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Behavior and physiology are orchestrated by neuropeptides acting as central neuromodulators and circulating hormones. An outstanding question is how these neuropeptides function to coordinate complex and competing behaviors. In Drosophila, the neuropeptide leucokinin (LK) modulates diverse functions, but mechanisms underlying these complex interactions remain poorly understood. As a first step towards understanding these mechanisms, we delineated LK circuitry that governs various aspects of post-feeding physiology and behavior. We found that impaired LK signaling in Lk and Lk receptor (Lkr) mutants affects diverse but coordinated processes, including regulation of stress, water homeostasis, feeding, locomotor activity, and metabolic rate. Next, we sought to define the populations of LK neurons that contribute to the different aspects of this physiology. We find that the calcium activity in abdominal ganglia LK neurons (ABLKs), but not in the two sets of brain neurons, increases specifically following water consumption, suggesting that ABLKs regulate water homeostasis and its associated physiology. To identify targets of LK peptide, we mapped the distribution of Lkr expression, mined a brain single-cell transcriptome dataset for genes coexpressed with Lkr, and identified synaptic partners of LK neurons. Lkr expression in the brain insulin-producing cells (IPCs), gut, renal tubules and chemosensory cells, correlates well with regulatory roles detected in the Lk and Lkr mutants. Furthermore, these mutants and flies with targeted knockdown of Lkr in IPCs displayed altered expression of insulin-like peptides (DILPs) and transcripts in IPCs and increased starvation resistance. Thus, some effects of LK signaling appear to occur via DILP action. Collectively, our data suggest that the three sets of LK neurons have different targets, but modulate the establishment of post-prandial homeostasis by regulating distinct physiological processes and behaviors such as diuresis, metabolism, organismal activity and insulin signaling. These findings provide a platform for investigating feeding-related neuroendocrine regulation of vital behavior and physiology.

Peptides are the largest and most diverse class of molecules used for neurochemical communication, playing key roles in the control of essentially all aspects of physiology and behavior. The American lobster, Homarus americanus, is a crustacean of commercial and biomedical importance; lobster growth and reproduction are under neuropeptidergic control, and portions of the lobster nervous system serve as models for understanding the general principles underlying rhythmic motor behavior (including peptidergic neuromodulation). While a number of neuropeptides have been identified from H. americanus, and the effects of some have been investigated at the cellular/systems levels, little is currently known about the molecular components of neuropeptidergic signaling in the lobster. Here, a H. americanus neural transcriptome was generated and mined for sequences encoding putative peptide precursors and receptors; 35 precursor- and 41 receptor-encoding transcripts were identified. We predicted 194 distinct neuropeptides from the deduced precursor proteins, including members of the adipokinetic hormone-corazonin-like peptide, allatostatin A, allatostatin C, bursicon, CCHamide, corazonin, crustacean cardioactive peptide, crustacean hyperglycemic hormone (CHH), CHH precursor-related peptide, diuretic hormone 31, diuretic hormone 44, eclosion hormone, FLRFamide, GSEFLamide, insulin-like peptide, intocin, leucokinin, myosuppressin, neuroparsin, neuropeptide F, orcokinin, pigment dispersing hormone, proctolin, pyrokinin, SIFamide, sulfakinin and tachykinin-related peptide families. While some of the predicted peptides are known H. americanus isoforms, most are novel identifications, more than doubling the extant lobster neuropeptidome. The deduced receptor proteins are the first descriptions of H. americanus neuropeptide receptors, and include ones for most of the peptide groups mentioned earlier, as well as those for ecdysis-triggering hormone, red pigment concentrating hormone and short neuropeptide F. Multiple receptors were identified for most peptide families. These data represent the most complete description of the molecular underpinnings of peptidergic signaling in H. americanus, and will serve as a foundation for future gene-based studies of neuropeptidergic control in the lobster.

