Neuropeptides are secreted molecules that have conserved roles modulating many processes, including mood, reproduction, and feeding. Dysregulation of neuropeptide signaling is also implicated in neurological disorders such as epilepsy. However, much is unknown about the mechanisms regulating specific neuropeptides to mediate behavior. Here, we report that the expression levels of dozens of neuropeptides are up-regulated in response to circuit activity imbalance in C. elegans. acr-2 encodes a homolog of human nicotinic receptors, and functions in the cholinergic motoneurons. A hyperactive mutation, acr-2(gf), causes an activity imbalance in the motor circuit. We performed cell-type specific transcriptomic analysis and identified genes differentially expressed in acr-2(gf), compared to wild type. The most over-represented class of genes are neuropeptides, with insulin-like-peptides (ILPs) the most affected. Moreover, up-regulation of neuropeptides occurs in motoneurons, as well as sensory neurons. In particular, the induced expression of the ILP ins-29 occurs in the BAG neurons, which were previously shown to function in gas-sensing. We also show that this up-regulation of ins-29 in acr-2(gf) animals is activity-dependent. Our genetic and molecular analyses support cooperative effects for ILPs and other neuropeptides in promoting motor circuit activity in the acr-2(gf) background. Together, this data reveals that a major transcriptional response to motor circuit dysregulation is in up-regulation of multiple neuropeptides, and suggests that BAG sensory neurons can respond to intrinsic activity states to feedback on the motor circuit.
22Neuropeptides are secreted molecules that have conserved roles modulating many processes, 23 including mood, reproduction, and feeding. Dysregulation of neuropeptide signaling is also implicated 24 in neurological disorders such as epilepsy. However, much is unknown about the mechanisms 25 regulating specific neuropeptides to mediate behavior. Here, we report that the expression levels of 26 dozens of neuropeptides are up-regulated in response to circuit activity imbalance in C. elegans. acr-2 27 encodes a homolog of human nicotinic receptors, and functions in the cholinergic motoneurons. A 28 hyperactive mutation, acr-2(gf), causes an activity imbalance in the motor circuit. We performed cell-29 type specific transcriptomic analysis and identified genes differentially expressed in acr-2(gf), compared 30 to wild type. The most over-represented class of genes are neuropeptides, with insulin-like-peptides 31 (ILPs) the most affected. Moreover, up-regulation of neuropeptides occurs in motoneurons, as well as 32 sensory neurons. In particular, the induced expression of the ILP ins-29 occurs in the BAG neurons, 33 which are previously shown to function in gas-sensing. We also show that this up-regulation of ins-29 in 34 acr-2(gf) animals is activity-dependent. Our genetic and molecular analyses support cooperative 35 effects for ILPs and other neuropeptides in promoting motor circuit activity in the acr-2(gf) background. 36Together, this data reveals that a major transcriptional response to motor circuit dysregulation is in up-37 regulation of multiple neuropeptides, and suggests that BAG sensory neurons can respond to intrinsic 38 activity states to feedback on the motor circuit. 39 40 41 42 43 44 45 46 2 AUTHOR SUMMARY 47Neuropeptides are secreted small molecules that regulate a variety of neuronal functions and are also 48 implicated in many diseases. However, it remains poorly understood how expression of neuropeptides 49 is regulated, particularly in disease states. Using a genetic animal model that mimics epilepsy, we 50 identified dozens of neuropeptides that are up-regulated when neuronal activities are altered. Some of 51 these neuropeptides share similarity to insulin-like properties (ILPs). Strikingly, one of these ILPs is 52 expressed in sensory neurons that normally respond to acute carbon dioxide exposure. We show that 53 the mis-regulation of this ILP expression is activity-dependent. Moreover, these neuropeptides act in 54 concert to modulate animal behaviors. The findings in this study provide further evidence that 55 neuropeptides are key mediators of aberrant cholinergic signaling, and suggest complex neural network 56 effects from sensory neurons onto motor function. 57 58 59 60 61 62 63 64 65 66 67 68 69 3 Neural circuits are dynamic, changing their properties in response to experience. These 71 changes are critical for maintaining circuit homeostasis and in processes like memory. Many factors 72 such as c-Fos and BDNF, are activated early in response to increased neural activity and further 73 ...
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