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Self-administration of addictive substances like heroin can couple the rewarding/euphoric effects of the drug with drug-associated cues, and opioid cue reactivity contributes to relapse vulnerability in abstinent individuals recovering from an opioid use disorder (OUD). Opioids are reported to alter the intrinsic excitability of medium spiny neurons (MSNs) in the nucleus accumbens (NAc), a key brain reward region linked to drug seeking, but how opioids alter NAc MSN neuronal excitability and the impact of altered MSN excitability on relapse-like opioid seeking remain unclear. Here, we discovered that self-administered, but not experimenter-administered, heroin reduced NAc protein levels of the voltage-gated sodium channel auxiliary subunit, SCN1b, in male and female rats. Viral-mediated reduction of NAc SCN1b increased the intrinsic excitability of MSNs, but without altering glutamatergic and GABAergic synaptic transmission. While reducing NAc SCN1b levels had no effect on acquisition of heroin self-administration or extinction learning, we observed a significant increase in cue-reinstated heroin seeking, suggesting that NAc SCN1b normally limits cue-reinstated heroin seeking. We also observed that NAc SCN1b protein levels returned to baseline following heroin self-administration, home-cage abstinence, and extinction training, suggesting that the noted reduction of NAc SCN1b during acquisition of heroin self-administration likely enhances MSN excitability and the strength of heroin-cue associations formed during active heroin use. As such, enhancing NAc SCN1b function might mitigate opioid cue reactivity and a return to active drug use in individuals suffering from OUD.

Neuroinflammation has been widely recognized as the primary pathophysiological mechanism underlying ischemic white matter lesions (IWML) in chronic cerebral hypoperfusion (CCH). Adenosine A2A receptor (A2aR), an important adenosine receptor, exhibits a dual role in neuroinflammation by modulating both proinflammatory and anti-inflammatory responses. This study aimed to investigate the specific functions and mechanisms of A2aR in neuroinflammation. The findings revealed that A2aR initially exerted a proinflammatory role in the CCH model, transitioning to an anti-inflammatory role in later stages by regulating the phenotypic transformation of microglia. Further analyses using coimmunoprecipitation couple with mass spectrometry, in situ proximity ligation assay, AlphaFold protein structure prediction, [³⁵S]GTPγS binding assay, and NanoBiT technology demonstrated that A2aR formed heteromers with mGluR5 during the early stage of CCH under high glutamate conditions, promoting the polarization of microglia toward a proinflammatory phenotype. In contrast, during later stages characterized by low glutamate levels, A2aR predominantly existed as a monomer, facilitating microglial polarization toward an anti-inflammatory phenotype. Our findings indicate that elevated glutamate levels drive the formation of A2aR-mGluR5 heteromers, contributing to neuroinflammation by promoting proinflammatory microglial polarization in CCH white matter. Conversely, under low glutamate conditions, A2aR primarily functions in its monomeric form, favoring an anti-inflammatory microglial phenotype and exerting a protective effect. This study elucidates the mechanism by which A2aR mediates microglial phenotypic transformation and participates in neuroinflammation under CCH. It also identifies A2aR as a potential therapeutic target for the treatment of IWML.

Human brain banks are essential for studying a wide variety of neurological and neurodegenerative diseases, yet the variability in postmortem interval (PMI)-the time from death to tissue preservation-poses significant challenges due to rapid cellular decomposition, protein alterations, and RNA degradation. Furthermore, the postmortem transcriptomic alterations occurring within distinct cell types are poorly understood. In this study, we analyzed the effect of a 3 h postmortem interval on single-nucleus RNA signatures in the brains of wild-type (WT) and PS19 mice, a common model of tauopathy. We observed that basic quality control metrics (such as the number of genes and reads per cell), total nuclei counts, and RNA integrity number (RIN^e) remained consistent across all samples, regardless of PMI or genotype. However, a 3 h PMI diminished the number of genes differentially expressed between PS19 and WT mice, suggesting an impact of delayed processing on the detection of disease-specific transcriptomic signatures. When directly comparing 3 h PMI versus freshly harvested 0 h mouse brains, we identified genes upregulated in neurons and interneurons involved in DNA repair, immune response, and stress pathways. Furthermore, genes that were altered in non-neuronal cell types at 3 versus 0 h PMI were associated with cell-cell adhesion processes. These findings highlight the effects of PMI on single-nucleus transcriptional changes that may dampen the true changes in cellular states in banked brain tissues.

