Journal of neurophysiology最新文献

Functional magnetic resonance imaging (fMRI) is a non-invasive method for measuring human brain activity based on blood oxygenation level-dependent (BOLD) responses. While many studies have reported positive BOLD responses evoked by sensory stimuli, others have reported negative BOLD responses (NBRs) in the sensory cortex when stimuli from different sensory modalities are presented (i.e., cross-modal NBRs). We conducted an fMRI experiment to better understand the characteristics of cross-modal NBRs in subcortical and cortical regions. Auditory and visual stimuli were presented unilaterally to one ear and to either the left or right visual field, respectively. The lateral geniculate nucleus and medial geniculate nucleus did not show a significant cross-modal NBR. In contrast, the primary auditory cortex showed a significant cross-modal NBR when visual stimuli were presented in either the contralateral or ipsilateral visual fields. Finally, we found that the cross-modal NBR in the early visual cortex was highly variable across subjects and did not exhibit consistent trends. However, each subject's data exhibited considerable split-half reliability. Our results suggest that cross-modal NBR in the auditory cortex likely reflects mechanisms such as interhemispheric suppression, rather than those coordinated within the same hemisphere.

Urethane anesthesia and vagotomy are common in neurophysiology but their impact on physiological homeostasis is not fully defined. We assessed arterial blood gases [arterial partial pressure of CO₂ ([Formula: see text]), arterial partial pressure of O₂ ([Formula: see text]), pH, and bicarbonate] and cardiorespiratory parameters in rats under baseline conditions and following anesthesia and vagotomy. Thirty minutes after urethane (1.2 g/kg, iv), heart rate (HR) and respiratory frequency (f_R) increased, whereas mean arterial pressure (MAP), tidal volume (V_T), and ventilation (V̇e) decreased. Increased [Formula: see text], and reduced levels of pH and [Formula: see text] were observed without changes in bicarbonate. Bilateral vagotomy further increased MAP, HR, and V_T but reduced f_R and V̇e, aggravating the increase in [Formula: see text] and acidosis. Artificial ventilation corrected blood gases but did not change the cardiovascular parameters. We next studied the activity of the retrotrapezoid nucleus (RTN) chemoreceptor neurons, because these neurons are involved in cardiorespiratory modulation. These neurons were activated by hypercapnia, inhibited by lung inflation, and displayed reduced CO₂ thresholds after vagotomy. Vagotomy also abolished phasic inhibition during inspiration and postinspiration, producing peak activity during inspiration. These findings show that urethane anesthesia and vagotomy profoundly alter cardiorespiratory parameters and demonstrate that vagal inputs dynamically modulate RTN neuronal activity and central respiratory control. Together, these findings demonstrate that urethane anesthesia and vagotomy significantly alter baseline cardiorespiratory parameters and dynamically modulate RTN chemoreceptor activity, highlighting the importance of vagal feedback in central respiratory control.NEW & NOTEWORTHY Urethane anesthesia and vagotomy, common procedures in neurophysiology, profoundly alter baseline cardiorespiratory parameters and arterial blood gases. We show that vagotomy not only exacerbates hypercapnia and acidosis but also reshapes retrotrapezoid nucleus chemoreceptor activity, abolishing phasic inhibition and shifting peak activity to inspiration. These findings highlight the critical role of vagal feedback in central respiratory control and caution against overlooking the physiological consequences of standard experimental manipulations.

Early-onset Pompe disease occurs due to mutations in the acid α-glucosidase (GAA) gene that result in the absence of functional GAA protein. This results in widespread glycogen accumulation and cardiorespiratory failure early in life. We used a Gaa null (Gaa^-/-) rat Pompe model and concurrent analysis of diaphragm electromyography (EMG) and plethysmography respiratory waveforms to determine whether a unique "respiratory signature" would develop over the lifespan. Intramuscular wires enabled diaphragm EMG recordings during whole body plethysmography. Measurements were taken from 4 to 10 mo of age, and respiratory events were detected by identifying the onset and offset of diaphragm EMG bursting. As compared with wild-type Sprague-Dawley rats, Pompe rats showed an age-dependent decrease in their frequency of sniffing during exploratory behaviors, potentially due to a decrease in the ability to engage in active expiration. In addition, Pompe rats exhibited an increased latency from the onset of the diaphragm EMG burst to inspiratory airflow under hypoxic conditions, suggesting dysfunction with neuromuscular coupling. These changes are consistent with a progressive decline in respiratory neuromuscular function, may be predictive of impending respiratory failure, and provide a metric to evaluate the impact of therapies intended to prevent respiratory neuromuscular decline. In addition, the metrics established here may be useful markers of dysfunction in other models of neuromuscular disease.NEW & NOTEWORTHY We used a novel algorithm for breath-by-breath detection on concurrent plethysmography and diaphragm EMG recordings to identify shifts in breathing throughout the lifespan of Pompe rats. We identified a "respiratory signature" of disease progression in the Pompe rat comprising a decrease in the frequency of sniffing behaviors and increased latency from diaphragm activation to inspiratory flow during hypoxia. This signature offers new metrics to evaluate the effectiveness of potential therapies.

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.