scholarly journals Nested calcium dynamics support daily cell unity and diversity in the suprachiasmatic nuclei of free-behaving mice

2021 ◽  
Author(s):  
Lama El Cheikh Hussein ◽  
Pierre Fontanaud ◽  
Patrice Mollard ◽  
Xavier Bonnefont
Keyword(s):  
Functional Organization ◽  
Activity Patterns ◽  
Time Of Day ◽  
Emergent Properties ◽  
Light Cycle ◽  
Circadian Pacemaker ◽  
Suprachiasmatic Nuclei ◽  
Neuronal Code ◽  
Clock Mechanism

The suprachiasmatic nuclei (SCN) of the anterior hypothalamus host the circadian pacemaker that synchronizes mammalian rhythms with the day-night cycle. SCN neurons are intrinsically rhythmic, thanks to a conserved cell-autonomous clock mechanism. In addition, circuit-level emergent properties confer a unique degree of precision and robustness to SCN neuronal rhythmicity. However, the multicellular functional organization of the SCN is not yet fully understood. Although SCN neurons are well coordinated, experimental evidences indicate that some neurons oscillate out of phase in SCN explants, and possibly to a larger extent in vivo. Here, we used microendoscopic Ca2+i imaging to investigate SCN rhythmicity at a single cell resolution in free-behaving mice. We found that SCN neurons in vivo exhibited fast Ca2+i spikes superimposed upon slow changes in baseline Ca2+i levels. Both spikes and baseline followed a time-of-day modulation in many neurons, but independently from each other. Daily rhythms in basal Ca2+i were well coordinated, while spike activity from the same neurons peaked at multiple times of the light cycle, and unveiled clock-independent interactions at the multicellular level. Hence, fast Ca2+i spikes and slow changes in baseline Ca2+i levels highlighted how diverse activity patterns could articulate within the temporal network unity of the SCN in vivo, and provided support for a multiplex neuronal code in the circadian pacemaker.

scholarly journals Molecular and Cellular Networks in The Suprachiasmatic Nuclei

2019 ◽  
Vol 20 (8) ◽  
pp. 2052 ◽  
Author(s):  
El Cheikh Hussein ◽  
Mollard ◽  
Bonnefont
Keyword(s):  
Circadian Clock ◽  
Functional Organization ◽  
Imaging Techniques ◽  
Internal Clock ◽  
Suprachiasmatic Nuclei ◽  
Daily Behavior ◽  
Freely Moving ◽  
Cell Networks ◽  
Night Shifts

Why do we experience the ailments of jetlag when we travel across time zones? Why is working night-shifts so detrimental to our health? In other words, why can’t we readily choose and stick to non-24 h rhythms? Actually, our daily behavior and physiology do not simply result from the passive reaction of our organism to the external cycle of days and nights. Instead, an internal clock drives the variations in our bodily functions with a period close to 24 h, which is supposed to enhance fitness to regular and predictable changes of our natural environment. This so-called circadian clock relies on a molecular mechanism that generates rhythmicity in virtually all of our cells. However, the robustness of the circadian clock and its resilience to phase shifts emerge from the interaction between cell-autonomous oscillators within the suprachiasmatic nuclei (SCN) of the hypothalamus. Thus, managing jetlag and other circadian disorders will undoubtedly require extensive knowledge of the functional organization of SCN cell networks. Here, we review the molecular and cellular principles of circadian timekeeping, and their integration in the multi-cellular complexity of the SCN. We propose that new, in vivo imaging techniques now enable to address these questions directly in freely moving animals.

scholarly journals Inhibitory connections in the honeybee antennal lobe are spatially patchy

2013 ◽  
Vol 109 (2) ◽  
pp. 332-343 ◽  
Author(s):  
Cyrille C. Girardin ◽  
Sabine Kreissl ◽  
C. Giovanni Galizia
Keyword(s):  
Sensory Processing ◽  
Antennal Lobe ◽  
Functional Organization ◽  
Classical Model ◽  
Activity Patterns ◽  
Spatial Logic ◽  
Brain Center ◽  
In Vivo Calcium Imaging ◽  
Inhibitory Interactions

