Correlated Neural Activity across the Brains of Socially Interacting Bats.

Social interactions occur between multiple individuals, but what is the detailed relationship between the neural dynamics across their brains? To address this question across timescales and levels of neural activity, we used wireless electrophysiology to simultaneously record from pairs of bats engaged in a wide range of natural social interactions. We found that neural activity was remarkably correlated between their brains over timescales from seconds to hours. The correlation depended on a shared social environment and was most prominent in high frequency local field potentials (>30 Hz), followed by local spiking activity. Furthermore, the degree of neural correlation covaried with the extent of social interactions, and an increase in correlation preceded their initiation. These results show that inter-brain correlation is an inherent feature of natural social interactions, reveal the domain of neural activity where it is most prominent, and provide a foundation for studying its functional role in social behaviors.

Cracking and Packing Information about the Features of Expected Rewards in the Orbitofrontal Cortex.

The orbitofrontal cortex (OFC) is crucial for tracking various aspects of expected outcomes, thereby helping to guide choices and support learning. Our previous study showed that the effects of reward timing and size on the activity of single units in OFC were dissociable when these attributes were manipulated independently ( Roesch et al., 2006). However, in real-life decision-making scenarios, outcome features often change simultaneously, so here we investigated how OFC neurons in male rats integrate information about the timing and identity (flavor) of reward and respond to changes in these features, according to whether they were changed simultaneously or separately. We found that a substantial number of OFC neurons fired differentially to immediate versus delayed reward and to the different reward flavors. However, contrary to the previous study, selectivity for timing was strongly correlated with selectivity for identity. Taken together with the previous research, these results suggest that when reward features are correlated, OFC tends to "pack" them into unitary constructs, whereas when they are independent, OFC tends to "crack" them into separate constructs. Furthermore, we found that when both reward timing and flavor were changed, reward-responsive OFC neurons showed unique activity patterns preceding and during the omission of an expected reward. Interestingly, this OFC activity is similar and slightly preceded the ventral tegmental area dopamine (VTA DA) activity observed in a previous study ( Takahashi et al., 2023), consistent with the role of OFC in providing predictive information to VTA DA neurons.

Distinct Action Signals by Subregions in the Nucleus Accumbens during STOP-Change Performance.

The nucleus accumbens (NAc) is thought to contribute to motivated behavior by signaling the value of reward-predicting cues and the delivery of anticipated reward. The NAc is subdivided into core and shell, with each region containing different populations of neurons that increase or decrease firing to rewarding events. While there are numerous theories of functions pertaining to these subregions and cell types, most are in the context of reward processing, with fewer considering that the NAc might serve functions related to action selection more generally. We recorded from single neurons in the NAc as rats of both sexes performed a STOP-change task that is commonly used to study motor control and impulsivity. In this task, rats respond quickly to a spatial cue on 80% of trials (GO) and must stop and redirect planned movement on 20% of trials (STOP). We found that the activity of reward-excited neurons signaled accurate response direction on GO, but not STOP, trials and that these neurons exhibited higher precue firing after correct trials. In contrast, reward-inhibited neurons significantly represented response direction on STOP trials at the time of the instrumental response. Finally, the proportion of reward-excited to reward-inhibited neurons and the strength of precue firing decreased as the electrode traversed the NAc. We conclude that reward-excited cells (more common in core) promote proactive action selection, while reward-inhibited cells (more common in shell) contribute to accurate responding on STOP trials that require reactive suppression and redirection of behavior.

Thalamocortical Dynamics during Rapid Eye Movement Sleep in the Mouse Somatosensory Pathway.

Rapid eye movement (REM) sleep, also referred to as paradoxical sleep for the striking resemblance of its electroencephalogram (EEG) to the one observed in wakefulness, is characterized by the occurrence of transient events such as limb twitches or facial and rapid eye movements. Here, we investigated the local activity of the primary somatosensory or barrel cortex (S1) in naturally sleeping head-fixed male mice during REM. Through local field potential recordings, we uncovered local appearances of spindle waves in the barrel cortex during REM concomitant with strong delta power, challenging the view of a wakefulness-like activity in REM. We further performed extra- and intracellular recordings of thalamic cells in head-fixed mice. Our data show high-frequency thalamic bursts of spikes and subthreshold spindle oscillations in approximately half of the neurons of the ventral posterior medial nucleus which further confirmed the thalamic origin of local cortical spindles in S1 in REM. Cortical spindle oscillations were suppressed, while thalamus spike firing increased, associated with rapid mouse whisker movements and S1 cortical activity transitioned to an activated state. During REM, the sensory thalamus and barrel cortex therefore alternate between high (wake-like) and low (non-REM sleep-like) activation states, potentially providing a neuronal substrate for mnemonic processes occurring during this paradoxical sleep stage.

