Relaxin‐3 innervation of the intergeniculate leaflet of the rat thalamus – neuronal tract‐tracing and in vitro electrophysiological studies

Behavioural state is controlled by a range of neural systems that are sensitive to internal and external stimuli. The relaxin‐3 and relaxin family peptide receptor 3 (RXFP3) system has emerged as a putative ascending arousal network with putative involvement in regulation of stress responses, neuroendocrine control, feeding and metabolism, circadian activity and cognition. Relaxin‐3/γ‐aminobutyric acid neuron populations have been identified in the nucleus incertus, pontine raphe nucleus, periaqueductal grey (PAG) and an area dorsal to the substantia nigra. Relaxin‐3‐positive fibres/terminals densely innervate arousal‐related structures in the brainstem, hypothalamus and limbic forebrain, but the functional significance of the heterogeneous relaxin‐3 neuron distribution and its inputs to specific brain areas are unclear. Therefore, in this study, we used neuronal tract‐tracing and immunofluorescence staining to explore the source of the dense relaxin‐3 innervation of the intergeniculate leaflet (IGL) of the thalamus, a component of the neural circadian timing system. Confocal microscopy analysis revealed that relaxin‐3‐positive neurons retrogradely labelled from the IGL were predominantly present in the PAG and these neurons expressed corticotropin‐releasing factor receptor‐like immunoreactivity. Subsequently, whole‐cell patch‐clamp recordings revealed heterogeneous effects of RXFP3 activation in the IGL by the RXFP3 agonist, relaxin‐3 B‐chain/insulin‐like peptide‐5 A‐chain (R3/I5). Identified, neuropeptide Y‐positive IGL neurons, known to influence suprachiasmatic nucleus activity, were excited by R3/I5, whereas neurons of unidentified neurotransmitter content were either depolarized or displayed a decrease in action potential firing and/or membrane potential hyperpolarization. Our data identify a PAG to IGL relaxin‐3/RXFP3 pathway that might convey stress‐related information to key elements of the circadian system and influence behavioural state rhythmicity.     

Visual attention,reaction time,and self-reported alertness upon awakening from sleep bouts of varying lengths

The aim of the present study was to examine visual attention, especially the executive control functions that deal with conflict, when participants were in a low arousal state shortly after a nighttime awakening. Fifteen participants spent four consecutive nights at a laboratory and performed a flankers task using two levels of target-distractor spacing (0.75° and 1.50°) and three trial types (compatible, incompatible, and neutral). The first night was a habituation night. For the next three nights, participants went to sleep at 2300 hours and were then awakened at either 2400 hours (1-h sleep bout), 0300 hours (4-h sleep bout), or 0600 hours (7-h sleep bout) and were administered a flankers task and a self-report questionnaire that measured arousal level. These testing times were counter-balanced across participants, and a 2100 hours (pre-sleep) flankers task was also randomly assigned to be completed on one of the testing nights. Response time on neutral-flanker trials was increased if participants were awakened from a sleep bout and was slowest at 0300 hours, appearing to parallel circadian body temperature. In contrast, failures of selective attention, as indexed by the difference between compatible and incompatible trials, increased linearly as a function of the length of the sleep bout. Compared to the 2100 hours pre-sleep condition, self-reported energy was lower and Tiredness was higher after awakening from a sleep bout. Taken together, the current data suggest a dissociation between the processes that perform a non-conflict task and the executive control of attention. Specifically, longer sleep bouts seem to be associated with greater difficulty in inhibiting task-irrelevant information, perhaps due to a sleep inertia effect affecting the anterior cingulate cortex.     

Advances in computational modeling approaches of pituitary gonadotropin signaling

Introduction: Pituitary gonadotropins play an essential and pivotal role in the control of human and animal reproduction within the hypothalamic–pituitary–gonadal (HPG) axis. The computational modeling of pituitary gonadotropin signaling encompasses phenomena of different natures such as the dynamic encoding of gonadotropin secretion, and the intracellular cascades triggered by gonadotropin binding to their cognate receptors, resulting in a variety of biological outcomes.

