Activity In Suprachiasmatic Nucleus Research Articles

The Effects of Light on Sleep Patterns and Circadian Rhythms

Although humans spend an increasingly considerable amount of time in front of light emitting diode (LED)/digital screens, little research has been conducted focusing on the effects of artificial light on circadian rhythm and sleep. A current theory suggests that exposure to light, artificial or natural, outside of daytime hours has a detrimental effect on the neurobiology of an individual. Furthermore, artificial light from these screens or at a larger scale, light pollution, defined as excessive outdoor artificial light, can affect the circadian rhythms. The central pacemaker in the brain, known as the suprachiasmatic nucleus (SCN) controls various essential biological processes. Current evidence suggests different wavelengths of light have contrasting impacts on SCN activity and subsequent circadian rhythms. Alterations to circadian rhythms can have a profound impact on sleep and mood. Therefore, understanding how artificial light impacts SCN function is critical for determining the psychological and biological consequences. This paper reviews the effects that artificial light has on the brain, and breaks down the biological and psychological processes that control sleep and mood.

Alleviating sleep disturbances and modulating neuronal activity after ischemia: Evidence for the benefits of zolpidem in stroke recovery.

Sleep disorders are prevalent among stroke survivors and impede stroke recovery, yet they are still insufficiently considered in the management of stroke patients, and the mechanisms by which they occur remain unclear. There is evidence that boosting phasic GABA signaling with zolpidem during the repair phase improves stroke recovery by enhancing neural plasticity; however, as a non-benzodiazepine hypnotic, the effects of zolpidem on post-stroke sleep disorders remain unclear. Transient ischemic stroke in male rats was induced with a 30-minute middle cerebral artery occlusion. Zolpidem or vehicle was intraperitoneally delivered once daily from 2 to 7 days after the stroke, and the electroencephalogram and electromyogram were recorded simultaneously. At 24 h after ischemia, c-Fos immunostaining was used to assess the effect of transient ischemic stroke and acute zolpidem treatment on neuronal activity. In addition to the effects on reducing brain damage and mitigating behavioral deficits, repeated zolpidem treatment during the subacute phase of stroke quickly ameliorated circadian rhythm disruption, alleviated sleep fragmentation, and increased sleep depth in ischemic rats. Immunohistochemical staining showed that in contrast to robust activation in para-infarct and some remote areas by 24 h after the onset of focal ischemia, the activity of the ipsilateral suprachiasmatic nucleus, the biological rhythm center, was strongly suppressed. A single dose of zolpidem significantly upregulated c-Fos expression in the ipsilateral suprachiasmatic nucleus to levels comparable to the contralateral side. Stroke leads to suprachiasmatic nucleus dysfunction. Zolpidem restores suprachiasmatic nucleus activity and effectively alleviates post-stroke sleep disturbances, indicating its potential to promote stroke recovery.

Diurnal Variation of Brain Activity in the Human Suprachiasmatic Nucleus.

The suprachiasmatic nucleus (SCN) is the central clock for circadian rhythms. Animal studies have revealed daily rhythms in the neuronal activity in the SCN. However, the circadian activity of the human SCN has remained elusive. In this study, to reveal the diurnal variation of the SCN activity in humans, we localized the SCN by employing an areal boundary mapping technique to resting-state functional images and investigated the SCN activity using perfusion imaging. In the first experiment (n = 27, including both sexes), we scanned each participant four times a day, every 6 h. Higher activity was observed at noon, while lower activity was recorded in the early morning. In the second experiment (n = 20, including both sexes), the SCN activity was measured every 30 min for 6 h from midnight to dawn. The results showed that the SCN activity gradually decreased and was not associated with the electroencephalography. Furthermore, the SCN activity was compatible with the rodent SCN activity after switching off the lights. These results suggest that the diurnal variation of the human SCN follows the zeitgeber cycles of nocturnal and diurnal mammals and is modulated by physical lights rather than the local time.

Timed restricted feeding cycles drive daily rhythms in female rats maintained in constant light but only partially restore the estrous cycle.

