LFP publications

The inferior colliculus (IC) is a major midbrain convergence site critical for processing complex sounds and undergoes fundamental changes with age-related hearing loss (ARHL). Local field potentials (LFPs) represent pre-synaptic integration of excitatory and inhibitory signals in local neural populations. Here, we assessed age-related changes in sound-evoked IC LFPs in the CBA/CaJ mouse model of ARHL across the tonotopic axis. We recorded from 495 sites across four age groups (young: 4-6 months; middle: 8-14 months; old: 24-25 months; “oldest old”: 27-31 months), examining LFP responses from dorsal (low-frequency), medial (mid-frequency), and ventral (high-frequency) IC regions. Analysis of the onset depolarization (N1 component) in response to broadband noise bursts revealed significant age-related hyperexcitability in medial and dorsal regions, with oldest old animals showing enhanced responses while ventral regions were unaffected. Amplitude-intensity functions demonstrated significant age × level interactions across all regions, with oldest old animals exhibiting level-dependent hyperexcitability most pronounced at suprathreshold intensities. Time-frequency analysis of LFP spectral content (30-100 Hz) revealed a crossover pattern across medial and dorsal regions, with oldest old animals showing reduced power at low-to-moderate stimulus levels but enhanced power at high stimulus levels. Ventral regions showed a low-level reduction without suprathreshold enhancement. These findings reveal paradoxical enhancement of neural activity in the aging IC, with the most pronounced changes in dorsal and medial regions rather than ventral regions most affected by peripheral hearing loss, suggesting that central hyperexcitability depends on residual afferent drive and implicating region-specific alterations in excitatory-inhibitory balance underlying central presbycusis.

Brain function relies on coordinated activity across spatial and temporal scales. Single neurons integrate local and long-range connectivity and reflect activity across brain-wide networks. Understanding integrated brain function requires tools capable of recording from anatomically connected populations in distributed brain areas to bridge local and global dynamics. Here, we present high-density, micro-electrocorticography arrays that facilitate multi-scale studies of brain activity. The hybrid arrays integrate the desirable features of silicone elastomers and polyimide films: silicone provides optical transparency and permits repeated penetration with intracortical arrays, while polyimide enables fine photolithographic feature definition. This combination facilitates high-throughput functional mapping to identify targets and insertion of intracortical arrays for dense local sampling. We demonstrate functional mapping in rats, cats, and marmosets, showing how functional maps guide multi-area laminar recordings. Finally, we demonstrate local and feedforward optogenetic stimulation to investigate cortico-cortical interactions. These capabilities establish the hybrid μECoG as a compelling tool for systems neuroscience.

Reconstructing speech from neural recordings is crucial for understanding human speech coding and developing brain-computer interfaces (BCIs). However, existing methods trade off acoustic richness (pitch, prosody) for linguistic intelligibility (words, phonemes). To overcome this limitation, we propose a dual-path framework to concurrently decode acoustic and linguistic representations. The acoustic pathway uses a long-short term memory (LSTM) decoder and a high-fidelity generative adversarial network (HiFi-GAN) to reconstruct spectrotemporal features. The linguistic pathway employs a transformer adaptor and text-to-speech (TTS) generator for word tokens. These two pathways merge via voice cloning to combine both acoustic and linguistic validity. Using only 20 min of electrocorticography (ECoG) data per human subject, our approach achieves highly intelligible synthesized speech (mean opinion score = 4.0/5.0, word error rate = 18.9%). Our dual-path framework reconstructs natural and intelligible speech from ECoG, resolving the acoustic-linguistic trade-off.

