ABSTRACT
The capacity of animals to respond to hazardous stimuli in their surroundings is crucial for their survival. In mammals, complex evaluations of the environment require large numbers and different subtypes of neurons. The nematode C. elegans avoids hazardous chemicals they encounter by reversing their direction of movement. How does the worms' compact nervous system process the spatial information and direct motion change? We show here that a single interneuron, AVA, receives glutamatergic excitatory and inhibitory signals from head and tail sensory neurons, respectively. AVA integrates the spatially distinct and opposing cues, whose output instructs the animal's behavioral decision. We further find that the differential activation of AVA stems from distinct localization of inhibitory and excitatory glutamate-gated receptors along AVA's process and from different threshold sensitivities of the sensory neurons. Our results thus uncover a cellular mechanism that mediates spatial computation of nociceptive cues for efficient decision-making in C. elegans.
ABSTRACT
Sexually dimorphic circuits underlie behavioral differences between the sexes, yet the molecular mechanisms involved in their formation are poorly understood. We show here that sexually dimorphic connectivity patterns arise in C. elegans through local ubiquitin-mediated protein degradation in selected synapses of one sex but not the other. Specifically, synaptic degradation occurs via binding of the evolutionary conserved E3 ligase SEL-10/FBW7 to a phosphodegron binding site of the netrin receptor UNC-40/DCC (Deleted in Colorectal Cancer), resulting in degradation of UNC-40. In animals carrying an undegradable unc-40 gain-of-function allele, synapses were retained in both sexes, compromising the activity of the circuit without affecting neurite guidance. Thus, by decoupling the synaptic and guidance functions of the netrin pathway, we reveal a critical role for dimorphic protein degradation in controlling neuronal connectivity and activity. Additionally, the interaction between SEL-10 and UNC-40 is necessary not only for sex-specific synapse pruning, but also for other synaptic functions. These findings provide insight into the mechanisms that generate sex-specific differences in neuronal connectivity, activity, and function.
Subject(s)
Caenorhabditis elegans Proteins/metabolism , Cell Adhesion Molecules/metabolism , Cell Cycle Proteins/metabolism , Sex Characteristics , Synapses/metabolism , Synaptic Transmission/physiology , Alleles , Animals , Animals, Genetically Modified , Axons/metabolism , Caenorhabditis elegans , Caenorhabditis elegans Proteins/genetics , Cell Adhesion Molecules/genetics , Gain of Function Mutation , Male , Proteolysis , Ubiquitination/geneticsABSTRACT
BACKGROUND: There seems to be a pathogenetic link between hemodynamics and inflammatory arterial wall alteration leading to the development and rupture of intracranial aneurysms (IAs). Noninvasive assessment of the inflammatory status of the aneurysm wall may guide the management of unruptured IAs by identifying reliable markers for increased rupture risk. METHODS: We conducted a qualitative systematic review following the ENTREQ (Enhancing Transparency in Reporting the Synthesis of Qualitative Research) framework. A search was made in MEDLINE/PubMed, Embase, and CINAHL from database inception to October 2017 using the terms "intracranial aneurysm" and "cerebral aneurysm" linked with the following key words: inflammation, hemodynamic(s), remodeling, macrophages, neutrophils, lymphocytes, complement system, vascular smooth muscle cells, mast cells, cytokines, and inflammatory biomarkers. RESULTS: One hundred and twenty-three articles were included in the review. CONCLUSIONS: In this systematic review, we explore the relationship between hemodynamic stress, inflammation, vascular remodeling, and the formation and rupture of IAs to develop novel strategies to predict the individual risk of aneurysmal rupture.