Light at night is an emergent problem for modern society. Rodents exposed to light at night develop a loss of circadian rhythms, which leads to increased adiposity, altered immune response, and increased growth of tumors. In female rats, constant light (LL) eliminates the estrous cycle leading to a state of persistent estrus. The suprachiasmatic nucleus (SCN) drives circadian rhythms, and it interacts with the neuroendocrine network necessary for reproductive function. Timed restricted feeding (RF) exerts a powerful entraining influence on the circadian system, and it can influence the SCN activity and can restore rhythmicity or accelerate re-entrainment in experimental conditions of shift work or jet lag. The present study explored RF in female rats exposed to LL, with the hypothesis that this cyclic condition can rescue or prevent the loss of daily rhythms and benefit the expression of the estrous cycle. Two different feeding schedules were explored: 1. A 12-h food/12-h fasting schedule applied to arrhythmic rats after 3 weeks in LL, visualized as a rescue strategy (LL + RFR, 3 weeks), or applied simultaneously with the first day of LL as a preventive strategy (LL + RFP, 6 weeks). 2. A 12-h window of food intake with food given in four distributed pulses (every 3 h), applied after 3 weeks in LL, as a rescue strategy (LL + PR, 3 weeks) or applied simultaneously with the first day of LL as a preventive strategy (LL + PP, 6 weeks). Here, we present evidence that scheduled feeding can drive daily rhythms of activity and temperature in rats exposed to LL. However, the protocol of distributed feeding pulses was more efficient to restore the day–night activity and core temperature as well as the c-Fos day–night change in the SCN. Likewise, the distributed feeding partially restored the estrous cycle and the ovary morphology under LL condition. Data here provided indicate that the 12-h feeding/12-h fasting window determines the rest-activity cycle and can benefit directly the circadian and reproductive function. Moreover, this effect is stronger when food is distributed along the 12 h of subjective night.

Generation and Disruption of Circadian Rhythms in the Suprachiasmatic Nucleus: A Core-Shell Model.

We focus our research on how the core-shell organization controls behavior of the suprachiasmatic nucleus (SCN), how the core and shell are synchronized to the environment, what impact they have on the behavior of the SCN under different lighting conditions, and what mechanisms disrupt synchronization. To this end, we use a reduced Kuramoto model, with parameters inferred from experimental observations and calibrated for mice, and perform a detailed comparison between the model and experimental data under light-dark (LD), dark-dark (DD), and light-light (LL) conditions. The operating limits of free-running and entrained SCN activity under symmetric LD cycles are analyzed, with particular focus on the phenomena of anticipation and dissociation. Results reveal that the core-shell organization of the SCN enables anticipation of future events over circadian cycles. The model predicts the emergence of a second (dissociated) rhythm for large and small LD periods. Our results are in good qualitative and quantitative agreement with experimental observations of circadian dissociation. We further describe SCN activity under LL conditions and show that our model satisfies Aschoff’s first rule, according to which the endogenous free-running circadian period observed under complete darkness will shorten in diurnal animals and lengthen in nocturnal animals under constant light. Our results strongly suggest that the Kuramoto model captures essential features of synchronization and entrainment in the SCN. Moreover, our approach is easily extendible to an arbitrary number of groups, with dynamics described by explicit equations for the group phase and synchronization index. Viewed together, the reduced Kuramoto model presents itself as a useful tool for exploring open problems in the study of circadian rhythms, one that can account for evolving views of the circadian system’s organization, including peripheral clocks and inter-hemispheric interaction, and can be translated to other nocturnal and diurnal animals, including humans.

Daily electrical activity in the master circadian clock of a diurnal mammal.

Circadian rhythms in mammals are orchestrated by a central clock within the suprachiasmatic nuclei (SCN). Our understanding of the electrophysiological basis of SCN activity comes overwhelmingly from a small number of nocturnal rodent species, and the extent to which these are retained in day-active animals remains unclear. Here, we recorded the spontaneous and evoked electrical activity of single SCN neurons in the diurnal rodent Rhabdomys pumilio, and developed cutting-edge data assimilation and mathematical modeling approaches to uncover the underlying ionic mechanisms. As in nocturnal rodents, R. pumilio SCN neurons were more excited during daytime hours. By contrast, the evoked activity of R. pumilio neurons included a prominent suppressive response that is not present in the SCN of nocturnal rodents. Our modeling revealed and subsequent experiments confirmed transient subthreshold A-type potassium channels as the primary determinant of this response, and suggest a key role for this ionic mechanism in optimizing SCN function to accommodate R. pumilio's diurnal niche.

