a way similar to the neuropeptides of higher animals. Due to their modulatory and diffusive nature, neuropeptides can act on multiple time and spatial scales. Below are some examples of neuropeptide actions: Corelease Neuropeptides are often co-released with other neurotransmitters and neuropeptides to modulate synaptic activity. Synaptic vesicles and dense core vesicles can have differential activation properties for release, resulting in context-dependent corelease combinations. For example, insect motor neurons are glutamatergic and some contain dense core vesicles with proctolin. At low frequency activation, only glutamate is released, yielding fast and rapid excitation of the muscle. At high frequency activation however, dense core vesicles release proctolin, inducing prolonged contractions. Thus, neuropeptide release can be fine-tuned to modulate synaptic activity in certain contexts. Some regions of the nervous system are specialized to release distinctive sets of peptides. For example, the hypothalamus and the pituitary gland release peptides (e.g. TRH, GnRH, CRH, SST) that act as hormones In one subpoplation of the arcuate nucleus of the hypothalamus, three anorectic peptides are co-expressed: α-melanocyte-stimulating hormone (α-MSH), galanin-like peptide, and cocaine-and-amphetamine-regulated transcript (CART), and in another subpopulation two orexigenic peptides are co-expressed, neuropeptide Y and agouti-related peptide (AGRP). These peptides are all released in different combinations to signal hunger and satiation cues. The following is a list of neuroactive peptides coreleased with other neurotransmitters. Transmitter names are shown in bold. Norepinephrine (noradrenaline). In neurons of the A2 cell group in the nucleus of the solitary tract), norepinephrine co-exists with: Galanin Enkephalin Neuropeptide Y GABA Somatostatin (in the hippocampus) Cholecystokinin Neuropeptide Y (in the arcuate nucleus) Acetylcholine VIP Substance P Dopamine Cholecystokinin Neurotensin Glucagon-like peptide-1 (in the nucleus accumbens) Epinephrine (adrenaline) Neuropeptide Y Neurotensin Serotonin (5-HT) Substance P TRH Enkephalin Some neurons make several different peptides. For instance, Vasopressin co-exists with dynorphin and galanin in magnocellular neurons of the supraoptic nucleus and paraventricular nucleus, and with CRF (in parvocellular neurons of the paraventricular nucleus) Oxytocin in the supraoptic nucleus co-exists with enkephalin, dynorphin, cocaine-and amphetamine regulated transcript (CART) and cholecystokinin. Evolution of Neuropeptide Signaling Peptides are ancient signaling systems that are found in almost all animals on Earth (sponges are the exception). Genome sequencing reveals evidence of neuropeptide genes in Cnidaria, Ctenophora, and Placozoa, some of oldest living animals with nervous systems or neural-like tissues. Recent studies also show genomic evidence of neuropeptide processing machinery in metazoans and choanoflagellates, suggesting that neuropeptide signaling may predate the