The mammillary body (MB) has traditionally been regarded as a relay station for the hippocampus and plays a pivotal role in the Papez circuit. However, its molecular and cellular organization remains inadequately characterized. This study focuses on the horizontally symmetrically distributed neurotensin (Nts)-expressing and nitric oxide synthase 1 (Nos1)-expressing neurons in the MB, demonstrating that Grik4 (encoding a high-affinity kainate receptor subunit) underlies their distinct electrophysiological properties. Within neural circuits, Nts and Nos1 neurons receive excitatory inputs from the ventral subiculum and send parallel excitatory projections to the dorsomedial and ventrolateral subdivisions of the anteroventral thalamus (AV). These 2 cell type-specific circuits are essential for working memory and exhibit selective activation during the maintenance phase with a marked temporal difference. Together, our findings establish a direct link from molecular identity to circuit architecture and cognitive processing by demonstrating that molecularly distinct Nts and Nos1 neurons constitute differential circuits with convergent inputs, divergent outputs, and dissociable roles in working memory maintenance. This work thus reveals a fundamental cross-scale organizational principle—molecule, cell, circuit, function—within the MB.

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.

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.

The thalamocortical pathways exhibit neuroplasticity not only during the critical period but also in adulthood. In this study, we investigated how cholecystokinin (CCK) modulates age-dependent thalamocortical plasticity. Our findings demonstrated that CCK is expressed in thalamocortical neurons and that high-frequency stimulation (HFS) of the thalamocortical pathway triggers the release of CCK in auditory cortex (ACx), as detected by a CCK sensor. HFS of the medial geniculate body (MGB) induced thalamocortical long-term potentiation (LTP) in wild-type young adult mice. However, knockdown of CCK expression in MGB neurons or blockade of the CCK-B receptor (CCKBR) in the ACx abolished HFS-induced LTP. Interestingly, this LTP could not be elicited in juvenile (3-week-old) or aged mice (over 18-month-old) due to distinct mechanisms: the absence of CCKBR in juveniles and the inability to release CCK in aged mice. Notably, exogenous administration of CCK into the ACx rescued LTP in aged mice and significantly improved frequency discrimination. These findings highlight the potential of CCK as a therapeutic intervention for ameliorating neuroplasticity deficits associated with thalamocortical connectivity.

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.

High-frequency stimulation (HFS)-induced long–term potentiation (LTP) is generally regarded as a homosynaptic Hebbian-type LTP, where synaptic changes are thought to occur at the synapses that project from the stimulation site and terminate onto the neurons at the recording site. In this study, we first investigated HFS-induced LTP on urethane-anesthetized rats and found that cortical HFS enhances neural responses at the recording site through the strengthening of local connectivity with nearby neurons at the stimulation site rather than through synaptic strengthening at the recording site. This enhanced local connectivity at the stimulation site leads to increased output propagation, resulting in signal potentiation at the recording site. Additionally, we discovered that HFS can also nonspecifically strengthen distant afferent synapses at the HFS site, thereby expanding its impact beyond local neural connections. This form of plasticity exhibits a neo-Hebbian characteristic as it exclusively manifests in the presence of cholecystokinin release, induced by HFS. The cortical HFS-induced local LTP was further supported by a behavioral task, providing additional evidence. Our results unveil a previously overlooked mechanism underlying cortical plasticity: synaptic plasticity is more likely to occur around the soma site of strongly activated cortical neurons rather than solely at their projection terminals.

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.

Typical statistical practices in the biological sciences have been increasingly called into question due to difficulties in the replication of an increasing number of studies, many of which are confounded by the relative difficulty of null significance hypothesis testing designs and interpretation of p -values. Bayesian inference, representing a fundamentally different approach to hypothesis testing, is receiving renewed interest as a potential alternative or complement to traditional null significance hypothesis testing due to its ease of interpretation and explicit declarations of prior assumptions. Bayesian models are more mathematically complex than equivalent frequentist approaches, which have historically limited applications to simplified analysis cases. However, the advent of probability distribution sampling tools with exponential increases in computational power now allows for quick and robust inference under any distribution of data. Here we present a practical tutorial on the use of Bayesian inference in the context of neuroscientific studies in both rat electrophysiological and computational modeling data. We first start with an intuitive discussion of Bayes' rule and inference followed by the formulation of Bayesian-based regression and ANOVA models using data from a variety of neuroscientific studies. We show how Bayesian inference leads to easily interpretable analysis of data while providing an open-source toolbox to facilitate the use of Bayesian tools.