Value-Based Search Efficiency Is Encoded in the Substantia Nigra Reticulata Firing Rate, Spiking Irregularity and Local Field Potential.

Recent results show that valuable objects can pop out in visual search, yet its neural mechanisms remain unexplored. Given the role of substantia nigra reticulata (SNr) in object value memory and control of gaze, we recorded its single-unit activity while male macaque monkeys engaged in efficient or inefficient search for a valuable target object among low-value objects. The results showed that efficient search was concurrent with stronger inhibition and higher spiking irregularity in the target-present (TP) compared with the target-absent (TA) trials in SNr. Importantly, the firing rate differentiation of TP and TA trials happened within ∼100 ms of display onset, and its magnitude was significantly correlated with the search times and slopes (search efficiency). Time-frequency analyses of local field potential (LFP) after display onset revealed significant modulations of the gamma band power with search efficiency. The greater reduction of SNr firing in TP trials in efficient search can create a stronger disinhibition of downstream superior colliculus, which in turn can facilitate saccade to obtain valuable targets in competitive environments.

Posterior parietal cortex predicts upcoming movement in dynamic sensorimotor control.

SignificanceMost studies in sensorimotor neurophysiology have utilized reactive movements to stationary goals pre-defined by sensory cues, but this approach is fundamentally incapable of determining whether the observed neural activity reflects current sensory stimuli or predicts future movements. In the present study, we recorded single-neuron activity from behaving monkeys engaged in a dynamic, flexible, stimulus-response contingency task that enabled us to distinguish activity co-varying with sensory inflow from that co-varying with motor outflow in the posterior parietal cortex.

Two kinds of memory signals in neurons of the human hippocampus.

Prior studies of the neural representation of episodic memory in the human hippocampus have identified generic memory signals representing the categorical status of test items (novel vs. repeated), whereas other studies have identified item specific memory signals representing individual test items. Here, we report that both kinds of memory signals can be detected in hippocampal neurons in the same experiment. We recorded single-unit activity from four brain regions (hippocampus, amygdala, anterior cingulate, and prefrontal cortex) of epilepsy patients as they completed a continuous recognition task. The generic signal was found in all four brain regions, whereas the item-specific memory signal was detected only in the hippocampus and reflected sparse coding. That is, for the item-specific signal, each hippocampal neuron responded strongly to a small fraction of repeated words, and each repeated word elicited strong responding in a small fraction of neurons. The neural code was sparse, pattern-separated, and limited to the hippocampus, consistent with longstanding computational models. We suggest that the item-specific episodic memory signal in the hippocampus is fundamental, whereas the more widespread generic memory signal is derivative and is likely used by different areas of the brain to perform memory-related functions that do not require item-specific information.

Fast-Spiking Interneurons of the Premotor Cortex Contribute to Initiation and Execution of Spontaneous Actions.

