduce the neuroinflammatory response and improve MEA performance in a rat MEA model. Daily treatment of DMF for 16 weeks resulted in a significant improvement in the recording capabilities of MEA devices during the sub-chronic (Weeks 5–11) phase (42% active electrode yield vs. 35% for control). However, these sub-chronic improvements were lost in the chronic implantation phase, as a more exacerbated neuroinflammatory response occurs in DMF-treated animals by 16 weeks post-implantation. Yet, neuroinflammation was indiscriminate between treatment and control groups during the sub-chronic phase. Although worse for chronic use, a temporary improvement (<12 weeks) in MEA performance is meaningful. Providing short-term improvement to MEA devices using DMF can allow for improved use for limited-duration studies. Further efforts should be taken to explore the mechanism behind a worsened neuroinflammatory response at the 16-week time point for DMF-treated animals and assess its usefulness for specific applications.

Prediction provides key advantages for survival, and cognitive studies have demonstrated that the brain computes multilevel predictions. Evidence for predictions remains elusive at the neuronal level because of the complexity of separating neural activity into predictions and stimulus responses. We overcome this challenge by recording from single neurons from cortical and subcortical auditory regions in anesthetized and awake preparations, during unexpected stimulus omissions interspersed in a regular sequence of tones. We find a subset of neurons that responds reliably to omitted tones. In awake animals, omission responses are similar to anesthetized animals, but larger and more frequent, indicating that the arousal and attentional state levels affect the degree to which predictions are neuronally represented. Omission-sensitive neurons also responded to frequency deviants, with their omission responses getting emphasized in the awake state. Because omission responses occur in the absence of sensory input, they provide solid and empirical evidence for the implementation of a predictive process.