The cerebral cortex is widely considered part of the neural substrate of consciousness, but direct causal evidence is missing. Here, we tested in mice whether optogenetic activation of cortical neurons in posterior parietal cortex (PtA) or medial prefrontal cortex (mPFC) is sufficient for arousal from three behavioral states characterized by progressively deeper unresponsiveness: sleep, a coma-like state induced by muscimol injection in the midbrain, and deep sevoflurane-dexmedetomidine anesthesia. We find that cortical stimulation always awakens the mice from both NREM sleep and REM sleep, with PtA requiring weaker/shorter light pulses than mPFC. Moreover, in most cases light pulses produce both cortical activation (decrease in low frequencies) and behavioral arousal (recovery of the righting reflex) from brainstem coma, as well as cortical activation from anesthesia. These findings provide evidence that direct activation of cortical neurons is sufficient for behavioral and/or cortical arousal from sleep, brainstem coma, and anesthesia.

In order to investigate the involvement of the primary visual cortex (V1) in working memory (WM), parallel, multisite recordings of multi-unit activity were obtained from monkey V1 while the animals performed a delayed match-to-sample (DMS) task. During the delay period, V1 population firing rate vectors maintained a lingering trace of the sample stimulus that could be reactivated by intervening impulse stimuli that enhanced neuronal firing. This fading trace of the sample did not require active engagement of the monkeys in the DMS task and likely reflects the intrinsic dynamics of recurrent cortical networks in lower visual areas. This renders an active, attention-dependent involvement of V1 in the maintenance of WM contents unlikely. By contrast, population responses to the test stimulus depended on the probabilistic contingencies between sample and test stimuli. Responses to tests that matched expectations were reduced which agrees with concepts of predictive coding.

We investigated whether neurons in monkey primary visual cortex (V1) exhibit mixed selectivity for sensory input and behavioral choice. Parallel multisite spiking activity was recorded from area V1 of awake monkeys performing a delayed match-to-sample task. The monkeys had to make a forced choice decision of whether the test stimulus matched the preceding sample stimulus. The population responses evoked by the test stimulus contained information about both the identity of the stimulus and with some delay but before the onset of the motor response the forthcoming choice. The results of subspace identification analysis indicate that stimulus-specific and decision-related information coexists in separate subspaces of the high-dimensional population activity, and latency considerations suggest that the decision-related information is conveyed by top-down projections.

Long-term potentiation (LTP), which underlies learning and memory, can be induced by high-frequency electrical stimulation (HFS or HFES) and is thought to occur at the synapses of efferent projection. Here, the contralateral connectivity in mice auditory cortex was investigated to reveal the fundamental corticocortical connection properties. After HFES, plasticity was not observed at the terminal synapses at the recording site. The optogenetic HFS at the recording site of the interhemispheric cortical projections could not induce LTP, but HFES at the recording site could induce the interhemispheric cortical LTP. Our subsequent results uncovered that it is the cholecystokinin (CCK) released from the entorhino-neocortical pathway induced by HEFS that modulates the neuroplasticity of the afferent projections, including interhemispheric auditory cortical afferents. Our study illustrates a heterosynaptic mechanism as the basis for cortical plasticity. This regulation might contribute new spots for the understanding and treatment of neurological disorders.

