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Human circadian, neuroendocrine, and neurobehavioral responses to light are mediated primarily by melanopsin-containing intrinsically-photosensitive retinal ganglion cells (ipRGCs) but they also receive input from visual photoreceptors. Relative photoreceptor contributions are irradiance- and duration-dependent but results for long-duration light exposures are limited. We constructed irradiance-response curves and action spectra for melatonin suppression and circadian resetting responses in participants exposed to 6.5-h monochromatic 420, 460, 480, 507, 555, or 620 nm light exposures initiated near the onset of nocturnal melatonin secretion. Melatonin suppression and phase resetting action spectra were best fit by a single-opsin template with lambdamax at 481 and 483 nm, respectively. Linear combinations of melanopsin (ipRGC), short-wavelength (S) cone, and combined long- and medium-wavelength (L+M) cone functions were also fit and compared. For melatonin suppression, lambdamax was 441 nm in the first quarter of the 6.5-h exposure with a second peak at 550 nm, suggesting strong initial S and L+M cone contribution. This contribution decayed over time; lambdamax was 485 nm in the final quarter of light exposure, consistent with a predominant melanopsin contribution. Similarly, for circadian resetting, lambdamax ranged from 445 nm (all three functions) to 487 nm (L+M-cone and melanopsin functions only), suggesting significant S-cone contribution, consistent with recent model findings that the first few minutes of a light exposure drive the majority of the phase resetting response. These findings suggest a possible initial strong cone contribution in driving melatonin suppression and phase resetting, followed by a dominant melanopsin contribution over longer duration light exposures.

The circadian system of the cyanobacterium Synechococcus elongatus PCC 7942 relies on a three-protein nanomachine (KaiA, KaiB, and KaiC) that undergoes an oscillatory phosphorylation cycle with a period of ~24 h. This core oscillator can be reconstituted in vitro and is used to study the molecular mechanisms of circadian timekeeping and entrainment. Previous studies showed that two key metabolic changes that occur in cells during the transition into darkness, changes in the ATP/ADP ratio and redox status of the quinone pool, are cues that entrain the circadian clock. By changing the ATP/ADP ratio or adding oxidized quinone, one can shift the phase of the phosphorylation cycle of the core oscillator in vitro. However, the in vitro oscillator cannot explain gene expression patterns because the simple mixture lacks the output components that connect the clock to genes. Recently, a high-throughput in vitro system termed the in vitro clock (IVC) that contains both the core oscillator and the output components was developed. Here, we used IVC reactions and performed massively parallel experiments to study entrainment, the synchronization of the clock with the environment, in the presence of output components. Our results indicate that the IVC better explains the in vivo clock-resetting phenotypes of wild-type and mutant strains and that the output components are deeply engaged with the core oscillator, affecting the way input signals entrain the core pacemaker. These findings blur the line between input and output pathways and support our previous demonstration that key output components are fundamental parts of the clock.

The temporal order of physiology and behavior in mammals is primarily regulated by the circadian pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN). Taking advantage of bioluminescence reporters, we monitored the circadian rhythms of the expression of clock genes Per1 and Bmal1 in the SCN of freely moving mice and found that the rate of phase shifts induced by a single light pulse was different in the two rhythms. The Per1-luc rhythm was phase-delayed instantaneously by the light presented at the subjective evening in parallel with the activity onset of behavioral rhythm, whereas the Bmal1-ELuc rhythm was phase-delayed gradually, similar to the activity offset. The dissociation was confirmed in cultured SCN slices of mice carrying both Per1-luc and Bmal1-ELuc reporters. The two rhythms in a single SCN slice showed significantly different periods in a long-term (3 wk) culture and were internally desynchronized. Regional specificity in the SCN was not detected for the period of Per1-luc and Bmal1-ELuc rhythms. Furthermore, neither is synchronized with circadian intracellular Ca2+ rhythms monitored by a calcium indicator, GCaMP6s, or with firing rhythms monitored on a multielectrode array dish, although the coupling between the circadian firing and Ca2+ rhythms persisted during culture. These findings indicate that the expressions of two key clock genes, Per1 and Bmal1, in the SCN are regulated in such a way that they may adopt different phases and free-running periods relative to each other and are respectively associated with the expression of activity onset and offset.

