Frontiers in Neural Circuits最新文献

The substantia nigra pars compacta (SNc), one of the main dopaminergic nuclei of the brain, exerts a regulatory function on the basal ganglia circuitry via the nigro-striatal pathway but its possible dopaminergic innervation of the thalamus has been only investigated in non-human primates. The impossibility of tract-tracing studies in humans has boosted advanced MRI techniques and multi-shell high-angular resolution diffusion MRI (MS-HARDI) has promised to shed more light on the structural connectivity of subcortical structures. Here, we estimated the possible dopaminergic innervation of the human thalamus via an MS-HARDI tractography of the SNc in healthy human young adults. Two MRI data sets were serially acquired using MS-HARDI schemes from ADNI and HCP neuroimaging initiatives in a group of 10 healthy human subjects (5 males, age range: 25-30 years). High resolution 3D-T1 images were independently acquired to individually segment the thalamus and the SNc. Starting from whole-brain probabilistic tractography, all streamlines through the SNc reaching the thalamus were counted, separately for each hemisphere, after excluding streamlines through the substantia nigra pars reticulata and all those reaching the basal ganglia, the cerebellum and the cortex. We found a reproducible structural connectivity between the SNc and the thalamus, with an average of ~12% of the total number of streamlines encompassing the SNc and terminating in the thalamus, with no other major subcortical or cortical structures involved. The first principal component map of dopamine receptor density from a normative PET image data set suggested similar dopamine levels across SNc and thalamus. This is the first quantitative report from in-vivo measurements in humans supporting the presence of a direct nigro-thalamic dopaminergic projection. While histological validation and concurrent PET-MRI remains needed for ultimate proofing of existence, given the potential role of this pathway, the possibility to achieve a good reproducibility of these measurements in humans might enable the monitoring of dopaminergic-related disorders, towards targeted personalized therapies.

A strong repetitive stimulus can occasionally enhance axonal excitability, leading to the generation of afterdischarge. This afterdischarge outlasts the stimulus period and originates either from the physiological spike initiation site, typically the axon initial segment, or from ectopic sites for spike generation. One of the possible mechanisms underlying the stimulus-induced ectopic afterdischarge is the local depolarization due to accumulated potassium ions surrounding the axonal membranes of the distal portion. In this study, the mechanisms were explored by computational approaches using a simple model of hippocampal mossy fibers implemented with the structure of en passant axons and experimentally obtained properties of ionic conductances. When slight depolarization of distal axons was given in conjunction with the high-frequency stimulus, robust afterdischarges were triggered after cessation of the repetitive stimulus and lasted for a prolonged period after the stimulus. Each spike during the afterdischarge recorded from distal axons precedes that recorded from the soma, suggesting that the afterdischarge was ectopically generated from distal axons and propagated antidromically toward the soma. Notably, when potassium channels in the model are replaced with non-inactivating ones, repetitive stimuli fail to induce afterdischarge. These results suggested that the inactivating property of axonal potassium channels plays a crucial role in generating the afterdischarge. Accumulated inactivation of potassium channels during strong repetitive stimulation may alter mossy fiber excitability, leading to ectopic afterdischarges from sites distinct from the physiological spike initiation region.

Introduction: Motor-imagery-based Brain-Machine Interface (MI-BMI) has been established as an effective treatment for post-stroke hemiplegia. However, the need for long-term intervention can represent a significant burden on patients. Here, we demonstrate that motor imagery (MI) instructions for BMI training, when supplemented with somatosensory stimulation in addition to conventional verbal instructions, can help enhance MI capabilities of healthy participants.

Methods: Sixteen participants performed MI during scalp EEG signal acquisition before and after somatosensory stimulation to assess MI-induced cortical excitability, as measured using the event-related desynchronization (ERD) of the sensorimotor rhythm (SMR). The non-dominant left hand was subjected to neuromuscular electrical stimulation above the sensory threshold but below the motor threshold (St-NMES), along with passive movement stimulation using an exoskeleton. Participants were randomly divided into an intervention group, which received somatosensory stimulation, and a control group, which remained at rest without stimulation.