The olfactory system is a classical model for studying sensory processing. The first olfactory brain center [the olfactory bulb of vertebrates and the antennal lobe (AL) of insects] contains spherical neuropiles called glomeruli. Each glomerulus receives the information from one olfactory receptor type. Interglomerular computation is accomplished by lateral connectivity via interneurons. However, the spatial and functional organization of these lateral connections is not completely understood. Here we studied the spatial logic in the AL of the honeybee. We combined topical application of neurotransmitters, olfactory stimulations, and in vivo calcium imaging to visualize the arrangement of lateral connections. Suppression of activity in a single glomerulus with γ-aminobutyric acid (GABA) while presenting an odor reveals the existence of inhibitory interactions. Stimulating a glomerulus with acetylcholine (ACh) activates inhibitory interglomerular connections that can reduce odor-evoked responses. We show that this lateral network is patchy, in that individual glomeruli inhibit other glomeruli with graded strength, but in a spatially discontinuous manner. These results suggest that processing of olfactory information requires combinatorial activity patterns with complex topologies across the AL.

Abstract 17021: Disruption in Circadian Rhythms Triggers Arrhythmias & Sudden Death in LQT3 Mice

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Elizabeth A Schroder ◽  
John L Stumpf ◽  
Tanya Seward ◽  
Karyn A Esser ◽  
Brian P Delisle
Keyword(s):  
Circadian Rhythms ◽  
Cardiac Fibrosis ◽  
Activity Patterns ◽  
Premature Mortality ◽  
Light Cycle ◽  
Qtc Interval ◽  
Cardiac Events ◽  
Α Subunit ◽  
Cardiac Sodium Channel

Introduction: The autosomal dominant long QT syndrome type 3 (LQT3) is caused by gain-of-function mutations in the pore-forming cardiac sodium channel α-subunit Na V 1.5 ( Scn5a ). A major challenge for treating LQT3 patients is predicting when or if a potentially life-threatening cardiac event (syncope or cardiac arrest) will strike. For example, longitudinal data from five LQT3 families with the Δ1505-1507KPQ mutation show only 33% of patients are symptomatic, and most symptomatic patients suffered only a single event (n = 46 patients; average age = 41 ± 23 years; average QTc interval = 510 ± 50 ms). The data suggest external stressors play a key role for triggering cardiac events in LQT3. Hypothesis: Disruptions in circadian rhythms can act as an external stressor to trigger LQT3-releated cardiac events. Methods: We disrupted the circadian rhythms in older wild type (WT) or Scn5a +/ΔKPQ mice using an established model of chronic jet lag (chronic light phase advance or CPA). The light cycle was advanced 6 hours every 4 days for 65 days. Mice were monitored using in vivo telemetry before and during CPA. Heart size and cardiac fibrosis were measured using immunohistochemistry. Results and Conclusions: Actograms for both WT and Scn5a +/ΔKPQ mice showed that CPA disrupted diurnal activity patterns. Before starting CPA, the Scn5a +/ΔKPQ mice had longer heart rate corrected QT (QTc) intervals compared to WT mice (Pre-WT = 45 ± 2 ms vs. Pre- Scn5a +/ΔKPQ = 54 ± 7 ms, n = 5, p<0.05). Twenty days after CPA, the QTc intervals in Scn5a +/ΔKPQ mice became even longer (CPA-WT = 47 ± 2 ms vs. CPA- Scn5a +/ΔKPQ = 63 ± 6 ms, p<0.05 compared to Pre-WT and Pre- Scn5a +/ΔKPQ ). Shockingly, all 5 of the Scn5a +/ΔKPQ mice undergoing CPA died within 65 days. Most deaths occurred after repeating patterns of premature contractions or prolonged episodes of bradycardia. In contrast, none of the age-matched control Scn5a +/ΔKPQ mice died (n = 5). Compared to the hearts of control Scn5a +/ΔKPQ mice, the hearts from CPA Scn5a +/ΔKPQ mice did not show changes in size or thickness but had more fibrosis (control = 9 ± 2%, CPA = 15 ± 2%; p<0.05). These data show that chronic disruption of circadian rhythms in Scn5a +/ΔKPQ mice exacerbates QTc prolongation, increases arrhythmias, and causes premature mortality.