Abstract Background Prior studies have shown that the auditory N1 event-related potential component elicited by self-generated vocalizations is reduced relative to played back vocalizations, putatively reflecting a corollary discharge mechanism. Schizophrenia patients and psychosis risk syndrome (PRS) youth show deficient N1 suppression during vocalization, consistent with corollary discharge dysfunction. Because N1 is an admixture of theta (4–7 Hz) power and phase synchrony, we examined their contributions to N1 suppression during vocalization, as well as their sensitivity, relative to N1, to corollary discharge dysfunction in schizophrenia and PRS individuals. Methods Theta phase and power values were extracted from electroencephalography data acquired from PRS youth (n = 71), early illness schizophrenia patients (ESZ; n = 84), and healthy controls (HCs; n = 103) as they said “ah” (Talk) and then listened to the playback of their vocalizations (Listen). A principal component analysis extracted theta intertrial coherence (ITC; phase consistency) and event-related spectral power, peaking in the N1 latency range. Talk–Listen suppression scores were analyzed. Results Talk–Listen suppression was greater for theta ITC (Cohen’s d = 1.46) than for N1 in HC (d = 0.63). Both were deficient in ESZ, but only N1 suppression was deficient in PRS. When deprived of variance shared with theta ITC suppression, N1 suppression no longer differentiated ESZ and PRS individuals from HC. Deficits in theta ITC suppression were correlated with delusions (P = .007) in ESZ. Theta power suppression did not differentiate groups. Conclusions Theta ITC-suppression during vocalization is a more sensitive index of corollary discharge-mediated auditory cortical suppression than N1 suppression and is more sensitive to corollary discharge dysfunction in ESZ than in PRS individuals.

Human locomotion may result from monotonic shifts in the referent position, R, of the body in the environment. R is also the spatial threshold at which muscles can be quiescent but are activated depending on the deflection of the current body configuration Q from R. Shifts in R are presumably accomplished with the participation of proprioceptive and visual feedback and responsible for transferring stable body balance (equilibrium) from one place in the environment to another, resulting in rhythmic activity of multiple muscles by a central pattern generator (CPG). We tested predictions of this two-level control scheme. In particular, in response to a transient block of vision during locomotion, the system can temporarily slow shifts in R. As a result, the phase of rhythmical movements of all four limbs will be changed for some time, even though the rhythm and other characteristics of locomotion will be fully restored after perturbation, a phenomenon called long-lasting phase resetting. Another prediction of the control scheme is that the activity of multiple muscles of each leg can be minimized reciprocally at specific phases of the gait cycle both in the presence and absence of vision. Speed of locomotion is related to the rate of shifts in the referent body position in the environment. Results confirmed that human locomotion is likely guided by feedforward shifts in the referent body location, with subsequent changes in the activity of multiple muscles by the CPG. Neural structures responsible for shifts in the referent body configuration causing locomotion are suggested.

The neural circuits that regulate sleep and arousal as well as their integration with circadian circuits remain unclear, especially in DROSOPHILA: This issue intersects with that of photoreception, because light is both an arousal signal in diurnal animals and an entraining signal for the circadian clock. To identify neurons and circuits relevant to light-mediated arousal as well as circadian phase-shifting, we developed genetic techniques that link behavior to single cell-type resolution within the Drosophila central brain. We focused on the unknown function of the 10 PDF-containing large ventral lateral neurons (l-LNvs) of the Drosophila circadian brain network and show here that these cells function in light-dependent arousal. They also are important for phase shifting in the late-night (dawn), indicating that the circadian photoresponse is a network property and therefore non-cell-autonomous. The data further indicate that the circuits underlying light-induced arousal and circadian photoentrainment intersect at the l-LNvs and then segregate.

The external segment of globus pallidus (GPe) is a network of oscillatory neurons connected by inhibitory synapses. We studied the intrinsic dynamic and the response to a shared brief inhibitory stimulus in a model GPe network. Individual neurons were simulated using a phase resetting model based on measurements from mouse GPe neurons studied in slices. The neurons showed a broad heterogeneity in their firing rates and in the shapes and sizes of their phase resetting curves. Connectivity in the network was set to match experimental measurements. We generated statistically equivalent neuron heterogeneity in a small-world model, in which 99% of connections were made with near neighbors and 1% at random, and in a model with entirely random connectivity. In both networks, the resting activity was slowed and made more irregular by the local inhibition, but it did not show any periodic pattern. Cross-correlations among neuron pairs were limited to directly connected neurons. When stimulated by a shared inhibitory input, the individual neuron responses separated into two groups: one with a short and stereotyped period of inhibition followed by a transient increase in firing probability, and the other responding with a sustained inhibition. Despite differences in firing rate, the responses of the first group of neurons were of fixed duration and were synchronized across cells.