Results: The intervention group exhibited a significant increase in SMR-ERD compared to the control group, indicating that somatosensory stimulation contributed to improving MI ability.

Discussion: This study demonstrates that somatosensory stimulation, combining electrical and mechanical stimuli, can improve MI capability and enhance the excitability of the sensorimotor cortex in healthy individuals.

According to the World Health Organization, the number of people suffering from depressive disorders worldwide is approaching 350 million. The consequences of depressive disorders include considerable worsening of the quality of life, which frequently leads to social isolation. One of the key factors which may cause depression in adulthood is early life stress, in particular, insufficient maternal care during infancy. Studies performed with children raised in orphanages have shown that long-term complete absence of maternal care (chronic early life stress) leads to vulnerability to emotional disorders, including depression, in adulthood. All of the above dictates the need for a deep understanding of the mechanisms of the pathogenicity of stress in neurogenesis. Therefore, the consequences of stress experienced in the early stages of development are actively studied in animal models. A large body of evidence has accumulated indicating stress-induced changes in gene expression and behavioral disorders in adulthood. However, the connection between the molecular biology of neurons and complex behavior runs through the synaptic connections linking these neurons into complex neural networks. In turn, coordinated activity in neuronal ensembles, achieved by a balance of synaptic excitation and inhibition, is the basis of complex behavior. Unfortunately, the effect of stress on synaptic interactions of neurons remains poorly understood.

Introduction: A fundamental property of the neocortex is its columnar organization in many species. Generally, neurons of the same column share stimulus preferences and have strong anatomical connections across layers. These features suggest that neurons within a column operate as one unified network. Other features, like the different patterns of input and output connections of neurons located in separate layers and systematic differences in feature tuning, hint at a more segregated and possibly flexible functional organization of neurons within a column.

Methods: To distinguish between these views of columnar processing, we conducted laminar recordings in macaques' area V1 while they performed a demanding attention task. We identified three separate regions with strong gamma oscillatory activity, located in the supragranular, granular, and infragranular laminar domains, based on the current source density (CSD).

Results and discussion: Their characteristics differed significantly in their dominant gamma frequency and attention-dependent modulation of their gramma power and gamma frequency. In line, spiking activity in the supragranular, infragranular, and upper part of the granular domain exhibited strong phase coherence with the CSD signals of their domain but showed much weaker coherence with the CSD signals of other domains.

Conclusion: These results indicate that columnar processing involves a certain degree of independence between neurons in the three laminar domains, consistent with the assumption of multiple, separate intracolumnar ensembles. Such a functional organization offers various possibilities for dynamic network configuration, indicating that neurons in a column are not restricted to operate as one unified network. Thus, the findings open interesting new possibilities for future concepts and investigations on flexible, dynamic cortical ensemble formation and selective information processing.

Our brain adapts to the environment by optimizing its function through experience-dependent cortical plasticity. This plasticity is transiently enhanced during a developmental stage, known as the "critical period," and subsequently maintained at lower levels throughout adulthood. Thus, understanding the mechanism underlying critical period plasticity is crucial for improving brain adaptability across the lifespan. Critical period plasticity relies on activity-dependent circuit remodeling through anatomical and functional changes at individual synapses. However, it remains challenging to identify the molecular signatures of synapses responsible for critical period plasticity and to understand how these plasticity-related synapses are spatiotemporally organized within a neuron. Recent advances in genetic tools and genome editing methodologies have enabled single-cell endogenous protein labeling in the brain, allowing for comprehensive molecular profiling of individual synapses within a neuron, namely "single-cell synaptome mapping." This promising approach can facilitate insights into the spatiotemporal organization of synapses that are sparse yet functionally important within single neurons. In this review, we introduce the basics of single-cell synaptome mapping and discuss its methodologies and applications to investigate the synaptic and cellular mechanisms underlying circuit remodeling during the critical period.

[This corrects the article DOI: 10.3389/fncir.2024.1497897.].

