Abstract
When dispersed and cultured in a multielectrode dish (MED), suprachiasmatic nucleus (SCN) neurons express fast oscillations of firing rate (FOFR; fast relative to the circadian cycle), with burst duration ∼10 min, and interburst interval varying from 20 to 60 min in different cells but remaining nevertheless rather regular in individual cells. In many cases, separate neurons in distant parts of the 1 mm recording area of a MED exhibited correlated FOFR. Neither the mechanism of FOFR nor the mechanism of their synchronization among neurons is known. Based on recent data implicating vasoactive intestinal polypeptide (VIP) as a key intercellular synchronizing agent, we built a model in which VIP acts as both a feedback regulator to generate FOFR in individual neurons, and a diffusible synchronizing agent to produce coherent electrical output of a neuronal network. In our model, VIP binding to its (VPAC2) receptors acts through Gs G-proteins to activate adenylyl cyclase (AC), increase intracellular cAMP, and open cyclic-nucleotide-gated (CNG) cation channels, thus depolarizing the cell and generating neuronal firing to release VIP. In parallel, slowly developing homologous desensitization and internalization of VPAC2 receptors terminates elevation of cAMP and thereby provides an interpulse silent interval. Through mathematical modeling, we show that this VIP/VPAC2/AC/cAMP/CNG-channel mechanism is sufficient for generating reliable FOFR in single neurons. When our model for FOFR is combined with a published model of synchronization of circadian rhythms based on VIP/VPAC2 and Per gene regulation synchronization of circadian rhythms is significantly accelerated. These results suggest that (a) auto/paracrine regulation by VIP/VPAC2 and intracellular AC/cAMP/CNG-channels are sufficient to provide robust FOFR and synchrony among neurons in a heterogeneous network, and (b) this system may also participate in synchronization of circadian rhythms.
Highlights
Rhythms of sleep and wakefulness, physiology, and metabolism are coordinated by a brain clock located in the paired suprachiasmatic nuclei (SCN) [1]
We have used the pulsatile activity in gonadotropin-releasing hormone (GnRH) neurons with a period about 30 min [16,17] as a useful analogy in our modeling because: i) both suprachiasmatic nucleus (SCN) and GnRH neurons are located in the hypothalamus and one could expect similarity in their properties; ii) both single GnRH neurons and the network of GnRH neurons as a whole fire in a pulsatile manner with pulse duration,5 min and interpulse interval,30 min, closely matching the properties of fast oscillations of firing rate (FOFR) in cultured SCN neurons; and iii) both circadian rhythmicity and synchrony in SCN neurons is partly mediated by vasoactive intestinal polypeptide (VIP) [13], a type of autocrine regulation of activity that is found in GnRH neurons [12,16,17]
For low VIP concentrations (,1 nM), the time course of simulated cAMP accumulation represented an exponential rise to some steady-state level, while for higher concentrations (.,1 nM) this accumulation demonstrated a transient peak within 5–10 min after the onset of VIP application followed by a slow decrease to a steady-state level
Summary
Rhythms of sleep and wakefulness, physiology, and metabolism are coordinated by a brain clock located in the paired suprachiasmatic nuclei (SCN) [1]. We have used the pulsatile activity in gonadotropin-releasing hormone (GnRH) neurons with a period about 30 min [16,17] as a useful analogy in our modeling because: i) both SCN and GnRH neurons are located in the hypothalamus and one could expect similarity in their properties; ii) both single GnRH neurons and the network of GnRH neurons as a whole fire in a pulsatile manner with pulse duration ,5 min and interpulse interval ,30 min, closely matching the properties of FOFR in cultured SCN neurons; and iii) both circadian rhythmicity and synchrony in SCN neurons is partly mediated by vasoactive intestinal polypeptide (VIP) [13], a type of autocrine regulation of activity that is found in GnRH neurons [12,16,17]. This work represents a step toward developing a multicellular, molecular model of the mammalian circadian clock exhibiting both fast oscillations of firing rate and circadian rhythms
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