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, 27 (7), 567-76

Circadian Tick-Talking Across the Neuroendocrine System and Suprachiasmatic Nuclei Circuits: The Enigmatic Communication Between the Molecular and Electrical Membrane Clocks


Circadian Tick-Talking Across the Neuroendocrine System and Suprachiasmatic Nuclei Circuits: The Enigmatic Communication Between the Molecular and Electrical Membrane Clocks

M D C Belle. J Neuroendocrinol.


As with many processes in nature, appropriate timing in biological systems is of paramount importance. In the neuroendocrine system, the efficacy of hormonal influence on major bodily functions, such as reproduction, metabolism and growth, relies on timely communication within and across many of the brain's homeostatic systems. The activity of these circuits is tightly orchestrated with the animal's internal physiological demands and external solar cycle by a master circadian clock. In mammals, this master clock is located in the hypothalamic suprachiasmatic nucleus (SCN), where the ensemble activity of thousands of clock neurones generates and communicates circadian time cues to the rest of the brain and body. Many regions of the brain, including areas with neuroendocrine function, also contain local daily clocks that can provide feedback signals to the SCN. Although much is known about the molecular processes underpinning endogenous circadian rhythm generation in SCN neurones and, to a lesser extent, extra-SCN cells, the electrical membrane clock that acts in partnership with the molecular clockwork to communicate circadian timing across the brain is poorly understood. The present review focuses on some circadian aspects of reproductive neuroendocrinology and processes involved in circadian rhythm communication in the SCN, aiming to identify key gaps in our knowledge of cross-talk between our daily master clock and neuroendocrine function. The intention is to highlight our surprisingly limited understanding of their interaction in the hope that this will stimulate future work in these areas.

Keywords: circadian rhythm; clock genes; electrical activity; ion channels; neuroendocrine system; reproduction; suprachiasmatic nuclei.


Figure 1
Figure 1
A schematic view of the daily electrical profiles of suprachiasmatic nucleus (SCN) neurones. (a) Over the day–night cycle, SCN neurones show overt changes in their resting membrane potential (RMP), and traverse through several points of neutral rest state (indicated by where the solid line crosses the dashed line). During the day, the RMP of SCN neurones is depolarised. In some cells, reduced activity of L‐type calcium and calcium activated potassium (KC a) channels partly underpins this up state 128. At night, increased conductivity of multiple potassium channels hyperpolarises the neurones, placing them into a down state 3, 4. (b) In some SCN neurones, this daytime up state causes action potential (AP) discharge (b1). In others, however, the RMP becomes too positive (~ −30 mV) to sustain AP production (b2). Instead, these neurones display depolarised low‐amplitude membrane oscillation (b2). At night, during the RMP down state, SCN neurones generate action potentials at a significantly reduced rate (b3). This shows the complexity, richness and diversity of electrical communication in SCN neurones. The light area indicates the day, whereas the shaded region shows the night. The increase or decrease underlying ion channel activity is indicated by upward‐ and downward‐pointing blue arrows, respectively.
Figure 2
Figure 2
Cross‐talk between the suprachiasmatic nucleus (SCN) and neuroendocrine cells. (a) Cross‐section of the mouse brain at the anatomical level of the SCN (in red). (b) Bidirectional communication between the molecular clock (transcription–translation molecular feedback loop; TTFL) and electrical/membrane clock. In this model, the TTFL clock drives day–night rhythms in the electrical activity of SCN neurones, and electrical activity feedback onto the TTFL clock through unknown mechanisms (light blue arrows). This may underlie how the TTFL outputs signals to neuroendocrine cells (c) and how neuroendocrine processes feedback to adjust circadian timing in the SCN (grey arrows). This drawing is superimposed on top of a modified image taken at the SCN mid‐coronal section showing Per1EGFP neurones (red arrows). Darker blue arrows represent inputs to the SCN, with their sizes denoting feedback magnitude. Solid arrows indicate an established link, whereas broken arrows show tentative interactions. (b1) Stylised waveform showing daily variation in SCN Per1 and electrical activity. White and black bars underneath represent day and night, respectively. RHT, retino‐hypothalamic tract; LHI, lateral hypothalamic input; GHT, geniculo‐hypothalamic tract; OX, optic chiasm; 3V, third ventricle; NPY, neuropeptide Y; VIP, vasoactive intestinal polypeptide; AVP, arginine vasopressin.
Figure 3
Figure 3
A schematic view of communication between the transcription–translation molecular feedback loop (TTFL) in the suprachiasmatic nucleus (SCN) and neuroendocrine cells through the membrane clock. In this model, signals travelling to and from the TTFL both in the SCN and neuroendocrine clock neurones must flow through the cell membrane (bidirectional arrows) by unknown mechanisms. This process may underlie how the SCN TTFL outputs circadian signals to neuroendocrine cells (blue solid axon and arrow) and how neuroendocrine TTFL feedback to adjust circadian timing in SCN neurones (orange dotted axon and arrow). Through similar unknown processes, environmental and/or homeostatic cues can sculpt the activity of the TTFL in SCN and endocrine neurones (grey solid and dotted axon terminals, and arrows). Solid and broken axons/arrows show known and tentative links, respectively.

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    1. Glossop NR. Circadian timekeeping in Drosophila melanogaster and Mus musculus. Essays Biochem 2011; 49: 19–35. - PubMed
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