Novel phase-shifting effects of GABAA receptor activation in the suprachiasmatic nucleus of a diurnal rodent

2004 ◽  
Vol 286 (5) ◽  
pp. R820-R825 ◽  
Author(s):  
C. M. Novak ◽  
H. E. Albers
Keyword(s):  
Suprachiasmatic Nucleus ◽  
Activity Rhythm ◽  
Receptor Activation ◽  
Phase Shifting ◽  
Circadian Pacemaker ◽  
Pacemaker Cells ◽  
Inhibitory Neurotransmitter ◽  
Large Phase ◽  
Neurochemical Signal

The vast majority of neurons in the suprachiasmatic nucleus (SCN), the primary circadian pacemaker in mammals, contain the inhibitory neurotransmitter GABA. Most studies investigating the role of GABA in the SCN have been performed using nocturnal rodents. Activation of GABAA receptors by microinjection of muscimol into the SCN phase advances the circadian activity rhythm of nocturnal rodents, but only during the subjective day. Nonphotic stimuli that reset the circadian pacemaker of nocturnal rodents also produce phase advances during the subjective day. The role of GABA in the SCN of diurnal animals and how it may differ from nocturnal animals is not known. In the studies described here, the GABAA agonist muscimol was microinjected directly into the SCN region of diurnal unstriped Nile grass rats ( Arvicanthis niloticus) at various times in their circadian cycle. The results demonstrate that GABAA receptor activation produces large phase delays during the subjective day in grass rats. Treatment with TTX did not affect the ability of muscimol to induce phase delays, suggesting that muscimol acts directly on pacemaker cells within the SCN. These data suggest that the circadian pacemakers of nocturnal and diurnal animals respond to the most abundant neurochemical signal found in SCN neurons in opposite ways. These findings are the first to demonstrate a fundamental difference in the functioning of circadian pacemaker cells in diurnal and nocturnal animals.

scholarly journals Functional Significance of the Excitatory Effects of GABA in the Suprachiasmatic Nucleus

2018 ◽  
Vol 33 (4) ◽  
pp. 376-387 ◽  
Author(s):  
John K. McNeill ◽  
James C. Walton ◽  
H. Elliott Albers
Keyword(s):  
Suprachiasmatic Nucleus ◽  
Constant Darkness ◽  
Circadian Pacemaker ◽  
Inhibitory Neurotransmitter ◽  
Subjective Night ◽  
Free Running ◽  
Excitatory Responses ◽  
Reduced Light

Over 90% of neurons within the suprachiasmatic nucleus (SCN) express γ-aminobutyric acid (GABA). Although GABA is primarily an inhibitory neurotransmitter, in vitro studies suggest that the activation of GABAA receptors (GABAAR) elicits excitation in the adult SCN. The ratio of excitatory to inhibitory responses to GABA depends on the balance of chloride influx by Na+-K+-Cl– cotransporter 1 (NKCC1) and chloride efflux by K+-Cl– cotransporters (KCCs). Excitatory responses to GABA can be blocked by inhibition of the inward chloride cotransporter, NKCC1, with the loop diuretic bumetanide. Here we investigated the role of NKCC1 activity in phase shifting the circadian pacemaker in response to photic and nonphotic signals in male Syrian hamsters housed in constant darkness. In the early subjective night (CT 13.5), injection of bumetanide into the SCN reduced light-induced phase delays. However, during the late subjective night (CT 19), bumetanide administration did not alter light-induced phase advances. Injection of bumetanide during the subjective day (CT 6) did not alter the phase of free-running circadian rhythms but attenuated phase advances induced by injection of the GABAAR agonist muscimol into the SCN. These data support the hypothesis that the excitatory effects of endogenously released GABA contribute to the ability of light to induce phase delays, thereby contributing to the most important function of the circadian system, its entrainment with the day-night cycle. Further, the finding that bumetanide inhibits the phase-advancing effects of muscimol during the subjective day supports the hypothesis that the excitatory responses to GABA also contribute to the ability of nonphotic stimuli to phase shift the circadian pacemaker.