Planning and execution of voluntary movement depend on the contribution of distinct classes of neurons in primary motor and premotor areas. However, timing and pattern of activation of GABAergic cells during specific motor behaviors remain only partly understood. Here, we directly compared the response properties of putative pyramidal neurons (PNs) and GABAergic fast-spiking neurons (FSNs) during spontaneous licking and forelimb movements in male mice. Recordings centered on the face/mouth motor field of the anterolateral motor cortex (ALM) revealed that FSNs fire longer than PNs and earlier for licking, but not for forelimb movements. Computational analysis revealed that FSNs carry vastly more information than PNs about the onset of movement. While PNs differently modulate their discharge during distinct motor acts, most FSNs respond with a stereotyped increase in firing rate. Accordingly, the informational redundancy was greater among FSNs than PNs. Finally, optogenetic silencing of a subset of FSNs reduced spontaneous licking movement. These data suggest that a global rise of inhibition contributes to the initiation and execution of spontaneous motor actions.SIGNIFICANCE STATEMENT Our study contributes to clarifying the causal role of fast-spiking neurons (FSNs) in driving initiation and execution of specific, spontaneous movements. Within the face/mouth motor field of mice premotor cortex, FSNs fire before pyramidal neurons (PNs) with a specific activation pattern: they reach their peak of activity earlier than PNs during the initiation of licking, but not of forelimb, movements; duration of FSNs activity is also greater and exhibits less selectivity for the movement type, as compared with that of PNs. Accordingly, FSNs appear to carry more redundant information than PNs. Optogenetic silencing of FSNs reduced spontaneous licking movement, suggesting that FSNs contribute to the initiation and execution of specific spontaneous movements, possibly by sculpting response selectivity of nearby PNs.

In search of the locus coeruleus: guidelines for identifying anatomical boundaries and electrophysiological properties of the blue spot in mice, fish, finches, and beyond.

Our understanding of human brain function can be greatly aided by studying analogous brain structures in other organisms. One brain structure with neurochemical and anatomical homology throughout vertebrate species is the locus coeruleus (LC), a small collection of norepinephrine (NE)-containing neurons in the brainstem that project throughout the central nervous system. The LC is involved in nearly every aspect of brain function, including arousal and learning, which has been extensively examined in rats and nonhuman primates using single-unit recordings. Recent work has expanded into putative LC single-unit electrophysiological recordings in a nonmodel species, the zebra finch. Given the importance of correctly identifying analogous structures as research efforts expand to other vertebrates, we suggest adoption of consensus anatomical and electrophysiological guidelines for identifying LC neurons across species when evaluating brainstem single-unit spiking or calcium imaging. Such consensus criteria will allow for confident cross-species understanding of the roles of the LC in brain function and behavior.

Rat anterior cingulate neurons responsive to rule or strategy changes are modulated by the hippocampal theta rhythm and sharp-wave ripples.

To better understand neural processing during adaptive learning of stimulus-response-reward contingencies, we recorded synchrony of neuronal activity in anterior cingulate cortex (ACC) and hippocampal rhythms in male rats acquiring and switching between spatial and visual discrimination tasks in a Y-maze. ACC population activity as well as single unit activity shifted shortly after task rule changes or just before the rats adopted different task strategies. Hippocampal theta oscillations (associated with memory encoding) modulated an elevated proportion of rule-change responsive neurons (70%), but other neurons that were correlated with strategy-change, strategy value and reward-rate were not. However, hippocampal sharp wave-ripples modulated significantly higher proportions of rule-change, strategy-change and reward-rate responsive cells during post-session sleep but not pre-session sleep. This suggests an underestimated mechanism for hippocampal mismatch and contextual signals to facilitate ACC to detect contingency changes for cognitive flexibility, a function that is attenuated after it is damaged.

Aging suppresses subthalamic neuronal activity in patients with Parkinson's disease.

Age is a primary risk factor for Parkinson's disease (PD); however, the effects of aging on the Parkinsonian brain remain poorly understood, particularly for deep brain structures. We investigated intraoperative micro-electrode recordings from the subthalamic nucleus (STN) of PD patients aged between 42 and 76 years. Age was associated with decreased oscillatory beta power and non-oscillatory high-frequency power, independent of PD-related variables. Single unit firing and burst rates were also reduced, whereas the coefficient of variation and the structure of burst activity were unchanged. Phase synchronization (debiased weighed phase lag index [dWPLI]) between sites was pronounced in the beta band between electrodes in the superficial STN but was unaffected by age. Our results show that aging is associated with reduced neuronal activity without changes to its temporal structure. We speculate that the loss of activity in the STN may mediate the relationship between PD and age.

Photobiomodulation transiently increases the spontaneous firing in the superficial layer of the rat spinal dorsal horn.

