Quantum mechanics insights into melatonin and analogs binding to melatonin MT1 and MT2 receptors.

Melatonin receptors MT1 and MT2 are G protein-coupled receptors that mediate the effects of melatonin, a hormone involved in circadian rhythms and other physiological functions. Understanding the molecular interactions between these receptors and their ligands is crucial for developing novel therapeutic agents. In this study, we used molecular docking, molecular dynamics simulations, and quantum mechanics calculation to investigate the binding modes and affinities of three ligands: melatonin (MLT), ramelteon (RMT), and 2-phenylmelatonin (2-PMT) with both receptors. Based on the results, we identified key amino acids that contributed to the receptor-ligand interactions, such as Gln181/194, Phe179/192, and Asn162/175, which are conserved in both receptors. Additionally, we described new meaningful interactions with Gly108/Gly121, Val111/Val124, and Val191/Val204. Our results provide insights into receptor-ligand recognition's structural and energetic determinants and suggest potential strategies for designing more optimized molecules. This study enhances our understanding of receptor-ligand interactions and offers implications for future drug development.

The circadian rest-activity pattern predicts cognitive decline among mild-moderate Alzheimer's disease patients.

BACKGROUND: Alterations in circadian rhythms are present in the presymptomatic stage of Alzheimer's disease (AD), possibly contributing to its pathogenesis. However, it is unknown whether such alterations are associated with worse outcomes once individuals are diagnosed with symptomatic disease. We aimed to evaluate the association between the circadian rest-activity pattern and AD-related features in patients with mild-moderate AD. METHODS: We assessed the circadian rest-activity pattern of consecutive patients with mild-moderate AD through actigraphy for 14 days. Cerebrospinal fluid was obtained to determine the levels of important pathological markers including amyloid-beta protein (Aß42), phosphorylated tau (P-tau), total tau (T-tau), and neurofilament light (NF-L). Neuropsychological evaluation was conducted at the beginning of the study and after 12 months of follow-up. Linear regression models were performed considering the global population and Aß42+ patients only. RESULTS: The cohort included 100 patients with mild-moderate AD. The median age [p25;p75] was 76.0 [73.0;80.0] years and 63.0% were female. Older age (effect size [SE] of 0.324 [0.096]; p = 0.001) and male sex (0.780 [0.193]; p = 0.001) were associated with increased fragmentation and decreased synchronization of the rhythm, respectively. After adjusting for age, sex, and season of the year, increased levels of T-tau (effect size [95% CI] of 0.343 [0.139 to 0.547]; p = 0.001) and NF-L (0.444 [0.212 to 0.676]; p = 0.001) were associated with a higher amplitude of the rest-activity rhythm. Increased fragmentation of the rhythm at baseline was associated with greater cognitive decline after one year of follow-up independent of age, sex, T-tau/Aß42 ratio, educational level, and season of the year (- 0.715 [- 1.272 to - 0.157]; p = 0.013). Similar findings were obtained considering only the Aß42+ patients. CONCLUSIONS: Our results suggest a potential role of the circadian rest-activity pattern in predicting the cognitive decline of patients with mild-moderate AD. Further studies are warranted to confirm these findings and to elucidate whether there is causality among the observed associations.

Disruption of neocortical synchronisation during slow-wave sleep in the rotenone model of Parkinson's disease.

Parkinson's disease motor dysfunctions are associated with improperly organised neural oscillatory activity. The presence of such disruption at the early stages of the disease in which altered sleep is one of the main features could be a relevant predictive feature. Based on this, we aimed to investigate the neocortical synchronisation dynamics during slow-wave sleep (SWS) in the rotenone model of Parkinson's disease. After rotenone administration within the substantia nigra pars compacta, one group of male Wistar rats underwent sleep-wake recording. Considering the association between SWS oscillatory activity and memory consolidation, another group of rats underwent a memory test. The fine temporal structure of synchronisation dynamics was evaluated by a recently developed technique called first return map. We observed that rotenone administration decreased the time spent in SWS and altered the power spectrum within different frequency bands, whilst it increased the transition rate from a synchronised to desynchronised state. This neurotoxin also increased the probability of longer and decreased the probability of shorter desynchronisation events. At the same time, we observed impairment in object recognition memory. These findings depict an electrophysiological fingerprint represented by a disruption in the typical oscillatory activity within the neocortex at the early stages of Parkinson's disease, concomitant with a decrease in the time spent in SWS and impairment in recognition memory.

