Journal of neurophysiology最新文献

Integration of autonomic and metabolic regulation, including hepatic function, is a critical role played by the brain's hypothalamic region. Specifically, the paraventricular nucleus of the hypothalamus (PVN) regulates autonomic functions related to metabolism, such as hepatic glucose production. Although insulin can act directly on hepatic tissue to inhibit hepatic glucose production, recent evidence implicates that central actions of insulin within PVN also regulate glucose metabolism. However, specific central circuits responsible for insulin signaling with relation to hepatic regulation are poorly understood. As a heterogeneous nucleus essential to controlling parasympathetic motor output with notable expression of insulin receptors, PVN is an appealing target for insulin-dependent modulation of parasympathetic activity. Here, we tested the hypothesis that insulin activates hepatic-related PVN (PVN^hepatic) neurons through a parasympathetic pathway. Using transsynaptic retrograde tracing, labeling within PVN was first identified 24 h after its expression in the dorsal motor nucleus of the vagus (DMV) and 72 h after hepatic injection. Critically, nearly all labeling in medial PVN was abolished after a left vagotomy, indicating that PVN^hepatic neurons in this region are part of a central circuit innervating parasympathetic motor neurons. Insulin also significantly increased the firing frequency of PVN^hepatic neurons in this subregion. Mechanistically, rapamycin pretreatment inhibited insulin-dependent activation of PVN^hepatic neurons. Therefore, central insulin signaling can activate a subset of PVN^hepatic neurons that are part of a unique parasympathetic network in control of hepatic function. Taken together, PVN^hepatic neurons related to parasympathetic output regulation could serve as a key central network in insulin's ability to control hepatic functions.NEW & NOTEWORTHY Increased peripheral insulin concentrations are known to decrease hepatic glucose production through both direct actions on hepatocytes and central autonomic networks. Despite this understanding, how (and in which brain regions) insulin exerts its action is still obscure. Here, we demonstrate that insulin activates parasympathetic hepatic-related PVN neurons (PVN^hepatic) and that this effect relies on mammalian target of rapamycin (mTOR) signaling, suggesting that insulin modulates hepatic function through autonomic pathways involving insulin receptor intracellular signaling cascades.

Successful reactive balance control requires coordinated modulation of hip, knee, and ankle torques. Stabilizing joint torques arise from neurally-mediated feedforward tonic muscle activation that modulates muscle short-range stiffness, which provides instantaneous "mechanical feedback" to the perturbation. In contrast, neural feedback pathways activate muscles in response to sensory input, generating joint torques after a delay. However, the specific contributions from feedforward and feedback pathways to the balance-correcting torque response are poorly understood. As feedforward- and feedback-mediated torque responses to balance perturbations act at different delays, we modified the sensorimotor response model (SRM), previously used to analyze the muscle activation response, to reconstruct joint torques using parallel feedback loops. Each loop is driven by the same information, center of mass (CoM) kinematics, but each loop has an independent delay. We evaluated whether a torque-SRM could decompose the reactive torques during balance-correcting responses to backward support surface translations at four magnitudes into the instantaneous "mechanical feedback" torque modulated by feedforward neural commands before the perturbation and neurally-delayed feedback components. The SRM accurately reconstructed torques at the hip, knee, and ankle, across all perturbation magnitudes (R² > 0.84 and VAF > 0.83). Moreover, the hip and knee exhibited feedforward and feedback components, while the ankle only exhibited feedback components. The lack of a feedforward component at the ankle may occur because the compliance of the Achilles tendon attenuates muscle short-range stiffness. Our model may provide a framework for evaluating changes in the feedforward and feedback contributions to balance that occur due to aging, injury, or disease.NEW & NOTEWORTHY Reactive balance control requires coordination of neurally-mediated feedforward and feedback pathways to generate stabilizing joint torques at the hip, knee, and ankle. Using a sensorimotor response model, we decomposed reactive joint torques into feedforward and feedback contributions based on delays relative to the center of mass kinematics. Responses across joints were driven by the same signals, but contributions from feedforward versus feedback pathways differed, likely due to differences in musculotendon properties between proximal and distal muscles.