Traveling phase waves are commonly observed in recordings of the cerebral cortex and are believed to organize behavior across different areas of the brain. We use this as motivation to analyze a one-dimensional network of phase oscillators that are nonlocally coupled via the phase response curve (PRC) and the Dirac delta function. Existence of waves is proven and the dispersion relation is computed. Using the theory of distributions enables us to write and solve an associated stability problem. First and second order perturbation theory is applied to get analytic insight and we show that long waves are stable while short waves are unstable. We apply the results to PRCs that come from mitral neurons. We extend the results to smooth pulse-like coupling by reducing the nonlocal equation to a local one and solving the associated boundary value problem.

There has been a long debate about the neural mechanism of event-related potentials (ERPs). Previously, no evidence or method was apparent to validate the two competing models, the evoked model and the oscillation model. One argument is whether the pre-stimulus brain oscillation could influence the following ERP. This study carried out an innovative visual oddball task experiment to investigate the dynamic process of visual evoked potentials. A period of stable oscillations of specified dominant frequencies and initial phases, i.e. the steady-state baseline, would be induced before responses to transient stimuli of different contrasts, which could overcome the artifact problem caused by the ‘sorting’ method. The result first revealed a ‘three-period-transition’ for the generation of visual evoked potentials by an objective decomposition. The ERP almost retained the preceding oscillation during the first period, provided an unstable negative potential in the second period, and generated the N1 component in the third period. The cross term analysis showed that the evoked model couldn't be the whole explanation for the ERP generation. Furthermore, the component analysis revealed that the N1 latency was sensitive to the initial phase under the low stimulus contrast (supporting the oscillation model) but not under the high stimulus contrast (supporting the evoked model). It demonstrated that the external stimulus contrast is a significant factor deciding the explicit model for ERPs. Our method and preliminary results may help reconcile the previous, seemly contradictory findings on the ERP mechanism. •The generation of VEPs undergoes the maintaining, transitional and stable periods.•The evoked model cannot completely explain the VEP generation.•The oscillation model is a necessary mechanism for generating VEPs.•The proportion of the two models for N1 changes with the contrast of external stimuli.

Humans walk adaptively in varying environments by manipulating their complicated and redundant musculoskeletal system. Although the central pattern generators in the spinal cord are largely responsible for adaptive walking through sensory-motor coordination, it remains unclear what neural mechanisms determine walking adaptability. It has been reported that locomotor rhythm and phase are regulated by the production of phase shift and rhythm resetting (phase resetting) for periodic motor commands in response to sensory feedback and perturbation. While the phase resetting has been suggested to make a large contribution to adaptive walking, it has only been investigated based on fictive locomotion in decerebrate cats, and thus it remains unclear if human motor control has such a rhythm regulation mechanism during walking. In our previous work, we incorporated a phase resetting mechanism into a motor control model and demonstrated that it improves the stability and robustness of walking through forward dynamic simulations of a human musculoskeletal model. However, this did not necessarily verify that phase resetting plays a role in human motor control. In our other previous work, we used kinematic measurements of human walking to identify the phase response curve (PRC), which explains phase-dependent responses of a limit cycle oscillator to a perturbation. This revealed how human walking rhythm is regulated by perturbations. In this study, we integrated these two approaches using a physical model and identification of the PRC to examine the hypothesis that phase resetting plays a role in the control of walking rhythm in humans. More specifically, we calculated the PRC using our neuromusculoskeletal model in the same way as our previous human experiment. In particular, we compared the PRCs calculated from two different models with and without phase resetting while referring to the PRC for humans. As a result, although the PRC for the model without phase resetting did not show any characteristic shape, the PRC for the model with phase resetting showed a characteristic phase-dependent shape with trends similar to those of the PRC for humans. These results support our hypothesis and will improve our understanding of adaptive rhythm control in human walking.