The therapeutic benefits of photobiomodulation (PBM) in pain management, although well documented, are accompanied by concerns about potential risks, including pain, particularly at higher laser intensities. This study investigated the effects of laser intensity on pain perception using behavioral and electrophysiological evaluations in rats. Our results show that direct laser irradiation of 1000 mW/cm2 to the sciatic nerve transiently increases the frequency of spontaneous firing in the superficial layer without affecting the deep layer of the spinal dorsal horn, and this effect reverses to pre-irradiation levels after irradiation. Interestingly, laser irradiation at 1000 mW/cm2, which led to an increase in spontaneous firing, did not prompt escape behavior. Furthermore, a significant reduction in the time to initiate escape behavior was observed only at 9500 mW/cm2 compared to 15, 510, 1000, and 4300 mW/cm2. This suggests that 1000 mW/cm2, the laser intensity at which an increase in spontaneous firing was observed, corresponds to a stimulus that did not cause pain. It is expected that a detailed understanding of the risks and mechanisms of PBM from a neurophysiological perspective will lead to safer and more effective use of PBM.

OFC neurons do not represent the negative value of a conditioned inhibitor.

The orbitofrontal cortex (OFC) is often proposed to function as a value integrator; however, alternative accounts focus on its role in representing associative structures that specify the probability and sensory identity of future outcomes. These two accounts make different predictions about how this area should respond to conditioned inhibitors of reward, since in the former, neural activity should reflect the negative value of the inhibitor, whereas in the latter, it should track the estimated probability of a future reward based on all cues present. Here, we assessed these predictions by recording from small groups of neurons in the lateral OFC of rats during training in a conditioned inhibition design. Rats showed negative summation when the inhibitor was compounded with a novel excitor, suggesting that they learned to respond to the conditioned inhibitor appropriately. Against this backdrop, we found unit and population responses that scaled with expected reward value on excitor + inhibitor compound trials. However, the responses of these neurons did not differentiate between the conditioned inhibitor and a neutral cue when both were presented in isolation. Further, when the ensemble patterns were analyzed, activity to the conditioned inhibitor did not classify according to putative negative value. Instead, it classified with a same-modality neutral cue when presented alone and as a unique item when presented in compound with a novel excitor. This pattern of results supports the notion that OFC encodes a model of the causal structure of the environment rather than either the modality or the value of cues.

Cell-type specific and multiscale dynamics of human focal seizures in limbic structures.

The relationship between clinically accessible epileptic biomarkers and neuronal activity underlying the transition to seizure is complex, potentially leading to imprecise delineation of epileptogenic brain areas. In particular, the pattern of interneuronal firing at seizure onset remains under debate, with some studies demonstrating increased firing and others suggesting reductions. Previous study of neocortical sites suggests that seizure recruitment occurs upon failure of inhibition, with intact feedforward inhibition in non-recruited territories. We investigated whether the same principle applies in limbic structures. We analysed simultaneous electrocorticography (ECoG) and neuronal recordings of 34 seizures in a cohort of 19 patients (10 male, 9 female) undergoing surgical evaluation for pharmacoresistant focal epilepsy. A clustering approach with five quantitative metrics computed from ECoG and multiunit data was used to distinguish three types of site-specific activity patterns during seizures, which at times co-existed within seizures. Overall, 156 single units were isolated, subclassified by cell-type and tracked through the seizure using our previously published methods to account for impacts of increased noise and single-unit waveshape changes caused by seizures. One cluster was closely associated with clinically defined seizure onset or spread. Entrainment of high-gamma activity to low-frequency ictal rhythms was the only metric that reliably identified this cluster at the level of individual seizures (P < 0.001). A second cluster demonstrated multi-unit characteristics resembling those in the first cluster, without concomitant high-gamma entrainment, suggesting feedforward effects from the seizure. The last cluster captured regions apparently unaffected by the ongoing seizure. Across all territories, the majority of both excitatory and inhibitory neurons reduced (69.2%) or ceased firing (21.8%). Transient increases in interneuronal firing rates were rare (13.5%) but showed evidence of intact feedforward inhibition, with maximal firing rate increases and waveshape deformations in territories not fully recruited but showing feedforward activity from the seizure, and a shift to burst-firing in seizure-recruited territories (P = 0.014). This study provides evidence for entrained high-gamma activity as an accurate biomarker of ictal recruitment in limbic structures. However, reduced neuronal firing suggested preserved inhibition in mesial temporal structures despite simultaneous indicators of seizure recruitment, in contrast to the inhibitory collapse scenario documented in neocortex. Further study is needed to determine if this activity is ubiquitous to hippocampal seizures or indicates a 'seizure-responsive' state in which the hippocampus is not the primary driver. If the latter, distinguishing such cases may help to refine the surgical treatment of mesial temporal lobe epilepsy.