In a natural acoustic environment, a preceding sound can suppress the perception of a succeeding sound which can lead to auditory phenomena such as forward masking and the precedence effect. The degree of suppression is dependent on the relationship between the sounds in sound quality, timing, and location. Correlates of such phenomena exist in sound-elicited activities of neurons in hearing-related brain structures. The present study recorded responses to pairs of leading-trailing sounds from ensembles of neurons in the rat’s inferior colliculus. Results indicated that a leading sound produced a suppressive aftereffect on the response to a trailing sound when the two sounds were colocalized at the ear contralateral to the site of recording (i.e., the ear that drives excitatory inputs to the inferior colliculus). The degree of suppression was reduced when the time gap between the two sounds was increased or when the leading sound was relocated to an azimuth at or close to the ipsilateral ear. Local blockage of the type-A γ-aminobutyric acid receptor partially reduced the suppressive aftereffect when a leading sound was at the contralateral ear but not at the ipsilateral ear. Local blockage of the glycine receptor partially reduced the suppressive aftereffect regardless of the location of the leading sound. Results suggest that a sound-elicited suppressive aftereffect in the inferior colliculus is partly dependent on local interaction between excitatory and inhibitory inputs which likely involves those from brainstem structures such as the superior paraolivary nucleus. These results are important for understanding neural mechanisms underlying hearing in a multiple-sound environment.

In humans, the level of consciousness is assessed by quantifying the spatiotemporal complexity of cortical responses using Perturbational Complexity Index (PCI) and related PCIst (st, state transitions). Here we validate PCIst in freely moving rats and mice by showing that it is lower in NREM sleep and slow wave anesthesia than in wake or REM sleep, as in humans. We then show that (1) low PCIst is associated with the occurrence of an OFF period of neuronal silence; (2) stimulation of deep, but not superficial, cortical layers leads to reliable PCIst changes across sleep/wake and anesthesia; (3) consistent PCIst changes are independent of which single area is being stimulated or recorded, except for recordings in mouse prefrontal cortex. These experiments show that PCIst can reliably measure vigilance states in unresponsive animals and support the hypothesis that it is low when an OFF period disrupts causal interactions in cortical networks.

Cholecystokinin (CCK) enables excitatory circuit long-term potentiation (LTP). Here, we investigated its involvement in the enhancement of inhibitory synapses. Activation of GABA neurons suppressed neuronal responses in the neocortex to a forthcoming auditory stimulus in mice of both sexes. High-frequency laser stimulation (HFLS) of GABAergic neurons potentiated this suppression. HFLS of CCK interneurons could induce the LTP of their inhibition toward pyramidal neurons. This potentiation was abolished in CCK knock-out mice but intact in mice with both CCK1R and 2R knockout of both sexes. Next, we combined bioinformatics analysis, multiple unbiased cell-based assays, and histology examinations to identify a novel CCK receptor, GPR173. We propose GPR173 as CCK3R, which mediates the relationship between cortical CCK interneuron signaling and inhibitory LTP in the mice of either sex. Thus, GPR173 might represent a promising therapeutic target for brain disorders related to excitation and inhibition imbalance in the cortex. SIGNIFICANCE STATEMENT CCK, the most abundant and widely distributed neuropeptide in the CNS, colocalizes with many neurotransmitters and modulators. GABA is one of the important inhibitory neurotransmitters, and much evidence shows that CCK may be involved in modulating GABA signaling in many brain areas. However, the role of CCK-GABA neurons in the cortical microcircuits is still unclear. We identified a novel CCK receptor, GPR173, localized in the CCK-GABA synapses and mediated the enhancement of the GABA inhibition effect, which might represent a promising therapeutic target for brain disorders related to excitation and inhibition imbalance in the cortex.

The cerebral cortex is spontaneously active during sleep, yet it is unclear how this global cortical activity is spatiotemporally organized, and whether such activity not only reflects sleep states but also contributes to sleep state switching. Here we report that cortex-wide calcium imaging in mice revealed distinct sleep stage-dependent spatiotemporal patterns of global cortical activity, and modulation of such patterns could regulate sleep state switching. In particular, elevated activation in the occipital cortical regions (including the retrosplenial cortex and visual areas) became dominant during rapid-eye-movement (REM) sleep. Furthermore, such pontogeniculooccipital (PGO) wave-like activity was associated with transitions to REM sleep, and optogenetic inhibition of occipital activity strongly promoted deep sleep by suppressing the NREM-to-REM transition. Thus, whereas subcortical networks are critical for initiating and maintaining sleep and wakefulness states, distinct global cortical activity also plays an active role in controlling sleep states.