scholarly journals Optimization of circadian responses with shorter and shorter millisecond flashes

2019 ◽  
Vol 15 (8) ◽  
pp. 20190371 ◽  
Author(s):  
Sevag Kaladchibachi ◽  
David C. Negelspach ◽  
Jamie M. Zeitzer ◽  
Fabian Fernandez
Keyword(s):  
Response Curve ◽  
Energy Content ◽  
Light Exposure ◽  
Activity Rhythm ◽  
Continuous Light ◽  
Phase Shifting ◽  
Maximal Response ◽  
Circadian Pacemaker ◽  
Circadian Activity ◽  
Left Shift

Recent work suggests that the circadian pacemaker responds optimally to millisecond flashes of light, not continuous light exposure as has been historically believed. It is unclear whether these responses are influenced by the physical characteristics of the pulsing. In the present study, Drosophila ( n = 2199) were stimulated with 8, 16 or 120 ms flashes. For each duration, the energy content of the exposure was systematically varied by changing the pulse irradiance and the number of stimuli delivered over a fixed 15 min administration window (64 protocols surveyed in all). Results showed that per microjoule invested, 8 ms flashes were more effective at resetting the circadian activity rhythm than 16- and 120 ms flashes (i.e. left shift of the dose–response curve, as well as a higher estimated maximal response). These data suggest that the circadian pacemaker's photosensitivity declines within milliseconds of light contact. Further introduction of light beyond a floor of (at least) 8 ms leads to diminishing returns on phase-shifting.

Effects of VPAC2 Receptor Activation on Membrane Excitability and GABAergic Transmission in Subparaventricular Zone Neurons Targeted by Suprachiasmatic Nucleus

2009 ◽  
Vol 102 (3) ◽  
pp. 1834-1842 ◽  
Author(s):  
M.L.H.J. Hermes ◽  
M. Kolaj ◽  
P. Doroshenko ◽  
E. Coderre ◽  
L. P. Renaud
Keyword(s):  
Suprachiasmatic Nucleus ◽  
Gaba Release ◽  
Receptor Activation ◽  
Presynaptic Receptors ◽  
Circadian Pacemaker ◽  
Membrane Excitability ◽  
Patch Clamp Recording ◽  
Subparaventricular Zone ◽  
Rat Brain Slice ◽  
Vip Receptor

The hypothalamic suprachiasmatic nucleus (SCN) harbors the master circadian pacemaker. SCN neurons produce the amino acid γ-aminobutyric acid (GABA) and several peptide molecules for coordination and communication of their circadian rhythms. A subpopulation of SCN cells synthesizes vasoactive intestinal polypeptide (VIP) and provides a dense innervation of the subparaventricular zone (SPZ), an important CNS target of the circadian pacemaker. In this study, using patch-clamp recording techniques and rat brain slice preparations, the contribution of VIP to SCN efferent signaling to SPZ was evaluated by examining membrane responses of SPZ neurons to exogenous VIP receptor ligands. In ∼50% of the SPZ neurons receiving monosynaptic GABAA receptor–mediated inputs from SCN, bath-applied VIP (0.5–1 μM) resulted in a membrane depolarization caused by tetrodotoxin-resistant inward currents reversing at ∼−23 mV. These data suggest the existence of postsynaptic receptors that activate a nonselective cationic conductance. In addition, a subset of SPZ neurons showed an increase in the amplitude of SCN-evoked GABAergic inhibitory postsynaptic currents (IPSCs) and a decrease in their paired-pulse ratios. This, together with an increase in frequency of spontaneous and miniature IPSCs, implies the presence of presynaptic receptors that facilitate GABA release from SCN and possibly other synaptic terminals. The effects occurred in separate neurons and could be mimicked by the selective VPAC2 receptor agonist BAY 55-9837 (0.2–0.5 μM) and partially blocked by the VIP receptor antagonist VIP(6-28) (5 μM). The results indicate that VIP acts via both post- and presynaptic VPAC2 receptors to differentially modulate SCN GABAergic signaling to distinct subpopulations of SPZ neurons.