The motor thalamus plays a crucial role in integrating and modulating sensorimotor information. Although voltage power spectral changes in the motor cortex with movement are well-characterized, corresponding activity in the motor thalamus, particularly broadband power change, remains unclear. The present study aims to characterize spectral changes in the motor thalamus during hand movements of 15 subjects undergoing awake deep brain stimulation surgery targeting the ventral intermediate (Vim) nucleus of the thalamus for disabling tremor. We analyzed power changes in subject-specific low-frequency oscillations (<30 Hz) and broadband power (captured in 65-115 Hz band) of serial field potential recordings. Consistent with previous studies, we found widespread decreases in low-frequency oscillations with movement. Importantly, in most subjects, we observed that sites with significant increases in broadband power were more spatially discrete, primarily involving the inferior recording sites within the ventral thalamus. One subject also performed an imagined movement task during which low-frequency oscillatory power was suppressed. These electrophysiological changes may be leveraged as biomarkers for thalamic functional mapping, DBS targeting, and closed-loop applications.NEW & NOTEWORTHY We studied movement-associated spectral changes in human motor thalamus and observed focal increases in broadband power with movement. This biomarker may be used as a tool for intraoperative functional mapping, DBS targeting, and closed-loop device control.

The midget pathway of the primate retina provides the visual system with the foundations for high spatial resolution and color perception. An essential contributor to these properties is center-surround organization, in which responses from the central area of a cell's receptive field are antagonized by responses from a surrounding area. Two key questions about center-surround organization are unresolved. First, the surround is largely or completely due to negative feedback from horizontal cells to cones: how can this feedback be reconciled with the popular difference of Gaussians (DOG) model, which implies feedforward inhibition? Second, can the spatial extent of center and surround be predicted from the components-optics, horizontal cell receptive field, ganglion cell dendrites-that give rise to them? We address these questions with a computational model of midget pathway signal processing in macaque retina; model parameters are derived from published literature. We show that, contrary to the DOG model, the surround's effect is better treated as divisive. A simplified version of our model-a ratio of Gaussians (ROG) model-has practical advantages over the DOG, such as accounting for spatiotemporal interactions and pulse responses. The ROG model also shows that both center and surround radii can be calculated from a sum of squared radii of their components. Finally, chromatic antagonism between center and surround in the full model predicts cone opponency as a function of eccentricity. We suggest that a signal-processing model gives new insight into retinal function.NEW & NOTEWORTHY We simulated signal processing from cones to midget ganglion cells in the monkey retina and found that: 1) center/surround structure is better described as a ratio of Gaussian functions than as the traditional difference of Gaussians; 2) ganglion cell center and surround radii can be calculated from a sum of squares of radii in upstream stages; 3) the model can predict chromatic dominance in the center and surround mechanisms as a function of eccentricity.

Movement planning consists of several processes related to the preparation of a movement such as decision making, target selection, application of task demands, action selection, and specification of movement kinematics. These numerous processes are reflected in the reaction time, which is the time that it takes to start executing the movement. However, not all the processes that lead to motor planning increase reaction time. In this paper, we wanted to test whether tuning the control policy to task demands contributes to reaction time. Taking into account that the tuning of the control policy differs for narrow and wide targets, we used a timed response paradigm to track the amount of time needed to tune the control policy appropriately to task demands. We discovered that it does not take any time during motor planning and even that it can occur indistinguishably during motor planning or during motor execution. That is, the tuning the control policy was equally good when the narrow or wide target was displayed before than when it was displayed after the start of the movement. These results suggest that the frontier between motor planning and execution is not as clear cut as it is often depicted.NEW & NOTEWORTHY Movement preparation consists of different processes such as target selection and movement parameters selection. We investigate the time that it takes to tune movement parameters to task demands. We found that the brain does this instantaneously and that this can even happen during movement. Therefore, this suggests that there exists an overlap during movement planning and execution.