Local neuronal excitation and global inhibition during epileptic fast ripples in humans.

Understanding the neuronal basis of epileptic activity is a major challenge in neurology. Cellular integration into larger scale networks is all the more challenging. In the local field potential, interictal epileptic discharges can be associated with fast ripples (200-600 Hz), which are a promising marker of the epileptogenic zone. Yet, how neuronal populations in the epileptogenic zone and in healthy tissue are affected by fast ripples remain unclear. Here, we used a novel 'hybrid' macro-micro depth electrode in nine drug-resistant epileptic patients, combining classic depth recording of local field potentials (macro-contacts) and two or three tetrodes (four micro-wires bundled together) enabling up to 15 neurons in local circuits to be simultaneously recorded. We characterized neuronal responses (190 single units) with the timing of fast ripples (2233 fast ripples) on the same hybrid and other electrodes that target other brain regions. Micro-wire recordings reveal signals that are not visible on macro-contacts. While fast ripples detected on the closest macro-contact to the tetrodes were always associated with fast ripples on the tetrodes, 82% of fast ripples detected on tetrodes were associated with detectable fast ripples on the nearest macro-contact. Moreover, neuronal recordings were taken in and outside the epileptogenic zone of implanted epileptic subjects and they revealed an interlay of excitation and inhibition across anatomical scales. While fast ripples were associated with increased neuronal activity in very local circuits only, they were followed by inhibition in large-scale networks (beyond the epileptogenic zone, even in healthy cortex). Neuronal responses to fast ripples were homogeneous in local networks but differed across brain areas. Similarly, post-fast ripple inhibition varied across recording locations and subjects and was shorter than typical inter-fast ripple intervals, suggesting that this inhibition is a fundamental refractory process for the networks. These findings demonstrate that fast ripples engage local and global networks, including healthy tissue, and point to network features that pave the way for new diagnostic and therapeutic strategies. They also reveal how even localized pathological brain dynamics can affect a broad range of cognitive functions.

Synthesis of Dendrimer-Like Molecules with Partial Carbon Chain via Iterative Single Unit Monomer Insertions.

Carbon-chain dendritic polymers hold unique properties and promising applications. However, synthesizing carbon-chain dendrimers, beyond conjugated ones, remains a challenge. Here, the use of the iterative single unit monomer insertion technique for synthesizing 2.5 generation partial-carbon-chain dendrimers (G2.5) is described, utilizing bismaleimide as the core, a maleimide-trithiocarbonate conjugate as the branching unit, and indene as the spacer unit, following a divergent growth strategy. The optimized conditions for synthesizing the maleimide-trithiocarbonate branching unit are a bismaleimide to trithiocarbonate ratio of 5:1 and a reaction time of 30 min. The structures are verified using 1H nuclear magnetic resonance, gel permeation chromatography, and matrix-assisted laser desorption/ionization-time of flight mass spectra. A four-arm star polymer is then synthesized using the G2.5 as the core. This synthesis of a partial-carbon-chain dendrimer establishes a foundational step toward creating all-carbon-chain ones and may open new application avenues in material science.

Spontaneous activity in cortical neurons is stereotyped and non-Poisson.

Neurons fire even in the absence of sensory stimulation or task demands. Numerous theoretical studies have modeled this spontaneous activity as a Poisson process with uncorrelated intervals between successive spikes and a variance in firing rate equal to the mean. Experimental tests of this hypothesis have yielded variable results, though most have concluded that firing is not Poisson. However, these tests say little about the ways firing might deviate from randomness. Nor are they definitive because many different distributions can have equal means and variances. Here, we characterized spontaneous spiking patterns in extracellular recordings from monkey, cat, and mouse cerebral cortex neurons using rate-normalized spike train autocorrelation functions (ACFs) and a logarithmic timescale. If activity was Poisson, this function should be flat. This was almost never the case. Instead, ACFs had diverse shapes, often with characteristic peaks in the 1-700 ms range. Shapes were stable over time, up to the longest recording periods used (51 min). They did not fall into obvious clusters. ACFs were often unaffected by visual stimulation, though some abruptly changed during brain state shifts. These behaviors may have their origin in the intrinsic biophysics and dendritic anatomy of the cells or in the inputs they receive.

