Abstract
Studies of circadian locomotor rhythms in Drosophila melanogaster gave evidence to the preceding theoretical predictions on circadian rhythms. The molecular oscillator in flies, as in virtually all organisms, operates using transcriptional-translational feedback loops together with intricate post-transcriptional processes. Approximately150 pacemaker neurons, each equipped with a molecular oscillator, form a circuit that functions as the central pacemaker for locomotor rhythms. Input and output pathways to and from the pacemaker circuit are dissected to the level of individual neurons. Pacemaker neurons consist of functionally diverse subclasses, including those designated as the Morning/Master (M)-oscillator essential for driving free-running locomotor rhythms in constant darkness and the Evening (E)-oscillator that drives evening activity. However, accumulating evidence challenges this dual-oscillator model for the circadian circuit organization and propose the view that multiple oscillators are coordinated through network interactions. Here we attempt to provide further evidence to the revised model of the circadian network. We demonstrate that the disruption of molecular clocks or neural output of the M-oscillator during adulthood dampens free-running behavior surprisingly slowly, whereas the disruption of both functions results in an immediate arrhythmia. Therefore, clocks and neural communication of the M-oscillator act additively to sustain rhythmic locomotor output. This phenomenon also suggests that M-oscillator can be a pacemaker or a downstream path that passively receives rhythmic inputs from another pacemaker and convey output signals. Our results support the distributed network model and highlight the remarkable resilience of the Drosophila circadian pacemaker circuit, which can alter its topology to maintain locomotor rhythms.
Highlights
Circadian oscillators across the evolutionary tree operate using transcriptional-translational feedback loops (Hurley et al, 2016)
Our results are summarized in three main points: (i) free-running locomotor rhythms are maintained for several days while molecular clocks are disrupted in the M-oscillator or in both M- and part of E-oscillators; (ii) morning anticipation does not require PER cycling but requires intact CLK; and (iii) disruption of M-oscillator’s neuronal output dampens free-running rhythms, and the disruption of both clocks and neural output of the M-cells results in an immediate behavioral arrhythmia under constant conditions
Whereas CRISPR-mediated clock knockout in both the M-cells and LNEO causes an immediate behavioral arrhythmia (Delventhal et al, 2019; Schlichting et al, 2019), adult-restricted expression of CLK with DvPdf-GAL4, which is expressed in the M-cells and two out of four Lateral Neuron-Evening oscillator (LN-EO) cells, gradually dampens the locomotor rhythmicity over several days
Summary
Circadian oscillators across the evolutionary tree operate using transcriptional-translational feedback loops (Hurley et al, 2016). In Drosophila, the transcriptional activators CLOCK/CYCLE (CLK/CYC) drive the expression of the period (per) and timeless (tim) genes. The PER-containing complexes inhibit the activity of CLK/CYC, thereby forming a principal negative feedback loop. Positive- and negative- feedback loops created by PAR DOMAIN PROTEIN 1 (PDP-1) and VRILLE (VRI) on Clk expression are, respectively, coupled with the main negative-feedback loop to ensure the generation of 24 h rhythms (Hardin, 2011). The s-LNvs are further divided into four neurons that express the neuropeptide pigment dispersing factor (PDF) and one PDF-negative neuron (5th s-LNv) (Figure 1A)
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