Different in vivo metabolic activities of suprachiasmatic nuclei of Turkish and golden hamsters

1990 ◽  
Vol 259 (5) ◽  
pp. R1083-R1085 ◽  
Author(s):  
W. J. Schwartz
Keyword(s):  
Energy Metabolism ◽  
Glucose Utilization ◽  
High Energy ◽  
Circadian Pacemaker ◽  
Suprachiasmatic Nuclei ◽  
Light Phase ◽  
Dark Cycle ◽  
Golden Hamsters ◽  
Metabolic Activities

The 14C-labeled 2-deoxy-D-glucose technique was used to measure in vivo glucose utilization of the suprachiasmatic nuclei (SCN) of Turkish and golden hamsters during the middle hours of the light phase of the 12:12 h light-dark cycle. The nuclei were clearly visible on autoradiographs made from the brains of Turkish hamsters, and their rate of glucose utilization (69 +/- 6 mumol.100 g-1.min-1) was similar to that previously measured in other rodents, whereas the nuclei were hardly visible on autoradiographs from golden hamsters, and their rate (33 +/- 2 mumol.100 g-1.min-1) was less than half this value. Thus the high energy metabolism characteristic of the SCN of most species is not required for the circadian pacemaker in the nuclei to generate its oscillation.

scholarly journals The roles of vasoactive intestinal polypeptide in the mammalian circadian clock

2003 ◽  
Vol 177 (1) ◽  
pp. 7-15 ◽  
Author(s):  
HD Piggins ◽  
DJ Cutler
Keyword(s):  
Circadian Clock ◽  
Vasoactive Intestinal Polypeptide ◽  
Chemical Constituents ◽  
Neural Pathways ◽  
Circadian Pacemaker ◽  
Suprachiasmatic Nuclei ◽  
Environmental Signals ◽  
Intestinal Polypeptide

Biological oscillations with an endogenous period of near 24 h (circadian rhythms) are generated by the master circadian pacemaker or clock located in the suprachiasmatic nuclei (SCN) of the hypothalamus. This clock is synchronised to recurring environmental signals conveyed by selective neural pathways. One of the main chemical constituents of SCN neurones is vasoactive intestinal polypeptide (VIP). Such neurones are retinorecipient and activated by light. Exogenous application of VIP resets the SCN circadian clock in a light-like manner, both in vivo and in vitro. These resetting actions appear to be mediated through the VPAC2 receptor (a type of receptor for VIP). Unexpectedly, genetically ablating expression of the VPAC2 receptor renders the circadian clock arrhythmic at the molecular, neurophysiological and behavioural levels. These findings indicate that this intrinsic neuropeptide acting through the VPAC2 receptor participates in both resetting to light and maintenance of ongoing rhythmicity of the SCN.

scholarly journals Circadian clock neurons mediate time-of-day dependent responses to light

2018 ◽  
Author(s):  
Jeff R. Jones ◽  
Tatiana Simon ◽  
Lorenzo Lones ◽  
Erik D. Herzog
Keyword(s):  
Suprachiasmatic Nucleus ◽  
Time Of Day ◽  
Light Cycle ◽  
Hormone Release ◽  
Daily Rhythms ◽  
Light Responses ◽  
And Behavior