Areas covered: The authors provide an overview of the historical and ongoing issues in modeling and data analysis related to gonadotropin secretion in the field of both physiology and neuroendocrinology. They mention the different mathematical formalisms involved, their interest and limits. They also discuss open statistical questions in signal analysis associated with key endocrine issues and review recent advances in the modeling of the intracellular pathways activated by gonadotropins, which yields promising development for innovative approaches in drug discovery.

Expert opinion: The greatest challenge to be tackled in computational modeling of pituitary gonadotropin signaling is the embedding of gonadotropin signaling within its natural multi-scale environment, from the single cell level, to the organic and whole HPG level. The development of modeling approaches of G protein-coupled receptor signaling, together with multicellular systems biology may lead to unexampled mechanistic understanding with critical expected fallouts in the therapeutic management of reproduction.     

Molecular mechanisms interlinking biological clock and diabetes mellitus: Effective tools for better management

Background and aimAdvances in circadian biology have delineated the link between perturbed biological clock and metabolic diseases. Circadian disturbances are associated with the onset, progression and severity of diabetes mellitus.MethodsWe conducted a literature survey using the key terms - circadian, diabetes, circadian and diabetes, clock genes and diabetes, chronotherapy and peripheral clocks in science direct, PubMed, Google, and Embase till August 23, 2021.ResultsMisalignment between peripheral clocks located in pancreas, intestine, liver, adipose tissue and skeletal muscle and with the central oscillator alters the secretion of insulin, incretins, adipokines and soluble factors resulting in the derangement of metabolism leading to chronic hyperglycemia.ConclusionManagement of circadian health restores glucose homeostasis confirming that chronotherapy will help in the management of diabetes mellitus. Further, administration of circadian clock modifiers has proved potential therapeutic agents to treat diabetes mellitus. The aim of the review is to highlight the molecular mechanisms linking biological clock and diabetes mellitus and how they are useful for effective management of the disease.     

不同静息心率的原发性高血压患者自主神经昼夜平衡变化规律

目的 探讨不同静息心率(resting heart rate,RHR)的原发性高血压患者自主神经昼夜平衡变化规律。 方法 选取2013年起就诊同济医学院附属武汉市第一医院门诊及住院的的原发性高血压患者314例。不同静息心率原发性高血压患者昼夜交感指标极低频值(VLF),低频值(LF)、迷走神经张力指标高频值(HF )以及交感迷走神经动态平衡指标低频与高频成分之比(LF/HF)均值水平。交感、迷走神经张力指标与昼夜静息心率的相关性分析。昼夜静息心率的交感、迷走神经张力影响因素分析采用单因素和多因素线性回归分析。结果 与RHR-L同时间段相比,VLF、LF、HF值较低［(731.77±1106.33;851.68±901.16)ms₂比(1476.01±1936.17)ms₂,P<0.05;(140.03±185.39;296.80±562.64)ms₂比(471.13±776.36)ms₂,P<0.05;(54.28±82.66;157.10±337.13)ms₂比(323.62±549.14)ms₂,P<0.01］,LF/HF值较高［(4.09±3.69)比(2.65±2.80),P<0.05］。与RHR-M同时间段相比,VLF、HF值较低［(731.77±1106.33)ms₂比(851.68±901.16)ms₂,P<0.05;(54.28±82.66)ms₂比(157.10±337.13)ms₂,P<0.05］,LF/HF值较高［(4.09±3.69)ms₂比(3.21±2.72)ms₂,P<0.05］。Spearman相关分析结果显示,昼间静息心率与VLF、LF、HF均呈负相关(r₂=0.103,P<0.05;r₂=0.082,P<0.05;r₂=0.191,P<0.05);与LF/HF呈正相关(r₂=0.0864,P<0.05)。夜间静息心率与VLF、LF、HF呈负相关(r₂=0.119,P<0.05;r₂=0.127,P<0.05;r₂=0.198,P<0.05);与LF/HF呈正相关(r₂=0.00723,P>0.05)。多元线性回归分析发现昼间VLF、HF、LF/HF是静息心率变化的影响因素(B=-0.001,P<0.01;B=-0.007,P<0.05;B=0.861,P<0.01);夜间VLF、LF、LF/HF是静息心率变化的影响因素(B=-0.001,P<0.05;B=-0.003,P<0.05;B=0.447,P<0.05)。结论 交感神经张力和迷走神经张力的差值与昼夜静息心率呈正相关。昼间迷走神经张力占主要影响,而夜间交感神经张力起主要作用。     

Delay in the Recovery of Normal Sleep-Wake Cycle after Disruption of the Light-Dark Cycle in Mice: A Bipolar Disorder-Prone Animal Model?