Parkinson's disease (PD) is a chronic neurodegenerative disorder caused by loss of dopaminergic neurons in the substantia nigra compacta, which may result from mitochondrial dysfunction and oxidative stress. Isorhamnetin (Iso) has important antioxidative stress and antiapoptotic effects, this study investigated the effects of Iso on PD in vitro and its underlying mechanisms using a model of 6-hydroxydopamine (6-OHDA)-induced SH-SY5Y cell damage. The results showed that Iso significantly ameliorated 6-OHDA-induced SH-SY5Y cell injury, including decreased cell viability, increased apoptosis and senescence, and oxidative stress injury. Senescence-associated β-galactosidase (SA-β) staining, Western blot (WB), and immunofluorescence suggested that Iso significantly decreased the number of SA-β+ cells and the levels of senescence-associated proteins p21 and p16, and enhanced tyrosine hydroxylase level. Iso markedly reduced the number of apoptotic cells and the levels of cleaved caspase-3 and BAX, as detected by CCK-8, flow cytometry, and WB. The results of DCFH-DA, JC-1 staining, and the measurement of malondialdehyde (MDA) and superoxide dismutase (SOD) content indicated that Iso elevated reactive oxygen species (ROS) generation and mitochondrial membrane potential, lowered MDA content and raised SOD level in the 6-OHDA group. In-depth investigation revealed that Iso activated the AKT/mTOR signal via reducing the expression level of Fos-like antigen (FOSL1), which further exerted the protective effect in SH-SY5Y cells. Overexpression of FOSL1 attenuated the effect of Iso by inhibiting the AKT/mTOR signaling pathway. Taken together, Iso protects against senescence, apoptotic, and oxidative stress injury by targeting FOSL1 to activate the AKT/mTOR signaling pathway in 6-OHDA-induced SH-SY5Y cells, which may provide new insights for PD treatment.NEW & NOTEWORTHY Isorhamnetin (Iso) ameliorated neuronal activity damage, senescence, apoptosis, and oxidative stress injury in 6-hydroxydopamine (6-OHDA)-induced SH-SY5Y cells. Iso activated AKT/mTOR signaling pathway via inhibiting Fos-like antigen (FOSL1) in 6-OHDA-induced SH-SY5Y cells. Overexpression of FOSL1 attenuated the protective effect of Iso against 6-OHDA-induced neuronal damage in SH-SY5Y cells.

The cardiorespiratory and metabolic response to exercise has been associated with meeting the organism's metabolic demands during physical exertion. Of note, an incremental exercise is characterized by 1) cardiodynamic phase related to cardiac output enhancement mainly determined by a positive chronotropic response, 2) ventilatory threshold one, associated with a significant contribution of cardiovascular and pulmonary ventilation, and 3) ventilatory threshold two, correlated with a tremendous increase in breathing and metabolic responses to exercise. Notably, it has been shown that the ventilatory response to exercise increases concomitantly with the release and accumulation of metabolites (i.e., lactate released from skeletal muscle). The principal peripheral chemoreceptors are the carotid bodies (CBs), allocated into the carotid bifurcation and demonstrated to respond to several stimuli, triggering autonomic and ventilatory responses. Indeed, in past and recent years, it has been shown that CB could respond to lactate in in vitro and in vivo preparations, eliciting an increase in CB activity and ventilation. However, not all evidence indicates that peripheral chemoreceptors respond to lactate. Thus, considering that CB chemoreceptors' role in lactate-dependent breathing response is not completely clear and their potential preponderance as metabolic sensors during exercise has not been thoroughly explored, the present review was focused on the possible role of CB chemoreceptors as metabolic sensors during physical exertion in a physiological context, proposing it as a new actor in exercise physiology.

