Peptide Neuromodulation in Invertebrate Model Systems Paul H. Taghert, Michael N. Nitabach  Neuron  Volume 76, Issue 1, Pages 82-97 (October 2012) DOI: 10.1016/j.neuron.2012.08.035 Copyright © 2012 Elsevier Inc. Terms and Conditions

Figure 1 Peptidergic Modulation of Behavior Features Feedforward Pathways (A) In the mollusk Aplysia, feedforward mechanisms coordinate neuropeptide modulation of feeding circuitry. Satiation is signaled by sensory afferents from the gut (here symbolized by EN1 and EN2, blue). EN1 signaling is mediated in part by the NPY homolog apNPY that modulates many different elements including the B20 interneuron to switch from ingestion to egestion modes. A parallel feedforward pathway is mediated by EN2 afferents to activate the B18 interneuron (red) that also releases apNPY to augment the ingestion-to-egestion switch. Adapted from Jing et al. (2007). (B) In the mollusk Aplysia, feedforward mechanisms provide neuropeptide-mediated compensation in feed circuitry. The allatotropin-related peptide (ATRP) is released centrally by the CBI-4 interneuron (blue) shortening protraction duration, but it also increases the rate of protraction motorneurons (MN, red). By this feedforward mechanism, MNs release ATRP (and another neuropeptide, MM) to increase muscle contraction amplitude and so compensate for the effect of a decreased duration. (C) In Drosophila, a feedforward mechanism is suggested by the arrangement of neuropeptide PDF signals to modulate circadian neural circuits. Genetic experiments suggest both the large LNv (blue) and the small LNv (red) contribute to coordination of daily locomotor rhythms under the influence of light and dark. Pharmacology and expression studies indicate the existence of a direct and an indirect (feedforward) PDF pathway to help synchronize other pacemakers in the circuit. Neuron 2012 76, 82-97DOI: (10.1016/j.neuron.2012.08.035) Copyright © 2012 Elsevier Inc. Terms and Conditions

Figure 2 The ETH Neuropeptide Triggers a Complex Behavioral Sequence by Direct and Sequential Activation of Intermediate Peptidergic Targets Ecdysis behavior in insects is a composite of several behavioral sub-sequences and is triggered by a complex set of neuropeptides. The ETH neuropeptide originating from peripheral endocrine cells acts high in the control hierarchy. It acts centrally to elicit a sequence of behaviors (timeline to the right) by directly activating a heterogeneous set of target neurons, most of which are peptidergic. Their activation is sequential, due to presumed parallel inhibitory pathways that are activated by ETH. Each peptidergic target has restricted and overlapping control of specific behavioral subsets. Arrowheads symbolize activating inputs; knobs symbolize inhibitory inputs. Adapted from Kim et al. (2006a). Neuron 2012 76, 82-97DOI: (10.1016/j.neuron.2012.08.035) Copyright © 2012 Elsevier Inc. Terms and Conditions

Figure 3 Peptidergic Modulation of Behavior Features Convergence with Specific Environmental Signals (A) Light activates CRY in non-PDF (“E”) pacemakers in Drosophila in parallel to PDF signaling: CRY and PDF-R are coexpressed in individual E pacemakers. The convergence supports rhythmic oscillations and locomotor activity. Adapted from Im et al. (2011). (B) Light triggers rapid adult eclosion in Drosophila during a narrow temporal gate, provided there was prior neuropeptide EH release. EH activates an excitatory pathway for behavior and a parallel inhibitory one; light disinhibits the inhibitory pathway and the convergence promotes eclosion behavior. Adapted from McNabb and Truman (2008). (C) Temperature triggers rapid avoidance behavior in C. elegans; heat sensation mediated in part by OSM9 (∼TRPV)-expressing sensory neuron(s); proper responses requires converging inputs from FLP21/NPR-1 peptide signaling that originates in RMG interneurons. Adapted from Glauser et al. (2011). Orange, environmental signal; blue, sensory receptor; red, peptidergic neuron. Neuron 2012 76, 82-97DOI: (10.1016/j.neuron.2012.08.035) Copyright © 2012 Elsevier Inc. Terms and Conditions

Figure 4 Control of Neuropeptide Release by Peptidergic Feedback Loops (A) Positive peptidergic feedback initiates the all-or-nothing insect eclosion behavior. Corazonin (COR) and diuretic hormone (DH) induce modest ETH secretion by the peripheral Inka cells. This ETH propagates through the hemolymph and acts on central EH neurons to induce modest EH secretion, which in turns propagates through the hemolymph and-closing the feedback loop-acts on the Inka cells to induce massive ETH secretion. These high levels of ETH then act on the central EH neurons to induce massive EH secretion. These high levels of EH finally act on the eclosion CPG to initiate eclosion. (B) Peptidergic feedback modulates sensory responses in C. elegans. The AWC sensory neuron releases NLP-1 neuropeptide in response to sensory stimuli. NLP-1 acts on the AIA interneuron to modulate INS-1 peptide secretion, which-closing the feedback loop-acts on the AWC sensory neuron to modulate its responsiveness to sensory stimuli. Neuron 2012 76, 82-97DOI: (10.1016/j.neuron.2012.08.035) Copyright © 2012 Elsevier Inc. Terms and Conditions