026 Vasoactive Intestinal Polypeptide Directly Excites Neurons of the Subparaventricular Zone

Abstract Introduction The suprachiasmatic nucleus (SCN) is responsible for generating the circadian rhythmicity in mammals. The ventral region or core of the SCN contains neurons that express the neuropeptide vasoactive intestinal polypeptide (VIP). VIP signaling is central for coherency and synchrony of SCN activity. VIP-expressing neurons in the SCN densely project to the ventral subregions of the subparaventricular zone (vSPZ). We studied the effects of VIP on vSPZ neurons in brain slices of mice with a combined calcium imaging and whole-cell patch-clamp recording techniques. We used calcium imaging to assess the effects of VIP on vSPZ neurons as a population and we acquired patch-clamp recordings to explore the effects of VIP on the electrical properties and the synaptic inputs to vSPZ neurons. Methods We expressed GCamp6 in vSPZ neurons by stereotaxically injecting AAV10-DIO-Ef1a-GCamp6 into the vSPZ of vGAT-IRES-Cre mice. Brain slices were prepared two weeks later and images were captured using a standard GFP filter set. We performed whole-cell recordings of the vSPZ neurons of wild-type mice. We assessed the effects of VIP on the membrane potential and the on excitatory synaptic input in vSPZ neurons. Results Using GCamp6-based in vitro calcium imaging we found that VIP excites 17% of vSPZ neurons and this effect was maintained in the presence of tetrodotoxin (TTX) and synaptic blockers for AMPA/NMDA and GABAA transmissions suggesting a direct effect of VIP on vSPZ neurons. We confirmed this result with patch-clamp recordings. We found that 29% of vSPZ neurons were excited by VIP. VIP produced a membrane depolarization of vSPZ neurons in the presence of antagonists for AMPA/NMDA and GABAA receptors. In addition, we found that in a small percentage of vSPZ neurons VIP increased the frequency of the glutamatergic excitatory postsynaptic currents, suggesting an additional excitatory mechanism. Conclusion Our results demonstrate that exogenous VIP directly excites the vSPZ neurons producing an increase in intracellular calcium and membrane depolarization. In addition, VIP increases glutamatergic afferent inputs to vSPZ neurons indicating an additional synergistic excitation. We conclude that when VIP is released from the SCN VIP fibers it can activate vSPZ neurons. Support (if any) NS091126 and HL149630.

Modulations in irradiance directed at melanopsin, but not cone photoreceptors, reliably alter electrophysiological activity in the suprachiasmatic nucleus and circadian behaviour in mice.

Intrinsically photosensitive retinal ganglion cells convey intrinsic, melanopsin-based, photoreceptive signals alongside those produced by rods and cones to the suprachiasmatic nucleus (SCN) circadian clock. To date, experimental data suggest that melanopsin plays a more significant role in measuring ambient light intensity than cone photoreception. Such studies have overwhelmingly used diffuse light stimuli, whereas light intensity in the world around us varies across space and time. Here, we investigated the extent to which melanopsin or cone signals support circadian irradiance measurements in the presence of naturalistic spatiotemporal variations in light intensity. To address this, we first presented high- and low-contrast movies to anaesthetised mice whilst recording extracellular electrophysiological activity from the SCN. Using a mouse line with altered cone sensitivity (Opn1mwR mice) and multispectral light sources we then selectively varied irradiance of the movies for specific photoreceptor classes. We found that steps in melanopic irradiance largely account for the light induced-changes in SCN activity over a range of starting light intensities and in the presence of spatiotemporal modulation. By contrast, cone-directed changes in irradiance only influenced SCN activity when spatiotemporal contrast was low. Consistent with these findings, under housing conditions where we could independently adjust irradiance for melanopsin versus cones, the period lengthening effects of constant light on circadian rhythms in behaviour were reliably determined by melanopic irradiance, regardless of irradiance for cones. These data add to the growing evidence that modulating effective irradiance for melanopsin is an effective strategy for controlling the circadian impact of light.

