Dissociation of circadian and light inhibition of melatonin release through forced desynchronization in the rat

Abstract

Pineal melatonin release exhibits a circadian rhythm with a tight nocturnal pattern. Melatonin synthesis is regulated by the master circadian clock within the hypothalamic suprachiasmatic nucleus (SCN) and is also directly inhibited by light. The SCN is necessary for both circadian regulation and light inhibition of melatonin synthesis and thus it has been difficult to isolate these two regulatory limbs to define the output pathways by which the SCN conveys circadian and light phase information to the pineal. A 22-h light-dark (LD) cycle forced desynchrony protocol leads to the stable dissociation of rhythmic clock gene expression within the ventrolateral SCN (vlSCN) and the dorsomedial SCN (dmSCN). In the present study, we have used this protocol to assess the pattern of melatonin release under forced desynchronization of these SCN subregions. In light of our reported patterns of clock gene expression in the forced desynchronized rat, we propose that the vlSCN oscillator entrains to the 22-h LD cycle whereas the dmSCN shows relative coordination to the light-entrained vlSCN, and that this dual-oscillator configuration accounts for the pattern of melatonin release. We present a simple mathematical model in which the relative coordination of a single oscillator within the dmSCN to a single light-entrained oscillator within the vlSCN faithfully portrays the circadian phase, duration and amplitude of melatonin release under forced desynchronization. Our results underscore the importance of the SCNs subregional organization to both photic input processing and rhythmic output control.circadian desynchronization ͉ dual oscillators ͉ suprachiasmatic I n mammals, circadian rhythms are governed by a master pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN) (1, 2). The SCN is a heterogeneous nucleus with major subregional differences in neurochemical phenotype, connectivity and patterns of gene expression (3-6). Light information is transmitted directly to the SCN via the retinohypothalamic tract (RHT) (7,8). In rats, RHT input is dense in the ventrolateral SCN (vlSCN), and relatively sparse in the dorsomedial SCN (dmSCN) (3). In this species, segregation of SCN afferents is paralleled by a segregation of efferent projections emerging from each subregion, and some SCN targets receive input from only the vl-or the dmSCN (9). This topographic organization of afferent and efferent projections suggests different roles for these subregions regarding processing of photic information and control of circadian outputs. Indeed, photic stimulation by light pulses applied during the subjective night or by abruptly shifting the light-dark (LD) cycle up-regulates expression of the clock gene Per1 in the vlSCN, inducing a transient desynchronization in gene expression between the two subregions (10-13). These data strongly suggest that the SCNЈs subregional organization is key to the processing of light information. Its role in the control of circadian outputs, however, is more difficult to assess and has been limited t...

Circadian desynchronization

“…Note that our model based on one driven selfsustained oscillator is not in contradiction with previous interpretations based on two oscillators [9,17,11]. A driven oscillator implies the presence of two oscillators, i.e.…”

“…The red-shaded pattern has a typical positive slope of shorter than 24 h period (compare with figure 1c), whereas the green-shaded that of a longer period (figure 1e). These two locomotor rhythms were associated with two neuronal subpopulations within the SCN that might act as independent oscillators under these challenging experimental conditions [9,17]. However, below we present an alternative interpretation involving only one driven neural population.…”

Na V 1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms

“…In the mouse, RHT fibers innervate predominantly the ventral SCN, and light pulses during the subjective night, but not during the subjective day, acutely induce the expression of the immediate-early gene c-Fos and the clock gene Per1 (27,28). This induction of gene expression takes place initially within the ventral SCN and later propagates to the dorsal SCN (28)(29)(30)(31)(32). Because the photic induction of both behavioral phase shifts and Per1 expression is restricted to the night, the acute induction of clock gene expression by light is thought to be critical for phase resetting of the clock.…”

Fragmentation of Rapid Eye Movement and Nonrapid Eye Movement Sleep without Total Sleep Loss Impairs Hippocampus-Dependent Fear Memory Consolidation

“…Additionally, during REM sleep these adaptive memories are stored as more stable traces in the neocortex, where they can be integrated with preexisting memory networks. The sequential hypothesis has received further support by growing evidence of repeated pii: sp-00116- 16 http://dx.doi.org/10.5665/sleep.6236…”

“…However, forced desynchronized rats show desynchrony in other circadian rhythms that could be responsible for memory deficits. 5,9,15,16 To determine whether memory deficits in LD22 misaligned animals are associated specifically with our observed fragmentation of NREM and REM sleep, we repeated our contextual fear conditioning experiments in all three experimental groups while simultaneously recording the vigilance states with ECoG electrodes after training for each animal. We plotted a survival curve and fitted an exponential decay curve for each animal and sleep stage during the light phase one day after training.…”