Hippocampal and cortical communication around micro-arousals in slow-wave sleep.

Sleep plays a crucial role in the regulation of body homeostasis and rhythmicity in mammals. Recently, a specific component of the sleep structure has been proposed as part of its homeostatic mechanism, named micro-arousal. Here, we studied the unique progression of the dynamic behavior of cortical and hippocampal local field potentials (LFPs) during slow-wave sleep-related to motor-bursts (micro-arousals) in mice. Our main results comprised: (i) an abrupt drop in hippocampal LFP amplitude preceding micro-arousals which persisted until the end of motor-bursts (we defined as t interval, around 4s) and a similar, but delayed amplitude reduction in cortical (S1/M1) LFP activity occurring at micro-arousal onset; (ii) two abrupt frequency jumps in hippocampal LFP activity: from Theta (6-12 Hz) to Delta (2-4 Hz), also t seconds before the micro-arousal onset, and followed by another frequency jump from Delta to Theta range (5-7 Hz), now occurring at micro-arousal onset; (iii) a pattern of cortico-hippocampal frequency communication precedes micro-arousals: the analysis between hippocampal and cortical LFP fluctuations reveal high coherence during τ interval in a broader frequency band (2-12 Hz), while at a lower frequency band (0.5-2 Hz) the coherence reaches its maximum after the onset of micro-arousals. In conclusion, these novel findings indicate that oscillatory dynamics pattern of cortical and hippocampal LFPs preceding micro-arousals could be part of the regulatory processes in sleep architecture.

Optimizing the detection of nonstationary signals by using recurrence analysis.

Recurrence analysis and its quantifiers are strongly dependent on the evaluation of the vicinity threshold parameter, i.e., the threshold to regard two points close enough in phase space to be considered as just one. We develop a new way to optimize the evaluation of the vicinity threshold in order to assure a higher level of sensitivity to recurrence quantifiers to allow the detection of even small changes in the dynamics. It is used to promote recurrence analysis as a tool to detect nonstationary behavior of time signals or space profiles. We show that the ability to detect small changes provides information about the present status of the physical process responsible to generate the signal and offers mechanisms to predict future states. Here, a higher sensitive recurrence analysis is proposed as a precursor, a tool to predict near future states of a particular system, based on just (experimentally) obtained signals of some available variables of the system. Comparisons with traditional methods of recurrence analysis show that the optimization method developed here is more sensitive to small variations occurring in a signal. The method is applied to numerically generated time series as well as experimental data from physiology.

Forced desynchronization model for a diurnal primate.