ABSTRACTCircadian (~24 h) rhythms influence nearly all aspects of physiology, including sleep/wake, metabolism, and hormone release. The suprachiasmatic nucleus (SCN) synchronizes these daily rhythms to the external light cycle, but the mechanisms by which this occurs is unclear. The neuropeptide vasoactive intestinal peptide (VIP) is the predominant contributor to synchrony within the SCN and is important for circadian light responses, but the role of VIP neurons themselves is unclear. Thus, we tested the hypothesis that rhythmic SCN VIP neurons mediate circadian light responses. Using in vivo fiber photometry recording of SCN VIP neurons we found daily rhythms in spontaneous calcium events that peaked during the subjective day and in light-evoked calcium events that exhibited the greatest response around subjective dusk. These rhythms were correlated with spontaneous and NMDA-evoked VIP release from SCN VIP neurons in vitro. Finally, in vivo hyperpolarization of VIP neurons attenuated light-induced shifts of daily rhythms in locomotion. We conclude that SCN VIP neurons are circadian and depolarize to light to modulate entrainment of daily rhythms in the SCN and behavior.

scholarly journals Circadian clock protein Rev-erbα regulates neuroinflammation

2019 ◽  
Vol 116 (11) ◽  
pp. 5102-5107 ◽  
Author(s):  
Percy Griffin ◽  
Julie M. Dimitry ◽  
Patrick W. Sheehan ◽  
Brian V. Lananna ◽  
Chun Guo ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Microglial Activation ◽  
Time Of Day ◽  
Resting State Functional Connectivity ◽  
Promoter Regions ◽  
Clock Component ◽  
Glial Cultures ◽  
Inflammatory Phenotype

Circadian dysfunction is a common attribute of many neurodegenerative diseases, most of which are associated with neuroinflammation. Circadian rhythm dysfunction has been associated with inflammation in the periphery, but the role of the core clock in neuroinflammation remains poorly understood. Here we demonstrate that Rev-erbα, a nuclear receptor and circadian clock component, is a mediator of microglial activation and neuroinflammation. We observed time-of-day oscillation in microglial immunoreactivity in the hippocampus, which was disrupted in Rev-erbα−/− mice. Rev-erbα deletion caused spontaneous microglial activation in the hippocampus and increased expression of proinflammatory transcripts, as well as secondary astrogliosis. Transcriptomic analysis of hippocampus from Rev-erbα−/− mice revealed a predominant inflammatory phenotype and suggested dysregulated NF-κB signaling. Primary Rev-erbα−/− microglia exhibited proinflammatory phenotypes and increased basal NF-κB activation. Chromatin immunoprecipitation revealed that Rev-erbα physically interacts with the promoter regions of several NF-κB–related genes in primary microglia. Loss of Rev-erbα in primary astrocytes had no effect on basal activation but did potentiate the inflammatory response to lipopolysaccharide (LPS). In vivo, Rev-erbα−/− mice exhibited enhanced hippocampal neuroinflammatory responses to peripheral LPS injection, while pharmacologic activation of Rev-erbs with the small molecule agonist SR9009 suppressed LPS-induced hippocampal neuroinflammation. Rev-erbα deletion influenced neuronal health, as conditioned media from Rev-erbα–deficient primary glial cultures exacerbated oxidative damage in cultured neurons. Rev-erbα−/− mice also exhibited significantly altered cortical resting-state functional connectivity, similar to that observed in neurodegenerative models. Our results reveal Rev-erbα as a pharmacologically accessible link between the circadian clock and neuroinflammation.

scholarly journals Serum Chemerin Levels Vary with Time of Day and Are Modified by Obesity and Tumor Necrosis Factor-α

Endocrinology ◽  
2010 ◽  
Vol 151 (6) ◽  
pp. 2590-2602 ◽  
Author(s):  
Sebastian D. Parlee ◽  
Matthew C. Ernst ◽  
Shanmugam Muruganandan ◽  
Christopher J. Sinal ◽  
Kerry B. Goralski
Keyword(s):  
Leptin Receptor ◽  
Elevated Serum ◽  
Time Of Day ◽  
Obese Mouse ◽  
Protein Synthesis Inhibitor ◽  
Low Grade ◽  
Rhythmic Pattern ◽  
Oscillatory Pattern ◽  
Primary Mouse

