One of the reasons that most multicellular animals survive and thrive is because of the adaptable and plastic nature of their nervous systems. For an organism to survive, it is essential for the animal to respond and adapt to environmental changes. This is achieved by sensing external cues and translating them into behaviors through changes in synaptic activity. The nervous system plays a crucial role in constantly evaluating environmental cues and allowing for behavioral plasticity in the organism. Multiple neurotransmitters and neuropeptides have been implicated as key players for integrating sensory information to produce the desired output. Because of its simple nervous system and well-established neuronal connectome, C. elegans acts as an excellent model to understand the mechanisms underlying behavioral plasticity. Here, we critically review how neuropeptides modulate a wide range of behaviors by allowing for changes in neuronal and synaptic signaling. This review will have a specific focus on feeding, mating, sleep, addiction, learning and locomotory behaviors in C. elegans. With a view to understand evolutionary relationships, we explore the functions and associated pathophysiology of C. elegans neuropeptides that are conserved across different phyla. Further, we discuss the mechanisms of neuropeptidergic signaling and how these signals are regulated in different behaviors. Finally, we attempt to provide insight into developing potential therapeutics for neuropeptide-related disorders.

Introduction: Repeated traumatic events result in long-lasting neuropsychiatric ailments, including neuroendocrine imbalances. Neuropeptide Y (NPY) in the arcuate nucleus (Arc) is an important orexigenic peptide. However, the molecular underpinnings of its dysregulation owing to traumatic brain injury remain unknown. Methods: Rats were subjected to repeated mild traumatic brain injury (rMTBI) using the closed-head weight drop model. Feeding behaviour and the regulatory epigenetic parameters of NPY expression were measured at 48 hrs and 30 days post rMTBI. Further, sodium butyrate, a pan-HDAC inhibitor, was administered to examine whether histone deacetylation is involved in NPY expression post rMTBI. Results: The rMTBI attenuated food intake, which was coincident with a decrease in NPY mRNA and protein levels in the Arc post rMTBI. Further, rMTBI also reduced the mRNA levels of the cAMP response element-binding protein (CREB) and CREB-binding protein (CBP) and altered the mRNA levels of the various isoforms of the histone deacetylases (HDACs). Concurrently, the acetylated H3-K9 levels and the binding of CBP at the NPY promoter in the Arc of the rMTBI-exposed rats were reduced. However, the treatment with sodium butyrate corrected the rMTBI-induced deficits in the H3-K9 acetylation levels and CBP occupancy at the NPY promoter, restoring both the NPY expression and the food intake. Conclusions: These findings suggest that histone deacetylation at the NPY promoter persistently controls NPY function in the Arc after rMTBI. This study also demonstrates the efficacy of HDAC inhibitors in mitigating trauma-induced neuroendocrine maladaptations in the hypothalamus.

The ubiquitin‐like protein Hub1/UBL‐5 associates with proteins non‐covalently. Hub1 promotes alternative splicing and splicing of precursor mRNAs with weak introns in yeast and mammalian cells; however, its splicing function has remained elusive in multicellular organisms. Here, we demonstrate the splicing function of Hub1/UBL‐5 in the free‐living nematode Caenorhabditis elegans. Hub1/UBL‐5 binds to the HIND‐containing splicing factors Snu66/SART‐1 and PRP‐38 and associates with other spliceosomal proteins. C. elegans hub1/ubl‐5 mutants die at the Larval 3 stage and show splicing defects for selected targets, similar to the mutants in yeast and mammalian cells. UBL‐5 complemented growth and splicing defects in Schizosaccharomyces pombe hub1 mutants, confirming its functional conservation. Thus, UBL‐5 is important for C. elegans development and plays a conserved pre‐mRNA splicing function.