The circadian system is organized in a hierarchy of multiple oscillators, with the suprachiasmatic nucleus (SCN) as the master oscillator in mammals. The SCN is formed by a group of coupled cell oscillators. Knowledge of this coupling mechanism is essential to understanding entrainment and the expression of circadian rhythms. Some authors suggest that light-dark (LD) cycles with periods near the limit of entrainment may be good models for promoting internal desynchronization, providing knowledge about the coupling mechanism. As such, we evaluated the circadian activity rhythm (CAR) pattern of marmosets in LD cycles at lower limits of entrainment in order to study induced internal dissociation. To that end, two experiments were conducted: (1) 6 adult females were under symmetrical LD cycles T21, T22 and T21.5 for 60, 35 and 48 days, respectively; and (2) 4 male and 4 female adults were under T21 for 24 days followed by 18 days of LL, back to T21 for 24 days, followed by 14 days of LL. The CAR of each animal was continuously recorded. In experiment 1, vocalizations were also recorded. Under Ts shorter than 24 days, a dissociation pattern was observed for CAR and vocalizations. Two simultaneous circadian components emerged, one with the same period as the LD cycle, called the light-entrained component, and the other in free-running, denominated the non-light-entrained component. Both components were displayed in the CAR for all the animals in T21, five animals (83.3%) in T21.5 and two animals (33.3%) in T22. Our results are in accordance with the multioscillatory nature of the circadian system. Dissociation is partial synchronization to the LD cycle, with at least one group of oscillators synchronized by relative coordination and masking, while another group of oscillators free runs, but is also masked by the LD cycle. Since only T21 promoted the emergence of both circadian components in the circadian rhythms of all marmosets, it was considered the promoter period of circadian rhythm dissociation in this species, and is proposed as a good animal model for forced desynchronization in non-human diurnal primates.

Latitudinal cline of chronotype.

The rotation of the Earth around its own axis and around the sun determines the characteristics of the light/dark cycle, the most stable and ancient 24 h temporal cue for all organisms. Due to the tilt in the earth's axis in relation to the plane of the earth's orbit around the sun, sunlight reaches the Earth differentially depending on the latitude. The timing of circadian rhythms varies among individuals of a given population and biological and environmental factors underlie this variability. In the present study, we tested the hypothesis that latitude is associated to the regulation of circadian rhythm in humans. We have studied chronotype profiles across latitudinal cline from around 0° to 32° South in Brazil in a sample of 12,884 volunteers living in the same time zone. The analysis of the results revealed that humans are sensitive to the different sunlight signals tied to differences in latitude, resulting in a morning to evening latitudinal cline of chronotypes towards higher latitudes.

Self-reported discomfort associated with Daylight Saving Time in Brazilian tropical and subtropical zones.

BACKGROUND: Daylight Saving Time (DST) annually moves clocks 1 hour forward, when daytime is longer than night. Previous studies from medium and high latitude locations have pointed to a disruptive effect of DST on human circadian rhythms. Since Brazil is an equatorial country implementing DST, a different relationship between photic and social synchronisers may interfere with DST effects. AIM: To explore the prevalence and duration of self-reported discomfort related to DST among Brazilian residents (latitude 12-33° S, longditude 39-57° W). It was hypothesised that an elevated prevalence of self-reported discomfort would be found in Brazil, due to the pronounced uncoupling between social and geophysical synchronisers. SUBJECTS AND METHODS: In total, 12 467 volunteers completed a web-based, Brazilian version of Horne-Östberg Morningness-Eveningness Questionnaire, provided demographic information, and answered questions related to DST complaints (discomfort, duration of discomfort). RESULTS: Of the total sample, 45.43% reported no discomfort related to DST, with meaningful proportions for all chronotypes. However, eveningness was most associated with discomfort. About one fourth of the total sample reported discomfort over the whole DST period. Gender interaction is largely supported by these results. CONCLUSIONS: DST at low latitude locations may be disruptive for circadian rhythms, since seasonality of sunrise near the equator is negligible or very mild.

Predictability of arousal in mouse slow wave sleep by accelerometer data.

