Journal of neurophysiology最新文献

For decades, major depressive disorder was attributed to a deficit in monoamine neurotransmitters. Clinical latency of tricyclic and selective serotonin reuptake inhibitors, high nonresponse rates, and inconsistent genetic findings challenged this view and redirected research toward downstream biology. Preclinical work revealed that chronic stress triggers dendritic and spine loss in the hippocampus and prefrontal cortex, whereas all effective treatments-including slow-acting monoaminergic drugs, rapid-acting ketamine, electroconvulsive therapy, and aerobic exercise-restore synapse number and function through brain-derived neurotrophic factor, TrkB, and mTOR signaling. Human connectomic studies then reframed depression as a disorder of mistimed large-scale networks; targeted neuromodulation of nodes intrinsically anticorrelated with the subgenual cingulate provides proof of concept. Parallel findings in immunology and gut-brain science show that psychosocial stress, peripheral cytokines, and metabolic cues converge on the same plasticity pathways, dissolving the historical boundary between "reactive" and "endogenous" depression. Ketamine crystallizes this multiscale model: within minutes, it induces dendritic-spine formation, normalizes default-mode and limbic connectivity, and relieves symptoms within hours. We synthesize these lines of evidence into a framework of precision synaptic psychiatry, in which pharmacological, neuromodulatory, and lifestyle interventions are selected according to biomarkers that index glutamatergic tone, inflammatory load, or network dynamics. Future therapeutics will be judged less by the neurotransmitters they influence and more by their capacity to restore flexible, resilient brain circuitry.

Astrocytes are increasingly recognized as active participants in sensory processing, but whether they show selective responses to stimulus features, analogous to neuronal receptive fields, is not yet established. To address this, we used two-photon calcium imaging in the auditory cortex of anesthetized mice during presentation of natural ultrasonic vocalizations. Our aim was to compare astrocytic responses with those of neighboring neurons and to determine whether astrocytes exhibit feature-selective receptive fields. Event detection showed that astrocytic calcium activity is highly heterogeneous, but only a minority of events were consistently stimulus-linked. To examine this stimulus-driven subset, we estimated receptive field features using maximum noise entropy modeling and compared them with those of concurrently recorded neurons. Despite qualitative similarities in receptive-field features, analysis of modulation spectra and principal angles showed that astrocytic and neuronal receptive fields overlap but occupy distinct regions of feature space. This indicates that astrocytes and neurons are tuned to partially shared, but not identical, dimensions of the sensory stimulus. Our findings indicate that astrocytes respond to diverse sensory features, playing a complementary role to neuronal encoding. This suggests that astrocytic calcium activity is not simply a reflection of neuronal firing, but instead represents a distinct component of cortical sensory processing.NEW & NOTEWORTHY We used two-photon imaging to record calcium activity in astrocytes and neighboring neurons during presentation of natural ultrasonic vocalizations. We show that astrocyte activity is highly heterogeneous across spatial and temporal scales. Further analyses indicate that a subset of astrocyte calcium activity is stimulus-linked and tuned to dimensions of the stimulus that partially overlap with, but are not identical to, those encoded by neurons.

Cough is a hallmark sign of tuberculosis and a key driver of transmission. Although traditionally attributed to host-driven inflammation, we previously demonstrated that Mycobacterium tuberculosis lipid extract (Mtb extract) and its component sulfolipid-1 (SL-1) directly act on nociceptive neurons to induce cough in guinea pigs. However, the cellular mechanisms by which Mtb extract and SL-1 modulate nociceptive sensory neurons remain incompletely understood. Using calcium imaging, we found that Mtb extract and SL-1 increased intracellular Ca²⁺ signals in TRPV1⁺ neurons from both mouse nodose and human dorsal root ganglia (hDRG). We observed that YM254890 (a Gαq/11 inhibitor) could attenuate these Ca²⁺ signaling events, even in the absence of extracellular Ca²⁺, suggesting a G protein-coupled receptor (GPCR)-mediated mechanism driven by Gαq/11 signaling to intracellular Ca²⁺ stores. Mtb extract treatment also enhanced action potential (AP) generation in mouse nodose nociceptors via an SL-1-dependent mechanism. Mtb extract increased the number and half-width of evoked APs, indicating direct modulation of voltage-gated ion channel activity. The Mtb extract-induced change in mouse nodose neuron excitability and in the AP half-width was blocked by YM254890 treatment. Taken together, these findings link TB pathogen-derived lipids to GPCR signaling that directly increases the excitability of sensory neurons.NEW & NOTEWORTHY Cough elicited by TB facilitates disease transmission; however, the underlying neuronal mechanisms responsible for this phenomenon are unknown. Our study demonstrates that Mtb lipid sulpholipid-1 can activate sensory neurons directly through Gαq/11-mediated mobilization of intracellular calcium stores and enhance neuronal excitability. These effects can be blocked by YM254890. These findings reveal a GPCR-mediated mechanism linking bacterial virulence to changes in neuronal excitability, identifying potential therapeutic targets for treating cough associated with TB.