Transmitterlike action of serotonin in phase shifting a rhythm from the Aplysia eye

1982 ◽  
Vol 242 (3) ◽  
pp. R333-R338
Author(s):  
G. Corrent ◽  
A. Eskin
Keyword(s):  
Phase Response Curve ◽  
Membrane Conductance ◽  
Phase Shifts ◽  
Phase Shifting ◽  
Circadian Pacemaker ◽  
Pacemaker Cell ◽  
Monoamine Neurotransmitters ◽  
Hydroxyindoleacetic Acid ◽  
High Degree

The presence of serotonin (5-HT) and the characteristics of the phase-response curve for 5-HT indicate that 5-HT acts as a transmitter of circadian information in the Aplysia eye. Additional evidence for such a neurotransmitter role of 5-HT in the eye is presented. The isolated eye has the capacity to synthesize 5-HT from exogenous tryptophan. The receptors mediating the phase-shifting effect of 5-HT have a high affinity for 5-HT (threshold for phase shifting is less than or equal to 10(-7) M). Also these receptors demonstrate a high degree of structural specificity for 5-HT. Some structurally similar indoles to 5-HT do not cause phase shifts (5-hydroxytryptophan, 5-hydroxyindoleacetic acid), whereas others (bufotenine, tryptamine, LSD) do cause phase shifts but are less effective than 5-HT. Furthermore phase shifts in the rhythm are not produced by other monoamine neurotransmitters (dopamine, octopamine) or acetylcholine. Changes in membrane conductance to Na+, Cl-, or Ca2+ do not appear to be involved in phase shifting by 5-HT. Since large reductions in extracellular Ca2+ did not affect phase shifting by 5-HT, 5-HT is acting either directly on the circadian pacemaker cell(s) or on cells electronically coupled to the pacemaker cell(s).

scholarly journals An autoantibody directed against human thrombin anion-binding exosite in a patient with arterial thrombosis: effects on platelets, endothelial cells, and protein C activation

Blood ◽  
1994 ◽  
Vol 84 (6) ◽  
pp. 1843-1850 ◽  
Author(s):  
E Arnaud ◽  
M Lafay ◽  
P Gaussem ◽  
V Picard ◽  
M Jandrot-Perrus ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Arterial Thrombosis ◽  
Protein C ◽  
Receptor Activation ◽  
Anion Binding ◽  
Thrombin Receptor ◽  
Cell Functions ◽  
Human Thrombin

Abstract An autoantibody, developed by a patient with severe and recurrent arterial thrombosis, was characterized to be directed against the anion- binding exosite of thrombin, and inhibited all thrombin interactions requiring this secondary binding site without interfering with the catalytic site. The effect of the antibody was studied on thrombin interactions with platelets and endothelial cells from human umbilical veins (HUVEC). The autoantibody specifically and concentration- dependently inhibited alpha-thrombin-induced platelet activation and prostacyclin (PGI2) synthesis from HUVEC. It had no effect when gamma- thrombin or the thrombin receptor activation peptide SFLLR were the inducers. The effect of the antibody on protein C activation has been studied. The antibody blocked the thrombin-thrombomodulin activation of protein C. The inhibition of the activation was maximal with a low concentration of thrombomodulin. The fact that the autoantibody inhibited concentration-dependent alpha-thrombin-induced platelet and endothelial cell functions emphasizes the crucial role of the anion- binding exosite of thrombin to activate its receptor. In regard to the pathology, the antibody inhibited two vascular processes implicated in thrombin-antithrombotic functions, PGI2 secretion, and protein C activation, which could be implicated in this arterial thrombotic disease.

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