Arousals can be roughly characterized by punctual intrusions of wakefulness into sleep. In a standard perspective, using human electroencephalography (EEG) data, arousals are associated to slow-wave rhythms and K-complex brain activity. The physiological mechanisms that give rise to arousals during sleep are not yet fully understood. Moreover, subtle body movement patterns, which may characterize arousals both in human and in animals, are usually not detectable by eye perception and are not in general present in sleep studies. In this paper, we focus attention on accelerometer records (AR) to characterize and predict arousal during slow wave sleep (SWS) stage of mice. Furthermore, we recorded the local field potentials (LFP) from the CA1 region in the hippocampus and paired with accelerometer data. The hippocampus signal was also used here to identify the SWS stage. We analyzed the AR dynamics of consecutive arousals using recurrence technique and the determinism (DET) quantifier. Recurrence is a fundamental property of dynamical systems, which can be exploited to characterize time series properties. The DET index evaluates how similar are the evolution of close trajectories: in this sense, it computes how accurate are predictions based on past trajectories. For all analyzed mice in this work, we observed, for the first time, the occurrence of a universal dynamic pattern a few seconds that precedes the arousals during SWS sleep stage based only on the AR signal. The predictability success of an arousal using DET from AR is nearly 90%, while similar analysis using LFP of hippocampus brain region reveal 88% of success. Noteworthy, our findings suggest an unique dynamical behavior pattern preceding an arousal of AR data during sleep. Thus, the employment of this technique applied to AR data may provide useful information about the dynamics of neuronal activities that control sleep-waking switch during SWS sleep period. We argue that the predictability of arousals observed through DET(AR) can be functionally explained by a respiratory-driven modification of neural states. Finally, we believe that the method associating AR data with other physiologic events such as neural rhythms can become an accurate, convenient and non-invasive way of studying the physiology and physiopathology of movement and respiratory processes during sleep.

Efeito da estimulação transcraniana por corrente continua (ETCC) no córtex préfrontal dorsolateral sobre a reprodução de intervalo de tempo / Effect of Transcranial direct current stimulation (tDCS) on dorsolateral prefrontal cortex on reproduction of time

Existem evidências que apontam para a importância do córtex préfrontal dorsolateral (CPFDL) na percepção de intervalos de tempo. A ETCC (eletroestimulação transcraniana por corrente contínua) modula a excitabilidade cortical, podendo ser utilizada para influenciar o desempenho de diferentes funções cerebrais, como a estimativa de tempo. Nosso objetivo foi avaliar o efeito da estimulação do CPFDL direito e esquerdo sobre a reprodução de intervalos de tempo. 26 indivíduos foram submetidos a estimulação transcraniana de 2mA no CPFDL por 20 min (anódica, catódica ou sham). Em seguida, participaram de uma tarefa de reprodução de intervalos de tempo de 4 e 8 segundos. Através de ANOVA para medidas repetidas para os fatores estimulação (anódica, catódica, sham), Intervalos (4s e/ou 8s) e local (esquerdo e direito), pudemos observar que a estimulação anódica do CPFDL do hemisfério direito resultou em subestimativa maior no intervalo de 4 segundos, enquanto o uso de corrente catódica sobre o CPFDL esquerdo provocou uma superestimativa do tempo para o intervalo de 4 segundos. Nossos resultados corroboram a importância do CPFDL direito na percepção de tempo. Ainda, o efeito assimétrico observado é interessante, confirmando que o CPFDL esquerdo está associado às funções executivas, importantes na percepção de tempo.

There is evidence supporting the importance of the dorsolateral prefrontal cortex (DLPFC) in the perception of time. The tDCS (transcranial direct current stimulation) modulates cortical excitability and can be applied to influence the performance of different brain functions, such as timing. Our objective was to evaluate the effect of stimulation of right and left DLPFC on a task of production of time. 26 patients underwent transcranial stimulation of 2mA over the DLPFC for 20 min (anodic, cathodic or sham). Then they participated in a reproduction task of 4 and 8 seconds. Through ANOVA for repeated measures for stimulating factors (anode, cathode, sham), intervals (4S and / or 8s) and location (left and right), we observed that the anodic stimulation of the right DLPFC resulted in greater underestimation in 4-seconds interval, while the use of cathodic current on the left DLPFC caused an overestimation of 4-seconds interval. Our results confirm the importance of the right DLPFC in the perception of time. Furthermore, the observed asymmetric effect is interesting, confirming that the left DLPFC is associated with the executive, important roles in perception of time.