Innate behaviors are often executed in concert with accompanying physiological programs. How this coordination is achieved is poorly understood. Mating behavior and the transfer of sperm and seminal fluid (SSFT) provide a model for understanding how concerted behavioral and physiological programs are coordinated. Here we identify a male-specific neural pathway that coordinates the timing of SSFT with the duration of copulation behavior in Drosophila. Silencing four abdominal ganglion (AG) interneurons (INs) that contain the neuropeptide corazonin (Crz) both blocked SSFT and substantially lengthened copulation duration. Activating these Crz INs caused rapid ejaculation in isolated males, a phenotype mimicked by injection of Crz peptide. Crz promotes SSFT by activating serotonergic (5-HT) projection neurons (PNs) that innervate the accessory glands. Activation of these PNs in copulo caused premature SSFT and also shortened copulation duration. However, mating terminated normally when these PNs were silenced, indicating that SSFT is not required for appropriate copulation duration. Thus, the lengthened copulation duration phenotype caused by silencing Crz INs is independent of the block to SSFT. We conclude that four Crz INs independently control SSFT and copulation duration, thereby coupling the timing of these two processes.

Orexin, a neuropeptide best known for its role in arousal and its absence in people with narcolepsy, is also involved in the pathophysiology of panic anxiety disorder. Panic disorder is a severe anxiety disorder with recurrent, debilitating panic attacks. In individuals with panic disorder there is evidence of decreased central γ-aminobutyric acid (GABA) activity as well as marked increases in autonomic and respiratory responses after intravenous infusions of hypertonic sodium lactate 1 , 2 , 3 . In a rat model of panic disorder, chronic inhibition of GABA synthesis in the dorsomedial-perifornical hypothalamus of rats produces anxiety-like states and a similar vulnerability to sodium lactate–induced cardioexcitatory responses 4 , 5 , 6 , 7 , 8 , 9 . The dorsomedial-perifornical hypothalamus is enriched in neurons containing orexin (ORX, also known as hypocretin) 10 , which have a crucial role in arousal 10 , 11 , vigilance 10 and central autonomic mobilization 12 , all of which are key components of panic. Here we show that activation of ORX-synthesizing neurons is necessary for developing a panic-prone state in the rat panic model, and either silencing of the hypothalamic gene encoding ORX ( Hcrt ) with RNAi or systemic ORX-1 receptor antagonists blocks the panic responses. Moreover, we show that human subjects with panic anxiety have elevated levels of ORX in the cerebrospinal fluid compared to subjects without panic anxiety. Taken together, our results suggest that the ORX system may be involved in the pathophysiology of panic anxiety and that ORX antagonists constitute a potential new treatment strategy for panic disorder.

Serotonin, a central neuromodulator with ancient ties to feeding and metabolism, is a major driver of body fat loss. However, mechanisms by which central serotonin action leads to fat loss remain unknown. Here, we report that the FLP-7 neuropeptide and its cognate receptor, NPR-22, function as the ligand-receptor pair that defines the neuroendocrine axis of serotonergic body fat loss in Caenorhabditis elegans . FLP-7 is secreted as a neuroendocrine peptide in proportion to fluctuations in neural serotonin circuit functions, and its release is regulated from secretory neurons via the nutrient sensor AMPK. FLP-7 acts via the NPR-22/Tachykinin2 receptor in the intestine and drives fat loss via the adipocyte triglyceride lipase ATGL-1. Importantly, this ligand-receptor pair does not alter other serotonin-dependent behaviours including food intake. For global modulators such as serotonin, the use of distinct neuroendocrine peptides for each output may be one means to achieve phenotypic selectivity. Serotonin is a potent stimulator of fat loss and energy expenditure in several species, including C. elegans . Here, Palamiuc et al . identify the neuropeptide, FP-7, and its receptor in the intestine, NRP-22 as mediators of serotonergic body fat loss in worms.

In mammals, hypocretin/orexin (HCRT) neuropeptides are important sleep-wake regulators and HCRT deficiency causes narcolepsy. In addition to fragmented wakefulness, narcoleptic mammals also display sleep fragmentation, a less understood phenotype recapitulated in the zebrafish HCRT receptor mutant (hcrtr-/-). We therefore used zebrafish to study the potential mediators of HCRT-mediated sleep consolidation. Similar to mammals, zebrafish HCRT neurons express vesicular glutamate transporters indicating conservation of the excitatory phenotype. Visualization of the entire HCRT circuit in zebrafish stably expressing hcrt:EGFP revealed parallels with established mammalian HCRT neuroanatomy, including projections to the pineal gland, where hcrtr mRNA is expressed. As pineal-produced melatonin is a major sleep-inducing hormone in zebrafish, we further studied how the HCRT and melatonin systems interact functionally. mRNA level of arylalkylamine-N-acetyltransferase (AANAT2), a key enzyme of melatonin synthesis, is reduced in hcrtr-/- pineal gland during the night. Moreover, HCRT perfusion of cultured zebrafish pineal glands induces melatonin release. Together these data indicate that HCRT can modulate melatonin production at night. Furthermore, hcrtr-/- fish are hypersensitive to melatonin, but not other hypnotic compounds. Subthreshold doses of melatonin increased the amount of sleep and consolidated sleep in hcrtr-/- fish, but not in the wild-type siblings. These results demonstrate the existence of a functional HCRT neurons-pineal gland circuit able to modulate melatonin production and sleep consolidation.