Epilepsy, affecting millions globally, often leads to significant cognitive and psychiatric comorbidities, particularly in children. Anxiety and depression are particularly prevalent, with roughly a quarter of pediatric epilepsy patients having a comorbid diagnosis. Current treatments inadequately address these issues. Adrenocorticotropic hormone (ACTH), a melanocortin peptide, has shown promise in mitigating deficits after early-life seizures (ELS), potentially through mechanisms beyond its canonical action on the melanocortin 2 receptor. This study explores the hypothesis that recurrent ELS is associated with long-term anxiety and that treatment with ACTH can prevent this anxiety through a mechanism that involves the melanocortin 4 receptor (MC4R) in the brain. Our findings reveal that ACTH ameliorates anxiety-like behavior associated with ELS, without altering seizure parameters, in wild-type but not in male and female MC4R knock-out mice. Our findings also show that knocking-in MC4R in either neurons or astrocytes was able to rescue the anxiety-like behavior after ACTH treatment. Furthermore, our results show that ACTH normalizes important astrocytic proteins like glial fibrillary acidic protein and aquaporin-4 after ELS. This suggests that ACTH's beneficial effects on anxiety are mediated through MC4R activation in both neuronal and astrocytic populations. This study underscores the therapeutic potential of targeting MC4R as a treatment, highlighting its role in mitigating anxiety-like behaviors associated with ELS.

Recent findings have shifted the view of cholecystokinin (CCK) from being a cellular neuronal marker to being recognized as a crucial neuropeptide pivotal in synaptic plasticity and memory processes. Despite its now appreciated importance in various brain regions and abundance in the basal ganglia, its role in the striatum, which is vital for motor control, remains unclear. This study sought to fill this gap by performing a comprehensive investigation of the role of CCK in modulating striatal medium spiny neuron (MSN) membrane properties, as well as the secondary somatosensory cortex S2 to MSN synaptic transmission and plasticity in rodents. Using in vivo optopatch-clamp recording in mice on identified MSNs, we showed that the application of CCK receptor Type 2 (CCK2R) antagonists decreases corticostriatal transmission in both direct and indirect pathway MSNs. Moving to an ex vivo rat preparation to maximize experimental access, we showed that CCK2R inhibition impacts MSN membrane properties by reducing spike threshold and rheobase, suggesting an excitability increase. Moreover, CCK modulates corticostriatal transmission mainly via CCK2R, and CCK2R blockage shifted spike-timing-dependent plasticity from long-term potentiation to long-term depression. Our study advances the understanding of CCK's importance in modulating corticostriatal transmission. By showing how CCK2R blockade influences synaptic function and plasticity, we provide new insights into the mechanisms underlying striatal functions, opening new paths for exploring its potential relevance to neurological disorders involving basal ganglia-related behaviors.

Electrophysiology recordings from the brain using laminar multielectrode arrays allow researchers to measure the activity of many neurons simultaneously. However, laminar microelectrode arrays move relative to their surrounding neural tissue for a variety of reasons, such as pulsation, changes in intracranial pressure, and decompression of neural tissue after insertion. Inferring and correcting for this motion stabilizes the recording and is critical to identify and track single neurons across time. Such motion correction is a preprocessing step of standard spike-sorting methods. However, estimating motion robustly and accurately in electrophysiology recordings is challenging due to the stochasticity of the neural data. To tackle this problem, we introduce MEDiCINe (Motion Estimation by Distributional Contrastive Inference for Neurophysiology), a novel motion estimation method. We show that MEDiCINe outperforms existing motion estimation methods on an extensive suite of simulated neurophysiology recordings and leads to more accurate spike sorting. We also show that MEDiCINe accurately estimates the motion in primate and rodent electrophysiology recordings with a variety of motion and stability statistics. We open-source MEDiCINe, usage instructions, examples integrating MEDiCINe with common tools for spike sorting, and data and code for reproducing our results. This open software will enable other researchers to use MEDiCINe to improve spike sorting results and get the most out of their electrophysiology datasets.

Beta event-related spectral perturbation (ERSP), including bilateral movement-related beta desynchronization (MRBD) and post-movement beta synchronization (PMBS), can be evoked by unilateral speed movement. A potential correlation might exist between power (de)synchronization and interhemispheric coherence during movement execution. However, during the PMBS phase, the existence of interhemispheric coupling and the effect of speed on it are largely undiscovered. This study aimed to answer this question. In the present study, we investigated eight healthy, right-handed volunteers using a combination of electroencephalography (EEG), transcranial magnetic stimulation (TMS), and electromyography (EMG). We explored interhemispheric (directed) coherence during isotonic right index finger abduction movements at two speeds: ballistic and self-paced. We discovered that: (i) Compared to the MRBD period, interhemispheric coherence was greater during the PMBS period. Furthermore, ballistic movement induced a larger coherence during the PMBS period, but not during the MRBD period. (ii) In the MRBD phase, directed coherence from the contralateral motor cortex (CM1) to the ipsilateral motor cortex (IM1) was larger, with a reverse tendency observed during the PMBS period. Additionally, in ballistic movement, directed coherence from IM1 to CM1 was stronger and positively correlated with coherence, with no effect of speed on directed coherence detected in the MRBD phase. To advance the understanding of neural mechanisms and the causality of interhemispheric coherence during the PMBS period, we investigated the interhemispheric inhibition (IHI) from IM1 to CM1 at different speeds. A stronger IHI from IM1 to CM1 at PMBS peak time was demonstrated, which was enhanced during ballistic movement. Additionally, IHI was negatively correlated with PMBS, and movement speed was positively associated with interhemispheric coupling during the PMBS period and IHI from IM1 to CM1.Significance Statement The present study explored interhemispheric (directed)coherence during isotonic right index finger abduction movements at two speeds: ballistic and self-paced. We discovered a dominance of interhemispheric coherence during the PMBS period of ballistic movement. Furthermore, directed coherence from the CM1 to the IM1 was more predominant in the MRBD phase, with a reverse tendency observed during the PMBS period. Additionally, directed coherence from IM1 to CM1 was stronger and positively correlated with coherence in ballistic movement. Advanced exploration revealed a stronger IHI from IM1 to CM1 at PMBS peak time, which was enhanced during ballistic movement. Additionally, IHI was negatively correlated with PMBS, and movement speed was positively associated with interhemispheric coupling during the PMBS period and IHI.