Social interaction masking contributes to changes in the activity of the suprachiasmatic nucleus and impacts on circadian rhythms

Light is the most powerful temporal cue that entrains physiology and behavior through modulation of the suprachiasmatic nucleus (SCN) of the hypothalamus. However, on a daily basis, individuals face a combination of light and several non-photic cues, such as social interaction. In order to investigate whether SCN activity and SCN-driven rhythms are altered by social interaction, adult male C57BLJ/6 mice were maintained in groups of 3–4 animals per cage or 1 animal per cage (socially isolated) under 12:12 h / light:dark (LD) cycles or constant darkness (DD). Analysis of the two anatomical subdivisions (ventral, v and dorsal, d) of the medial SCN revealed an effect of housing conditions on the d-SCN but not on the v-SCN on the number of c-Fos immunoreactive (ir) neurons. As such, 2 h after the light-phase onset d-SCN c-Fos-ir number was lower in single-housed mice under LD. Importantly, under DD there were no effect of housing conditions in the number of c-Fos-ir SCN neurons. Social isolation increased the amplitude and strength of SCN-driven rhythm of body temperature (Tc) entrained to LD and it advanced its onset, uncoupling with spontaneous locomotor activity (SLA) rhythm, without altering endogenous Tc and SLA rhythms expressed under DD. Associated with reduced Tc in the light phase, single-housed mice showed reduced body weight. However, these phenotypes were not accompanied by changes in the number of c-Fos-ir neurons in the preoptic area (POA), which are known to regulate energy metabolism and Tc. Altogether, these results imply that the social interaction masking effect on the d-SCN is added to that of light stimulus, in order to achieve full c-Fos expression in the SCN, which, in turn seems to be required to maintain daily-phase coherence between the photo-entrained rhythms of Tc and SLA. There might be an inter-relationship between masking (social interaction) and entrainment stimulus (light) that impacts the circadian parameters of the photo-entrained Tc rhythm. As such, in the absence of social interactions a more robust Tc rhythm is shown. This inter-relationship seems to occur in the dorsal subdivision of the SCN but not in the POA.

Brief light exposure at dawn and dusk can encode day-length in the neuronal network of the mammalian circadian pacemaker.

The central circadian pacemaker in mammals, the suprachiasmatic nucleus (SCN), is important for daily as well as seasonal rhythms. The SCN encodes seasonal changes in day length by adjusting phase distribution among oscillating neurons thereby shaping the output signal used for adaptation of physiology and behavior. It is well-established that brief light exposure at the beginning and end of the day, also referred to as "skeleton" light pulses, are sufficient to evoke the seasonal behavioral phenotype. However, the effect of skeleton light exposure on SCN network reorganization remains unknown. Therefore, we exposed mice to brief morning and evening light pulses that mark the time of dawn and dusk in a short winter- or a long summer day. Single-cell PER2::LUC recordings, electrophysiological recordings of SCN activity, and measurements of GABA response polarity revealed that skeleton light-regimes affected the SCN network to the same degree as full photoperiod. These results indicate the powerful, yet potentially harmful effects of even relatively short light exposures during the evening or night for nocturnal animals.

Prenatal exposure to lipopolysaccharide induces changes in the circadian clock in the SCN and AA-NAT activity in the pineal gland

The mammalian circadian pacemaker in the suprachiasmatic nucleus (SCN) regulates behavioral and physiological processes in a 24-h cycle. During its development, the SCN can be sensitive to external stimuli which may change the circadian phenotypes in adulthood. Here, we investigated the effects of prenatal exposure to endotoxin lipopolysaccharide (LPS) on the developing rhythms in expression of Per1, Per2, Nr1d1 and Rasd1 along the rostrocaudal axis of the SCN, and on the rhythm of the rate-limiting enzyme in melatonin synthesis, pineal alkylamine N-acetyltransferase (AA-NAT). The prenatal LPS treatment induced anxiety-like behavior in adulthood as shown before and affected the rhythmicity of clock genes in the SCN. The major effect was observed for Nr1d1 expression; the least affected gene was Per2. The Nr1d1 in the LPS-treated group was arrhythmic at postnatal day 3, but showed significantly higher amplitude at postnatal day 20 at all SCN parts, similarly to the AA-NAT activity in pineal glands, thus suggesting adaptive flexibility of the developing SCN to immune challenges in early development.