This review examines our current understanding of the roles of some of the best known neuropeptides that have played major roles in our combined research programmes. Evidence obtained from over 75 years of research shows involvement of these transmitters in a wide range of organs relevant to cardiovascular, respiratory, cutaneous, neuronal and intestinal systems. There is an increasing understanding of the mechanisms involved in the release of the peptides (substance P and calcitonin gene‐related peptide (CGRP)) from sensory nerves or, neuropeptide Y (NPY) from sympathetic, parasympathetic and nonadrenergic, noncholinergic (NANC) neurons. Responses in target tissues result from interactions of the neuropeptides, or related forms, with specific G‐protein coupled receptors (GPCRs or 7 transmembrane‐spanning, 7TM proteins) that belong to either rhodopsin‐like, class 1 (neurokinin (NK) and NPY Y receptors) or secretin‐like, class 2 GPCRs (CGRP receptors). The majority of receptors activated by our chosen neuropeptides are now cloned, with knowledge of preferred agonists and selective antagonists for many receptor subtypes within these families. The study of neuropeptides in animal models has additionally revealed physiological and pathophysiological roles that in turn have led to the ongoing development of new drugs, through utilization predominantly of antagonist activities. British Journal of Pharmacology (2006) 147, S202–S211. doi:10.1038/sj.bjp.0706461

Life-cycle transitions connecting larval and juvenile stages in metazoans are orchestrated by neuroendocrine signals including neuropeptides and hormones. In marine invertebrate life cycles, which often consist of planktonic larval and benthic adult stages, settlement of the free-swimming larva to the sea floor in response to environmental cues is a key life cycle transition. Settlement is regulated by a specialized sensory–neurosecretory system, the larval apical organ. The neuroendocrine mechanisms through which the apical organ transduces environmental cues into behavioral responses during settlement are not yet understood. Here we show that myoinhibitory peptide (MIP)/allatostatin-B, a pleiotropic neuropeptide widespread among protostomes, regulates larval settlement in the marine annelid Platynereis dumerilii . MIP is expressed in chemosensory–neurosecretory cells in the annelid larval apical organ and signals to its receptor, an orthologue of the Drosophila sex peptide receptor, expressed in neighboring apical organ cells. We demonstrate by morpholino-mediated knockdown that MIP signals via this receptor to trigger settlement. These results reveal a role for a conserved MIP receptor–ligand pair in regulating marine annelid settlement.

Acute hypercapnia (elevated arterial CO(2)/H(+)) is a suffocation signal that is life threatening and rapidly mobilizes adaptive changes in breathing and behavioral arousal in order to restore acid-base homeostasis. Severe hypercapnia, seen in respiratory disorders (eg, asthma or bronchitis, chronic obstructive pulmonary disease (COPD)), also results in high anxiety and autonomic activation. Recent evidence has demonstrated that wake-promoting hypothalamic orexin (ORX: also known as hypocretin) neurons are highly sensitive to local changes in CO(2)/H(+), and mice lacking prepro-ORX have blunted respiratory responses to hypercapnia. Furthermore, in a recent clinical study, ORX-A, which crosses blood-brain barrier easily, was dramatically increased in the plasma of patients with COPD and hypercapnic respiratory failure. This is consistent with a rodent model of COPD where chronic exposure to cigarette smoke led to a threefold increase in hypothalamic ORX-A expression. In the present study, we determined the role of ORX in the anxiety-like behavior and cardiorespiratory responses to acute exposure to a threshold panic challenge (ie, 20% CO(2)/normoxic gas). Exposing conscious rats to such hypercapnic, but not atmospheric air, resulted in respiratory, pressor, and bradycardic responses, as well as anxiety-like behavior and increased cellular c-Fos responses in ORX neurons. Systemically, pre-treating rats with a centrally active ORX1 receptor antagonist (30 mg/kg SB334867) attenuated hypercapnic gas-induced pressor and anxiety responses, without altering the robust bradycardia response, and only attenuated breathing responses at offset of the CO(2) challenge. Our results show that the ORX system has an important role in anxiety and sympathetic mobilization during hypercapnia. Furthermore, ORX1 receptor antagonists may be a therapeutic option rapidly treating increased anxiety and sympathetic drive seen during panic attacks and in hypercapnic states such as COPD.