The known fluctuations in ovarian hormone concentrations across the eumenorrheic menstrual cycle contribute to modulations in cortical excitability and inhibition. However, how such changes affect spike-timing-dependent plasticity (STDP) has not been systematically studied. This research aimed to determine the effect of the menstrual cycle on corticospinal excitability and STDP. Twelve eumenorrheic female participants (age: 25 ± 5 yr) visited the lab in three menstrual cycle phases: early follicular (EF), late follicular (LF), and mid-luteal (ML). Visits comprised of corticospinal excitability [motor evoked potential (MEP)/M_max], short-intracortical inhibition (SICI), and intracortical facilitation (ICF) measures, recorded in the resting first dorsal interosseous. Followed by a paired associative stimulation (PAS) protocol, utilizing ulnar nerve and transcranial magnetic stimulation (25-ms interstimulus interval) to elicit neuroplasticity. To assess the time course of STDP, measurements were repeated at 15 and 30-min post PAS. Corticospinal excitability (MEP/M_max) was greater in the LF phase (P ≤ 0.001) compared with EF and ML, with no phase effects observed for SICI or ICF (P ≥ 0.170). PAS elicited an increase in MEP/M_max across all phases at 15-min (112 ± 5, 116 ± 5, and 114 ± 7% baseline, P ≤ 0.037), whereas at 30 min only ML was facilitated (126 ± 5% baseline, P = 0.044). The present data demonstrate facilitatory STDP can be induced with PAS across the tested menstrual cycle phases, but responses are prolonged and potentiated in the ML phase. In addition, increased corticospinal excitability in the LF phase is likely due to intrinsic changes within the descending tract, as no changes in intracortical neurotransmission were observed.NEW & NOTEWORTHY Does the menstrual cycle modulate spike-timing-dependent plasticity? In the present study, a facilitatory paired associative stimulation protocol was used to probe Hebbian plasticity in three hormonally distinct menstrual cycle phases. Facilitation was induced in all menstrual cycle phases, but this effect lasted longer and was of greater magnitude in the luteal phase when estrogens and progesterone were both elevated. This provides insights into the potential mechanisms by which these hormones influence neuroplasticity in females.

The language with which the neurons of the cerebellum encode information appears distinct from the rest of the brain. For example, while in the cerebral cortex and the superior colliculus neurons display a retinotopic map that indicates the location of the visual event with respect to the fovea, and in the brainstem saccade related neurons have a motor map to translate that goal into muscle activation patterns, in the cerebellum the Purkinje cells (P-cell) associated with control of saccades are neither organized spatially to reflect a retinotopic map, nor do their firing rates encode the motor commands. Instead, P-cells are active for all saccades, producing only small time-shifts in their firing rates in response to changes in movement parameters. To understand what the P-cells are computing, we can use their climbing fiber inputs as an anatomical prior to assign a potent vector for each P-cell, where the potent vector is an estimate of the downstream influence of that neuron on kinematics. This spike-to-vector transformation allows for summing the activities of the P-cells, producing a time-varying resultant vector that is an estimate of the neuronal output of the population in the vector space of behavior. Here, we review the idea of using anatomical priors coupled with spike-triggered averaging to find potent vectors for P-cells, then summarize how these vectors provide insights into what the cerebellum is computing. It appears that P-cells rely on phase differences in their individual firing patterns to partially or completely cancel each other's potent vectors, conveying a resultant that in the case of saccades steers the eyes to the target. These patterns suggest that P-cells are akin to vector generating basis functions whose firing rates individually exhibit little relationship to behavior, but in a population can orchestrate an output critical for control of that behavior.

Mechanical gait asymmetry is a prevalent deficit in many forms of locomotion impairment. While spatial gait asymmetry adaptations can be elicited with split belt treadmill training, weight bearing and propulsion asymmetry remain resistant to improvement. As an alternative approach, we tested asymmetric surface stiffness walking to induce neuromotor adaptation of weight bearing and propulsion asymmetries. We hypothesized that a bout of asymmetric stiffness walking would elicit aftereffects in the form of asymmetries in weight bearing, propulsion, and plantar flexor activity. Twelve healthy young adults performed a 10-minute bout of asymmetric stiffness walking on an adjustable stiffness treadmill. We measured baseline and post-perturbation ground reaction forces (GRF) and spatio-temporal measures during 5-minute walking bouts on a dual-belt instrumented treadmill. After asymmetric surface stiffness walking, participants exhibited 2.8% asymmetry in vertical GRF at push off, as well as increased plantarflexor muscle activity (20.7% GAS, 9.5% SOL) during push off on the perturbed side relative to the unperturbed. Participants also decreased their mid-stance vertical GRF (2.2%) and increased their peak braking GRF (6.8%) on the perturbed side relative to unperturbed. Counter to our hypothesis, they did not increase their propulsion GRF on the perturbed side. We conclude that asymmetric stiffness walking elicited a neuromotor adaptation towards a relative increase in push-off in the target limb, albeit primarily vertically aligned in our cohort of healthy young adults, and that gait adaptation to asymmetric stiffness walking should be investigated in individuals with push-off asymmetries.