Dim light at night attenuates circadian rhythms in the cardiovascular system and suppresses melatonin in rats

AimsCardiovascular parameters exhibit significant 24-h variability, which is coordinated by the suprachiasmatic nucleus (SCN), and light/dark cycles control SCN activity. We aimed to study the effects of light at night (ALAN; 1–2 lx) on cardiovascular system control in normotensive rats. Main methodsHeart rate (HR) and blood pressure (BP) were measured by telemetry during five weeks of ALAN exposure. From beat-to-beat telemetry data, we evaluated spontaneous baroreflex sensitivity (sBRS). After 2 (A2) and 5 (A5) weeks of ALAN, plasma melatonin concentrations and the response of BP and HR to norepinephrine administration were measured. The expression of endothelial nitric oxide synthase (eNOS) and endothelin-1 was determined in the aorta. Spontaneous exploratory behaviour was evaluated in an open-field test. Key findingsALAN significantly suppressed the 24-h variability in the HR, BP, and sBRS after A2, although the parameters were partially restored after A5. The daily variability in the BP response to norepinephrine was reduced after A2 and restored after A5. ALAN increased the BP response to norepinephrine compared to the control after A5. Increased eNOS expression was found in arteries after A2 but not A5. Endothelin-1 expression was not affected by ALAN. Plasma melatonin levels were suppressed after A2 and A5. Spontaneous exploratory behaviour was reduced. SignificanceALAN decreased plasma melatonin and the 24-h variability in the haemodynamic parameters and increased the BP response to norepinephrine. A low intensity ALAN can suppress circadian control of the cardiovascular system with negative consequences on the anticipation of a load.

Functional Peptidomics: Stimulus- and Time-of-Day-Specific Peptide Release in the Mammalian Circadian Clock.

Daily oscillations of brain and body states are under complex temporal modulation by environmental light and the hypothalamic suprachiasmatic nucleus (SCN), the master circadian clock. To better understand mediators of differential temporal modulation, we characterize neuropeptide releasate profiles by nonselective capture of secreted neuropeptides in an optic nerve horizontal SCN brain slice model. Releasates are collected following electrophysiological stimulation of the optic nerve/retinohypothalamic tract under conditions that alter the phase of the SCN activity state. Secreted neuropeptides are identified by intact mass via matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). We found time-of-day-specific suites of peptides released downstream of optic nerve stimulation. Peptide release was modified differentially with respect to time-of-day by stimulus parameters and by inhibitors of glutamatergic or PACAPergic neurotransmission. The results suggest that SCN physiology is modulated by differential peptide release of both known and unexpected peptides that communicate time-of-day-specific photic signals via previously unreported neuropeptide signatures.

Neurobiological fundamentals of posttrumatic stress disorder – a possible role of circadian rhythms deregulations

Posttraumatic stress disorder is a complex anxiety disorder induced by a stress factor. It is believed that this fear conditioning impairment may be crucial to PTSD development. Stress induced electrophysiological and neurohormonal changes within the hippocampus, amygdala, prefrontal cortex or locus coeruleus may impair other regional functions of the central nervous system like suprachiasmatic nuclei functions. Furthermore, the activation of llocus coeruleus or its impact on the activity of superchiasmatic nuclei may influence the circadian rhythm. The influence of stress factor on the hypothalamus – pituitary – adrenal gland axis (HPA) activity is well documented. Also PTSD accompanied changes of the HPA axis are well known. Unfortunately, due to methodological problems, the evaluation of stress induced HPA axis circadian rhythm changes is limited. Another physiological parameter, characterised by circadian rhythm is body temperature. Stress factor exposure induced a strong decrease in the daily rhythm amplitude during day/night cycles in the animal model of PTSD. Described disturbances to the rhythm was suprachiasmatic nuclei activity independent.

The Suprachiasmatic Nucleus and the Intergeniculate Leaflet of the Flat-Faced Fruit-Eating Bat (Artibeus planirostris): Retinal Projections and Neurochemical Anatomy.