Alpha (8-12 Hz) oscillations and default mode network (DMN) activity dominate the brain's intrinsic activity in the temporal and spatial domains, respectively. They are thought to play crucial roles in the spatiotemporal organization of the complex brain system. Relatedly, both have been implicated, often concurrently, in diverse neuropsychiatric disorders, with accruing electroencephalogram/magnetoencephalogram (EEG/MEG) and functional magnetic resonance imaging (fMRI) data linking these two neural activities both at rest and during key cognitive operations. Prominent theories and extant findings thus converge to suggest a mechanistic relationship between alpha oscillations and the DMN. Here, we leveraged simultaneous EEG-fMRI data acquired before and after alpha-frequency transcranial alternating current stimulation (α-tACS) and observed that α-tACS tightened the dynamic coupling between spontaneous fluctuations in alpha power and DMN connectivity (especially, in the posterior DMN, between the posterior cingulate cortex and the bilateral angular gyrus). In comparison, no significant changes were observed for temporal correlations between power in other oscillatory frequencies and connectivity in other major networks. These results thus suggest an inherent coupling between alpha and DMN activity in humans. Importantly, these findings highlight the efficacy of α-tACS in regulating the DMN, a clinically significant network that is challenging to target directly with non-invasive methods.Significance Statement Alpha (8-12 Hz) oscillations and the default mode network (DMN) represent two major intrinsic activities of the brain. Prominent theories and extant findings converge to suggest a mechanistic relationship between alpha oscillations and the DMN. Combining simultaneous electroencephalogram-functional-magnetic-resonance imaging (EEG-fMRI) with alpha-frequency transcranial alternating current stimulation (α-tACS), we demonstrated tightened coupling between alpha oscillations and DMN connectivity. These results lend credence to an inherent alpha-DMN link. Given DMN dysfunctions in multiple major neuropsychiatric conditions, the findings also highlight potential utility of α-tACS in clinical interventions by regulating the DMN.

Zebrafish have gained prominence as a model organism in neuroscience over the past several decades, generating key insight into the development and functioning of the vertebrate brain. However, techniques for whole brain mapping in adult stage zebrafish are lacking. Here, we describe a pipeline built using open-source tools for whole-brain activity mapping in adult zebrafish. Our pipeline combines advances in histology, microscopy, and machine learning to capture cfos activity across the entirety of the brain. Following tissue clearing, whole brain images are captured using light-sheet microscopy and registered to the recently created adult zebrafish brain atlas (AZBA) for automated segmentation. By way of example, we used our pipeline to measure brain activity after zebrafish were subject to the novel tank test, one of the most widely used behaviors in adult zebrafish. Cfos levels peaked 15 minutes following behavior and several regions, including those containing serotoninergic and dopaminergic neurons, were active during exploration. Finally, we generated a novel tank test functional brain network. This revealed that several regions of the subpallium form a cohesive sub-network during exploration. Functional interconnections between the subpallium and other regions appear to be mediated primarily by ventral nucleus of the ventral telencephalon (Vv), the olfactory bulb, and the anterior part of the parvocellular preoptic nucleus (PPa). Taken together, our pipeline enables whole-brain activity mapping in adult zebrafish while providing insight into neural basis for the novel tank test.Significance statement Zebrafish have grown in popularity as a model organism over the past several decades due to their low cost, ease of genetic manipulation, and similarity to other vertebrates like humans and rodents. However, to date, tools for whole-brain mapping in adult stage animals has been lacking. Here, we present an open-source pipeline for whole-brain mapping in adult zebrafish. We demonstrate the use of our pipeline by generating a functional brain network for one of the most widely used behavioral assays in adult zebrafish, the novel tank test. We found that exploration of a novel tank engages the olfactory bulb and a network of subpallial regions that correspond to the mammalian subpallial amygdala and basal ganglia.