The crustacean cardiac ganglion network coordinates rhythmic contractions of the heart muscle to control the circulation of blood. The specific network of the crab (Cancer borealis) consists of 9 cells: 5 large cell motor neurons (LC1-5) and 4 small endogenous pacemaker cells (SCs). We report a new three-compartmental biophysical LC model that includes synaptic inputs from SCs onto gap-junction coupled spike-initiation-zone (SIZ) compartments. To determine physiologically viable LC models in this realistic configuration, we sampled maximal conductances from a biologically constrained 9D-parameter space, followed by a selection protocol that had three levels. Our results provide previously unknown structure-function insights related to the crustacean cardiac ganglion large cell, including predictions about morphology, SIZ, and the differential roles of active conductances in the three compartments. An analysis of conductance relationships in model neurons revealed a lack of notable correlations among active conductances in the model population, despite clear reports of such relationships in biological neurons. When combined with the interpretations from other model systems, we hypothesize that modes of bursting driven by a strong presynaptic influence (i.e., "forced" bursting) may not require such conductance relationships, whereas endogenous bursters may require them. We further suggest that conductance relationships in a forced burster neuron will more likely serve to shape the characteristics of the firing pattern in the burst, once generated, rather than contribute to a generative mechanism for bursting itself.

The aim of this study was to describe the age-related differences in motor unit behavior during concentric, isometric, and eccentric ankle dorsiflexions. Fourteen young adults (age: 23±3 years) and 12 older adults (age: 68±5 years) performed cycles of concentric/isometric/eccentric ankle dorsiflexions at low velocity (5°/s) and low force level (10% maximum isometric voluntary contraction). Muscle activity was recorded using high-density surface electromyography (HD-sEMG) and decomposed using blind source separation. Motor units were divided into continuous motor units (CNT_MU, e.g., units recruited >=90% of the task duration) and intermittent motor units (INT_MU, e.g., units recruited <90% of the task duration). The average discharge rate (AVR_DR) and discharge rate slopes (SLOPE_DR) were estimated from each extracted motor unit. Joint torque, position and motor unit discharge rate variability were assessed using coefficient of variation (COV). The results revealed that older adults present significantly greater variability in torque, position and discharge rates, especially in dynamic contractions. Regarding motor unit discharge properties statistics, older adults presented reduced AVR_DR for CNT_MU during concentric contractions, whereas their AVR_DR was increased for INT_MU during eccentric contractions compared to young adults, with no differences during isometric contractions. Moreover, older adults presented reduced concentric SLOPE_DR for INT_MU when compared to young adults. Our results demonstrate that older adults present altered neural drive to the muscles, reducing their ability to modulate rate coding and subsequently maintain force steadiness at low force levels in concentric and eccentric contractions.

Human locomotion exhibits remarkable adaptability, allowing individuals to dynamically adjust their gait patten in response to changing environmental demands. Locomotor adaptation on a split-belt treadmill has been a widely studied motor learning technique where two independent treadmill belts move at different speeds, generating adaptation of stepping symmetry over time. This review synthesizes current knowledge on how distinct neural substrates modulate gait in response to the split-belt treadmill through reactive and adaptive processes, highlighting the cerebellum's role in forward model recalibration driven by sensory prediction errors. Particular emphasis is placed on integrating findings across all investigated modulators of locomotor adaptation, including error size, sensory environment, visual feedback, neuromodulation, and cognitive demands, examining both well-established effects on adaptation dynamics and areas where knowledge remains limited. Despite considerable research on the locomotor adaptation paradigm with robust effects on the treadmill, the limited transfer of locomotor adaptation to overground walking remains a major clinical barrier, likely due to the sensory differences between walking contexts. Recent evidence supporting a credit assignment framework is discussed, which suggests that the nervous system attributes motor errors to either shared or context-specific forward models, influencing generalization. Understanding and manipulating this mechanism, with a focus on the sensory environment during adaptation, may be essential to improving the clinical utility of locomotor adaptation and enhancing neurorehabilitation strategies aimed at restoring symmetrical walking in neurological populations.