Cortical and thalamic modulation of auditory gating in the posterior parietal cortex of awake mice.

Auditory gating (AG) is an adaptive mechanism for filtering out redundant acoustic stimuli to protect the brain against information overload. AG deficits have been found in many mental illnesses, including schizophrenia (SZ). However, the neural correlates of AG remain poorly understood. Here, we found that the posterior parietal cortex (PPC) shows an intermediate level of AG in auditory thalamocortical circuits, with a laminar profile in which the strongest AG is in the granular layer. Furthermore, AG of the PPC was decreased and increased by optogenetic inactivation of the medial dorsal thalamic nucleus (MD) and auditory cortex (AC), respectively. Optogenetically activating the axons from the MD and AC drove neural activities in the PPC without an obvious AG. These results indicated that AG in the PPC is determined by the integrated signal streams from the MD and AC in a bottom-up manner. We also found that a mouse model of SZ (postnatal administration of noncompetitive N-methyl-d-aspartate receptor antagonist) presented an AG deficit in the PPC, which may be inherited from the dysfunction of MD. Together, our findings reveal a neural circuit underlying the generation of AG in the PPC and its involvement in the AG deficit of SZ.

Effect of theanine on the hyperexcitability of trigeminal secondary nociceptive neurons following orofacial inflammation in rats.

The present in vivo study investigated whether systemic administration of theanine attenuates the inflammation-induced hyperexcitability of trigeminal spinal nucleus caudalis (SpVc) neurons associated with hyperalgesia. Complete Freund's adjuvant (CFA) was injected into the whisker pads of 24 rats to induce inflammation, and then mechanical stimulation was applied to the orofacial area to assess the threshold of escape. The mechanical threshold was statistically significantly lower in CFA-inflamed rats compared to uninjected naïve rats, and this lowered threshold returned to control levels after 2 days of theanine administration. The mean discharge frequency of SpVc wide-dynamic range (WDR) neurons to mechanical stimuli in anesthetized CFA-inflamed rats was statistically significantly lower after two days of theanine administration. In addition, the increased mean spontaneous discharge of SpVc WDR neurons in CFA-inflamed rats statistically significantly decreased after theanine administration. Similarly, theanine restored the expanded mean receptive field size in CFA-inflamed rats to control levels. Taken together, these results suggest that administration of theanine attenuates inflammatory hyperalgesia associated with hyperexcitability of nociceptive SpVc WDR neurons. These findings support the potential of theanine as a therapeutic agent in complementary alternative medicine strategies to prevent inflammatory hyperalgesia.

Clinical and radiographic evaluation of implant-supported single-unit crowns with cantilever extensions: A systematic review and meta-analysis.

PURPOSE: The purpose of this systematic review and meta-analysis was to analyze the clinical and radiographic outcomes of patients rehabilitated using a single implant supporting a crown with a cantilever extension or two implants supporting two single crowns. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 guidelines, a systematic review of relevant literature published from 2000 was conducted in the Cochrane Library, Scopus, and MEDLINE databases. Moreover, a manual search was performed. A meta-analysis of the resulting data was carried out. Peri-implant marginal bone level, probing pocket depth, prevalence of technical and mechanical complications, implant survival rate, and prosthesis survival rate were assessed. RESULTS: The meta-analysis showed a non-statistically significant change in the peri-implant marginal bone level and probing pocket depth in the cantilever group and revealed a non-significant prevalence of technical complications, showing a 27% rate in the cantilever group. The analysis of the prosthesis survival rate in the cantilever group showed a mean survival rate of 99% while the comparison of the implant survival between the two groups revealed an odds ratio of 0.50. CONCLUSIONS: The use of a single implant supporting a crown with a cantilever extension does not result in lower implant survival rate if compared with two implants supporting two single crowns. Moreover, a high prosthesis survival rate was observed in the cantilever group even if the high prevalence of complications should be carefully considered by the clinician.