Chemerin is an adipokine with important regulatory roles in adipogenesis. In humans, serum total chemerin (i.e. prochemerin plus chemerin) levels are positively associated with body mass index and metabolic syndrome. However, the mechanisms that increase serum chemerin concentration are unknown. We hypothesized that chronic low-grade inflammation that occurs in obesity promotes chemerin production by adipocytes. Consistent with this, TNFα treatment of 3T3-L1 adipocytes increased bioactive chemerin levels in the cell media as detected using a CMKLR1 cell-based bioassay. This effect was blocked by the protein synthesis inhibitor cycloheximide and protein secretion inhibitor brefeldin A, indicating that TNFα may enhance prochemerin synthesis and secretion from adipocytes. In vivo, TNFα produced a time-dependent increase in serum total chemerin and bioactive chemerin. Bioactive chemerin was produced by primary mouse adipocytes and hepatocytes. Only primary adipocyte-derived chemerin was responsive to TNFα regulation implicating adipocytes as a potential source of elevated serum chemerin after TNFα exposure in vivo. In lean mice, serum total chemerin levels oscillated with peak levels occurring during daytime and trough levels at night. Comparatively, leptin- and leptin receptor-deficient obese mice, which have elevated adipose tissue expression of TNFα, displayed elevated serum total chemerin levels with an enhanced oscillatory pattern. In summary, our novel results identified TNFα as a positive regulator of adipocyte-derived chemerin. We corroborate the finding of elevated chemerin in obese humans by identifying elevated serum levels of total chemerin in two obese mouse models with a corresponding alteration in the rhythmic pattern of serum chemerin levels.

Disrupted circadian rhythms in VIP- and PHI-deficient mice

2003 ◽  
Vol 285 (5) ◽  
pp. R939-R949 ◽  
Author(s):  
Christopher S. Colwell ◽  
Stephan Michel ◽  
Jason Itri ◽  
Williams Rodriguez ◽  
J. Tam ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Wheel Running ◽  
Activity Rhythm ◽  
Activity Patterns ◽  
Circadian System ◽  
Diurnal Rhythms ◽  
Constant Darkness ◽  
Light Cycle ◽  
Wild Type ◽  
Deficient Mice

The related neuropeptides vasoactive intestinal peptide (VIP) and peptide histidine isoleucine (PHI) are expressed at high levels in the neurons of the suprachiasmatic nucleus (SCN), but their function in the regulation of circadian rhythms is unknown. To study the role of these peptides on the circadian system in vivo, a new mouse model was developed in which both VIP and PHI genes were disrupted by homologous recombination. In a light-dark cycle, these mice exhibited diurnal rhythms in activity which were largely indistinguishable from wild-type controls. In constant darkness, the VIP/PHI-deficient mice exhibited pronounced abnormalities in their circadian system. The activity patterns started ∼8 h earlier than predicted by the previous light cycle. In addition, lack of VIP/PHI led to a shortened free-running period and a loss of the coherence and precision of the circadian locomotor activity rhythm. In about one-quarter of VIP/PHI mice examined, the wheel-running rhythm became arrhythmic after several weeks in constant darkness. Another striking example of these deficits is seen in the split-activity patterns expressed by the mutant mice when they were exposed to a skeleton photoperiod. In addition, the VIP/PHI-deficient mice exhibited deficits in the response of their circadian system to light. Electrophysiological analysis indicates that VIP enhances inhibitory synaptic transmission within the SCN of wild-type and VIP/PHI-deficient mice. Together, the observations suggest that VIP/PHI peptides are critically involved in both the generation of circadian oscillations as well as the normal synchronization of these rhythms to light.

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