Abstract
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.
Highlights
Neural circuits are dynamic, changing their properties in response to experience
Using neuronal-type specific RNA-seq, we identified over 200 genes whose expression levels are altered in response to hyperactivity in the motor circuit of C. elegans
Genes encoding neuropeptides were over-represented in this list, and we validated that fluorescent reporters for ins-29, flp-12, and nlp-1 were over- and/or ectopically-expressed in acr-2(gf) animals compared to wild type
Summary
Neural circuits are dynamic, changing their properties in response to experience. These changes are critical for maintaining circuit homeostasis and in processes like memory. Many factors such as c-Fos and BDNF, are activated early in response to increased neural activity and further regulate the expression of downstream genes [1]. These early-acting genes are involved in many neurological diseases. Mutations in the activity-dependent transcriptional repressor gene Mecp are associated with Rett’s syndrome [2].
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