In mammals, the suprachiasmatic nucleus (SCN) and the intergeniculate leaflet (IGL) are the main components of the circadian timing system. The SCN, classically known as the master circadian clock, generates rhythms and synchronizes them to environmental cues. The IGL is a key structure that modulates SCN activity. Strategies on the use of time by animals can provide important clues about how some species are adapted to competitive process in nature. Few studies have provided information about temporal niche in bats with special attention on the neural substrate underlies circadian rhythms. The aim of this study was to investigate these circadian centers with respect to their cytoarchitecture, chemical content and retinal projections in the flat-faced fruit-eating bat (Artibeus planirostris), a chiropteran endemic to South America. Unlike other species of phyllostomid bats, the flat-faced fruit-eating bat’s peak of activity occurs 5 h after sunset. This raises several questions about the structure and function of the SCN and IGL in this species. We carried out a mapping of the retinal projections and cytoarchitectural study of the nuclei using qualitative and quantitative approaches. Based on relative optical density findings, the SCN and IGL of the flat-faced fruit-eating bat receive bilaterally symmetric retinal innervation. The SCN contains vasopressin (VP) and vasoactive intestinal polypeptide (VIP) neurons with neuropeptide Y (NPY), serotonin (5-HT) and glutamic acid decarboxylase (GAD) immunopositive fibers/terminals and is marked by intense glial fibrillary acidic protein (GFAP) immunoreactivity. The IGL contains NPY perikarya as well as GAD and 5-HT immunopositive terminals and is characterized by dense GFAP immunostaining. In addition, stereological tools were combined with Nissl stained sections to estimate the volumes of the circadian centers. Taken together, the present results in the flat-faced fruit-eating bat reveal some differences compared to other bat species which might explain the divergence in the hourly activity among bats in order to reduce the competitive potential and resource partitioning in nature.

Functional connectivity of suprachiasmatic nucleus in major depressive episodes patients with morning heavy night light rhythm

Objective To explore the variations of functional connectivity in depressive episode patients with diurnal rhythm. Methods Totaly 44 patients with depressive episode with diurnal rhythm(rhythm group), 58 patients with depressive episode without diurnal rhythm(non-rhythm group) and 56 matched healthy volunteer controls(healthy group)were scanned with 3.0 T MRI Scanner.Functional connectivity (FC) were calculated between suprachiasmatic nucleus(SCN) and whole brain regions.According to results of ANOVA, group-wise two sample t-test was completed.Correlation analysis were conducted between FC of significant difference brain regions and the score of Hamilton rating scale(HAMD-24) for depression. Results The brain regions showing differences among three groups were located in the left medial superior frontal gyrus(MNI: x=0, y=39, z=51; K=14) and right cerebellum crus 1(MNI: x=39, y=-48, z=-36; K=18)(P<0.05, Alphasim). Compared with non-rhythm group, the FC of rhythm group showed significantly increased in the left medial superior frontal gyrus and right triangular inferior frontal gyrus(MNI: x=39, y=27, z=27; K=10)(P<0.05, Alphasim). Compared with healthy group, the FC of non-rhythm group showed significantly decreased in left medial superior frontal gyrus(P<0.05, Alphasim). Positive correlation was found between FC in left medial superior frontal gyrus and despair score of HAMD-24(r=0.31, P=0.041). Conclusion The synergistic increase in SCN and prefrontal activity in patients with depressive episodes with morning heavy night light rhythm which may be involved in the formation mechanism of the diurnal rhythm. Key words: Depressive episode; Diurnal rhythm; Functional magnetic resonance; Suprachiasmatic nucleus; Functional connectivity

Clock-dependent and system-driven oscillators interact in the suprachiasmatic nuclei to pace mammalian circadian rhythms.

Circadian clocks drive biological rhythms with a period of approximately 24 hours and keep in time with the outside world through daily resetting by environmental cues. While this external entrainment has been extensively investigated in the suprachiasmatic nuclei (SCN), the role of internal systemic rhythms, including daily fluctuations in core temperature or circulating hormones remains debated. Here, we show that lactating mice, which exhibit dampened systemic rhythms, possess normal molecular clockwork but impaired rhythms in both heat shock response gene expression and electrophysiological output in their SCN. This suggests that body rhythms regulate SCN activity downstream of the clock. Mathematical modeling predicts that systemic feedback upon the SCN functions as an internal oscillator that accounts for in vivo and ex vivo observations. Thus we are able to propose a new bottom-up hierarchical organization of circadian timekeeping in mammals, based on the interaction in the SCN between clock-dependent and system-driven oscillators.