Objective

Disruption of the circadian rhythm is known as a provoking factor for manic episodes. Individual differences exist in the recovery rate from disruption in the general population. To develop a screening method to detect individuals vulnerable to bipolar disorder, the authors observed the relationship between the recovery of the normal sleep-wake cycle after switching the light-dark (LD) cycle and quinpirole-induced hyperactivity in mice.

Methods

Sixteen male mice (age of 5 weeks, weight 28-29 gm) were subjected to a circadian rhythm disruption protocol. Sleep-wake behaviors were checked every 5 min for a total duration of 15 days, i.e., 2 days of baseline observations, 3 days of LD cycle changes, and 10 days of recovery. During the dark cycle on the 16th experimental day, their general locomotor activities were measured in an open field for 120 minutes after an injection of quinpirole (0.5 mg/kg, s.c.).

Results

The individual differences in the recovery rate of the baseline sleep-wake cycle were noted after 3 days of switching the LD cycle. Fifty percent (n=8) of the mice returned to the baseline cycle within 6 days after normalizing the LD cycle (early recovery group). The locomotor activities of mice that failed to recover within 6 days (delayed recovery group) were significantly higher (mean rank=12.25) than those of the early recovery group (mean rank=4.75, u=62.0, p=0.001, Mann-Whitney U test).

Conclusion

Given that the quinpirole-induced hyperactivity is an animal model of bipolar disorder, our results suggest individuals who have difficulties in recovery from circadian rhythm disruption may be vulnerable to bipolar disorder.     

Should we listen to our clock to prevent type 2 diabetes mellitus?

The circadian clock drives a number of metabolic processes including energy intake, storage and utilization coupled with the sleep/wake cycles. Globally, the increasing prevalence of type 2 diabetes (T2DM) has become a significant international public health concern. In view of the heavy societal burden caused by diabetes, and further, to reduce its growing incidence, it is clearly essential to understand the causes of this disease and to devise more effective strategies for its treatment. Although many factors cause T2DM, this article centers on the role of circadian regulation of metabolism. The correlation between the increased occurrence of T2DM and the ubiquity of modern social pressures such as 24/7 lifestyles as well as nocturnal lighting conditions point strongly to the hypothesis that malfunctioning of circadian controls may be involved in the etiology of the illness. Nocturnal light exposure, unusual timing of food, irregular sleep/wake schedules and traveling between different time zones are some of the factors responsible for improper entrainment of the clock. Recent reports have proposed that strengthening of circadian clock functioning and proper timing of food intake could stabilize glucose homeostasis. This strategy thus represents a chronotherapeutic option for non-pharmaceutical intervention in treating T2DM patients.     

老年高血压合并糖尿病患者心率变异性及其昼夜变化临床分析

目的研究老年高血压合并糖尿病患者的心率变异性(HRV)及其昼夜变化规律,探讨老年糖尿病患者心脏自主神经变化的临床意义。方法选择87例原发性高血压患者(EH组)及68例高血压合并糖尿病患者(EH+DM组),监测24 h动态心电图,进行HRV时域指标SDNN、SDANN、SDNN Index、RMSSD、PNN50的分析。比较2组间HRV指标的差异以及HRV昼夜指标差异。结果 EH+DM组较EH组24 h、日间、夜间HRV各项指标均明显降低,且有统计学差异;EH组SDNN以及RMSSD呈昼低夜高,但无明显统计学差异,SDNN Index和PNN50仍呈昼低夜高现象(P0.01);EH+DM组SDNN以及RMSSD呈昼高夜低现象(P0.05),SDNN Index和PNN50昼夜间无统计学差异。结论老年高血压合并糖尿病患者HRV显著降低,高血压患者昼夜节律已有明显受损,高血压合并糖尿病患者昼夜节律进一步受损,心脏自主神经功能失调。