Functional recovery from brain damage, such as stroke, is a plastic process in the brain. The excitatory glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) plays a crucial role in neuronal functions, and the synaptic trafficking of AMPAR is a fundamental mechanism underlying synaptic plasticity. We recently identified a collapsin response mediator protein 2 (CRMP2)-binding compound, edonerpic maleate, which augments rehabilitative training-dependent functional recovery from brain damage by facilitating experience-driven synaptic delivery of AMPARs. In animals recovering from cryogenic brain injury, a potential compensatory area adjacent to the injured region was observed, where the injection of CNQX, an AMPAR antagonist, significantly attenuated functional recovery. In the compensatory brain area of animals recovering from cryogenic injury, the administration of edonerpic maleate enhanced both excitatory and inhibitory synaptic inputs at pyramidal neurons. In contrast, recovered animals that did not receive the drug exhibited augmentation of only excitatory synaptic input. The threshold of picrotoxin-induced epileptic seizure in recovered animals without edonerpic maleate treatment was lower than in intact animals and recovered animals with edonerpic maleate. Thus, edonerpic maleate enhances motor function recovery from brain damage by balancing excitatory and inhibitory synaptic inputs, which helps prevent epileptic seizures during recovery.

The Golgi apparatus is a central hub in the intracellular secretory pathway. By positioning in the specific intracellular region and transporting materials to spatially restricted compartments, the Golgi apparatus contributes to the cell polarity establishment and morphological specification in diverse cell types. In neurons, the Golgi apparatus mediates several essential steps of initial neural circuit formation during early brain development, such as axon-dendrite polarization, neuronal migration, primary dendrite specification, and dendritic arbor elaboration. Moreover, neuronal activity-dependent remodeling of the Golgi structure enables morphological changes in neurons, which provides the cellular basis of circuit reorganization during postnatal critical period. In this review, I summarize recent findings illustrating the unique Golgi positioning and its developmental dynamics in various types of neurons. I also discuss the upstream regulators for the Golgi positioning in neurons, and functional roles of the Golgi in neural circuit formation and reorganization. Elucidating how Golgi apparatus sculpts neuronal connectivity would deepen our understanding of the cellular/molecular basis of neural circuit development and plasticity.

Introduction: Parkinson's disease (PD) is commonly characterized by severe dopamine (DA) depletion within the substantia nigra (SN) leading to a myriad of motor and non-motor symptoms. One underappreciated and prevalent non-motor symptom, Parkinson's disease-associated psychosis (PDAP), significantly erodes patient and caregiver quality of life yet remains vastly understudied. While the gold standard pharmacotherapy for motor symptoms Levodopa (LD) is initially highly effective, it can lead to motor fluctuations like LD-induced dyskinesia (LID) and non-motor fluctuations such as intermittent PDAP. One source of these fluctuations could be the serotonergic raphe nuclei and their projections. Serotonin (5-HT) neurons possess the machinery necessary to convert and release DA from exogenous LD. In DA-depleted brain regions these 5-HT projections can act as surrogates to the DA system initially compensating but chronically leading to aberrant neuroplasticity which has been linked to LID and may also contribute to non-motor fluctuations. In support, recent work from our lab established a positive relationship between LID and PDAP in parkinsonian rats. Therefore, it was hypothesized that normalizing 5-HT forebrain input would reduce the co-expression of LID and PDAP.

Methods: To do so, we expressed 5-HT projection specific inhibitory designer receptor exclusively activated by designer drugs (DREADDs) using Cre-dependent AAV9-hM4di in tryptophan hydroxylase 2 (TPH2)-Cre bilaterally 6-OHDA-lesioned rats. Thereafter we used the designer drug Compound 21 to selectively inhibit 5-HT raphe projections during LD treatment to modulate the expression of PDAP, assayed by prepulse inhibition (PPI) and LID, quantified by the abnormal involuntary movements (AIMs) test.

Results: Our results suggest that chemogenetic inhibition of 5-HT raphe-projecting cells significantly reduces LID without affecting stepping ability or established sensorimotor gating deficits.

Discussion: Overall, this study provides further evidence for the complex influence of 5-HT raphe-projecting neurons on LD's neurobehavioral effects.