The Hepato-Hypothalamic-Pituitary-Adrenal-Renal Axis: Mathematical Modeling of Cortisol's Production, Metabolism, and Seasonal Variation.

Cortisol dynamics are governed by the integration of influences from the suprachiasmatic nucleus (SCN), the hypothalamic-pituitary-adrenal (HPA) axis, and metabolic enzymes, such as the 11β-hydroxysteroid dehydrogenase (HSD) family, which are highly expressed in hepatic and renal tissue. The coordinated regulation of cortisol dynamics is essential for the maintenance of a healthy state, and aberrant cortisol circadian rhythms are associated with various pathophysiological conditions. The duration of the light-dark cycle, or photoperiod, which regulates SCN activity, varies seasonally, and the shorter photoperiod winter season is associated with elevated cortisol levels, peak inflammatory disease incidence, and symptom exacerbation. Elevated expression and activity of 11β-HSD1 protein, assumed to also occur during the winter, have been allied with numerous inflammatory conditions. A comprehensive understanding of the communication between the underlying regulatory mechanisms of cortisol as well as how changes in their activity could lead to the development of disease is yet to be elucidated. In this work, we propose the use of a semimechanistic mathematical model to explore the impact of the hepato-hypothalamic-pituitary-adrenal-renal axis in modulating neuroendocrine-immune system dynamics. Our model predicts the predominance of a winter proinflammatory state and that genetic variations could alter 11β-HSD enzyme functionality, rendering certain subpopulations more susceptible to disease as a consequence of HPA axis dysregulation.

Molecular and neural basis of contagious itch behavior in mice.

Socially contagious itch is ubiquitous in human society, but whether it exists in rodents is unclear. Using a behavioral paradigm that does not entail prior training or reward, we found that mice scratched after observing a conspecific scratching. Molecular mapping showed increased neuronal activity in the suprachiasmatic nucleus (SCN) of the hypothalamus of mice that displayed contagious scratching. Ablation of gastrin-releasing peptide receptor (GRPR) or GRPR neurons in the SCN abolished contagious scratching behavior, which was recapitulated by chemogenetic inhibition of SCN GRP neurons. Activation of SCN GRP/GRPR neurons evoked scratching behavior. These data demonstrate that GRP-GRPR signaling is necessary and sufficient for transmitting contagious itch information in the SCN. The findings may have implications for our understanding of neural circuits that control socially contagious behaviors.

Neural activity in the suprachiasmatic circadian clock of nocturnal mice anticipating a daytime meal

Circadian rhythms in mammals are regulated by a system of circadian oscillators that includes a light-entrainable pacemaker in the suprachiasmatic nucleus (SCN) and food-entrainable oscillators (FEOs) elsewhere in the brain and body. In nocturnal rodents, the SCN promotes sleep in the day and wake at night, while FEOs promote an active state in anticipation of a predictable daily meal. For nocturnal animals to anticipate a daytime meal, wake-promoting signals from FEOs must compete with sleep-promoting signals from the SCN pacemaker. One hypothesis is that FEOs impose a daily rhythm of inhibition on SCN output that is timed to permit the expression of activity prior to a daytime meal. This hypothesis predicts that SCN activity should decrease prior to the onset of anticipatory activity and remain suppressed through the scheduled mealtime. To assess the hypothesis, neural activity in the SCN of mice anticipating a 4–5-h daily meal in the light period was measured using FOS immunohistochemistry and in vivo multiple unit electrophysiology. SCN FOS, quantified by optical density, was significantly reduced at the expected mealtime in food-anticipating mice with access to a running disk, compared to ad libitum-fed and acutely fasted controls. Group differences were not significant when FOS was quantified by other methods, or in mice without running disks. SCN electrical activity was markedly decreased during locomotion in some mice but increased in others. Changes in either direction were concurrent with locomotion, were not specific to food anticipation, and were not sustained during longer pauses. Reduced FOS indicates a net suppression of SCN activity that may depend on the intensity or duration of locomotion. The timing of changes in SCN activity relative to locomotion suggests that any effect of FEOs on SCN output is mediated indirectly, by feedback from neural or systemic correlates of locomotion.