We normally perceive a stable visual environment despite eye movements. To achieve such stability, visual processing integrates information across a given saccade, and laboratory hallmarks of such integration are robustly observed by presenting brief perisaccadic visual probes. In one classic phenomenon, probe locations are grossly mislocalized. This mislocalization is believed to depend, at least in part, on corollary discharge associated with saccade-related neuronal movement commands. However, we recently found that superior colliculus motor bursts, a known source of corollary discharge, can be different for different image appearances of the saccade target. Therefore, here we investigated whether perisaccadic mislocalization also depends on saccade target appearance. We asked human participants to generate saccades to either low (0.5 cycles/°) or high (5 cycles/°) spatial frequency gratings. We always placed a high-contrast target spot at grating center, to ensure matched saccades across image types. We presented a single, brief perisaccadic probe, which was high in contrast to avoid saccadic suppression, and the subjects pointed (via mouse cursor) at the seen probe location. We observed stronger perisaccadic mislocalization for low-spatial frequency saccade targets and for upper visual field probe locations. This was despite matched saccade metrics and kinematics across conditions, and it was also despite matched probe visibility for the different saccade target images (low vs. high spatial frequency). Assuming that perisaccadic visual mislocalization depends on corollary discharge, our results suggest that such discharge might relay more than just spatial saccade vectors to the visual system; saccade target visual features can also be transmitted.NEW & NOTEWORTHY Brief visual probes are grossly mislocalized when presented in the temporal vicinity of saccades. Although the mechanisms of such mislocalization are still under investigation, one component of them could derive from corollary discharge signals associated with saccade movement commands. Here, we were motivated by the observation that superior colliculus movement bursts, one source of corollary discharge, vary with saccade target image appearance. If so, then perisaccadic mislocalization should also do so, which we confirmed.

This study investigated torque production resulting from the combined application of wide-pulse neuromuscular electrical stimulation (NMES), delivered over the posterior tibial nerve, and muscle lengthening at two distinct amplitudes. Wide-pulse NMES (pulse duration: 1 ms; stimulation intensity: 5-10% of maximal voluntary contraction) was delivered at both low- (20 Hz) and high- (100 Hz) stimulation frequencies, either alone (NMES condition) or combined with a muscle lengthening at two amplitudes (10 or 20° ankle joint rotation; NMES + LEN₁₀ and NMES + LEN₂₀ conditions, respectively). For each frequency, the torque-time integral (TTI) and the muscle activity following the cessation of stimulation trains (sustained EMG activity) were calculated. At 20 Hz, TTI was higher (P = 0.007) during NMES + LEN₁₀ (233.2 ± 101.5 Nm·s) and NMES + LEN₂₀ (229.2 ± 92.1 Nm·s) than during the NMES condition (187.5 ± 74.5 Nm·s), without any change in sustained EMG activity (P = 0.54). At 100 Hz, TTI was higher (P = 0.038) during NMES + LEN₁₀ (226.6 ± 115.3 Nm·s) than during NMES + LEN₂₀ (180.6 ± 84.0 Nm·s) and NMES (173.9 ± 94.9 Nm·s). This torque enhancement was accompanied by a higher sustained EMG activity (P = 0.045) in the NMES + LEN₁₀ condition. These findings show that, for low-frequency NMES, significant torque increases were observed with both a 10- or a 20-degree lengthening amplitude, probably linked to increased afferents' activation. In contrast, with high-frequency NMES, a significant TTI enhancement was observed only with the 10-degree amplitude, accompanied by increased sustained EMG activity, suggesting neural mechanisms' involvement. When a greater lengthening amplitude was superimposed during high-frequency NMES, these mechanisms were probably inhibited, precluding torque enhancement.NEW & NOTEWORTHY This study demonstrates that combining wide-pulse low-frequency NMES and muscle lengthening can increase torque production compared with the sole application of NMES. Torque enhancement is most likely linked to the persistent firing of muscle afferents. Although muscle lengthening superimposition also permitted torque increases during wide-pulse high-frequency NMES, increasing the muscle lengthening amplitude did not allow further torque enhancements, probably due to presynaptic inhibitory mechanisms.