Adipokinetic hormones (AKHs) are metabolic neuropeptides, mediating mobilization of energy substrates from the fat body in many insects. In delving into the roles of the Drosophila Akh (dAkh) gene, its developmental expression patterns were examined and the physiological functions of the AKH-producing neurons were investigated using animals devoid of AKH neurons and ones with ectopically expressing dAkh. The dAkh gene is expressed exclusively in the corpora cardiaca from late embryos to adult stages. Projections emanating from the AKH neurons indicated that AKH has multiple target tissues as follows: the prothoracic gland and aorta in the larva and the crop and brain in the adult. Studies using transgenic manipulations of the dAkh gene demonstrated that AKH induced both hypertrehalosemia and hyperlipemia. Starved wild-type flies displayed prolonged hyperactivity prior to death; this novel behavioral pattern could be associated with food-searching activities in response to starvation. In contrast, flies devoid of AKH neurons not only lacked this type of hyperactivity, but also displayed strong resistance to starvationinduced death. From these findings, we propose another role for AKH in the regulation of starvationinduced foraging behavior.

Animals display stereotyped behavioral modifications during development, but little is known about how genes and neural circuits are regulated to turn on/off behaviors. Here we report that Drosophila neuropeptide F (dNPF), a human NPY homolog, coordinates larval behavioral changes during development. The brain expression of npf is high in larvae attracted to food, whereas its downregulation coincides with the onset of behaviors of older larvae, including food aversion, hypermobility, and cooperative burrowing. Loss of dNPF signaling in young transgenic larvae led to the premature display of behavioral phenotypes associated with older larvae. Conversely, dNPF overexpression in older larvae prolonged feeding, and suppressed hypermobility and cooperative burrowing behaviors. The dNPF system provides a new paradigm for studying the central control of cooperative behavior.

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Regulation of the Drosophila pigment-dispersing factor (pdf ) gene products was analyzed in wild-type and clock mutants. Mutations in the transcription factors CLOCK and CYCLE severely diminish pdf RNA and neuropeptide (PDF) levels in a single cluster of clockgene-expressing brain cells, called small ventrolateral neurons (s-LN vs). This clock-gene regulation of specific cells does not operate through an E-box found within pdf regulatory sequences. PDF immunoreactivity exhibits daily cycling, but only within terminals of axons projecting from the s-LN vs. This posttranslational rhythm is eliminated by period or timeless null mutations, which do not affect PDF staining in cell bodies or pdf mRNA levels. Therefore, within these chronobiologically important neurons, separate elements of the central pacemaking machinery regulate pdf or its product in novel and different ways. Coupled with contemporary results showing a pdf-null mutant to be severely defective in its behavioral rhythmicity, the present results reveal PDF as an important circadian mediator whose expression and function are downstream of the clockworks. Daily rhythms of physiology and behavior are generated by endogenous circadian oscillators. In Drosophila, this timekeeping is controlled by several clock genes (reviewed in ref.1). The current model posits that the Clock-and cycle-encoded products-basic helix-loop-helix proteins that dimerize by means of their PAS domains-activate period (per) and timeless (tim) transcription by interactions with E-boxes located in the 5Ј-f lanking region of these clock genes and a circadian enhancer upstream of (at least) per's transcription unit (2, 3). After PER and TIM proteins accumulate in the cytoplasm and form heterodimers, they translocate to the nucleus and negatively regulate their own genes by interfering with CLK:CYC function (3, 4).A similar negative-feedback loop operates in the circadian clocks of other animals. Mammalian homologs of Drosophila clock genes have been identified or originally discovered in mice and humans (1). Circadian oscillations of mPer mRNAs occur in the suprachiasmatic nucleus of mouse, a circadian-pacemaker structure in the brain. The amplitude of these mRNA rhythms is reduced in the murine Clock mutant, consistent with the fly paradigm (5). In addition to the central time-keeping functions of clock transcription factors, they may also regulate downstream rhythm-relevant genes, which are thought to control physiological and behavioral rhythms. In this respect, CLK:BMAL1 heterodimers can activate transcription of a clock-regulated vasopressin gene in mice (5). In Drosophila, cyclically expressed genes whose mRNA oscillations are affected by clock mutations have been described (6, 7). Additional factors putatively functioning as clock outputs were originally identified by mutations (8, 9). However, the manner by which clock genes actpresumably upon these and other output factors-to effect the pacemaker's control of an overt rhythm is unknown.It has been suggested that a neuropeptide,...