Key Points The hypocretins (orexins), Hcrt1 and Hcrt2, are expressed only in a few thousand neurons in the dorsolateral hypothalamus. These secreted peptides are found in both rat and human brain, and a gene for their precursor (preprohypocretin) is also found in pufferfish and frog species. The gene, Hcrt , seems to have arisen by genetic rearrangement of the secretin gene. There are two G-protein-coupled receptors for the hypocretins, Hcrtr1 and Hcrtr2. They have different distributions within the brain and bind the two hypocretin peptides with different affinities. The hypocretin neurons of the hypothalamus project widely to many areas of the brain, consistent with the expression of the hypocretin receptors. The hypocretins are found in dense-core vesicles at synapses and can be neuroexcitatory. They can increase the presynaptic release of neurotransmitters and can also have a postsynaptic effect by opening Ca 2+ channels in the plasma membrane. Intracerebroventricular administration of hypocretin in rats increases short-term food consumption, and food deprivation can lead to increased concentrations of hypocretin peptides in the hypothalamus. Although these and other observations point to a function for the hypocretins in the control of feeding, it is unclear whether this is a primary role. Findings that relate to the feeding-related activities of the hypocretins have been inconsistent, and it is possible that their influence on feeding might be indirect, through their effects on arousal. Studies of three colonies of dogs in which narcolepsy was inherited showed that the affected gene in each case was the Hcrtr2 gene. Mice in which the Hcrt gene is inactivated show a marked narcoleptic-like phenotype, whereas knocking out either of the hypocretin receptor genes produces a milder phenotype. Knocking out both receptor genes reproduces the severe Hcrt knockout phenotype. In humans with narcolepsy, concentrations of hypocretins are severely reduced and hypocretin neurons are reduced in number or missing altogether, indicating that human narcolepsy results from degeneration of these neurons, possibly as a result of an autoimmune process. It is clear that the hypocretins are central to the control of sleep and arousal. The hypocretin neurons project to areas involved in these processes, including the ascending reticular activating system, and hypocretin levels fluctuate across the sleep–wake cycle and increase with sleep deprivation. Hypocretin neurons activate brainstem 'REM-off' neurons (which are active during wakefulness but not during rapid eye movement (REM) sleep) during arousal to maintain the awake state, and reduce the activity of 'REM-on' neurons (active during both wakefulness and REM sleep), acting as a gate to entry into REM sleep. A fuller understanding of the functions of the hypocretins and the control of sleep and arousal will aid the treatment of narcolepsy and other sleep disorders. Patients with narcolepsy and animals with mutations in the hypocretin system also show reduced feeding together with increased weight. It is proposed that the effect of the hypocretins on feeding behaviour comes from a 'resetting' of the metabolic 'set point' in patients and animal models in which hypocretin signalling is perturbed. In this model, the hypocretins provide a means by which metabolic needs can influence arousal, rather than being orexigenic or anorexigenic per se . Over a short period in the late 1990s, three groups converged on the discovery of a neuropeptide system, centred in the dorsolateral hypothalamus, that regulates arousal states, influences feeding and is implicated in the sleep disorder narcolepsy. Subsequent studies have illuminated many aspects of the circuitry of the hypocretin (also called orexin) system, which also influences hormone secretion and autonomic homeostasis, and have led to the hypothesis that most human narcolepsies result from an autoimmune attack against the hypocretin-producing neurons. The biochemical, physiological and anatomical components that regulate the switch between waking and sleeping are becoming clear. The rapidity with which the hypocretin story has emerged is a testament to both the conceptual and the technical evolution of genomic science in the past two decades.