Cell- or network-driven oscillators underlie motor rhythmicity. The identity of C. elegans oscillators remains unknown. Through cell ablation, electrophysiology, and calcium imaging, we show: (1) forward and backward locomotion is driven by different oscillators; (2) the cholinergic and excitatory A-class motor neurons exhibit intrinsic and oscillatory activity that is sufficient to drive backward locomotion in the absence of premotor interneurons; (3) the UNC-2 P/Q/N high-voltage-activated calcium current underlies A motor neuron’s oscillation; (4) descending premotor interneurons AVA, via an evolutionarily conserved, mixed gap junction and chemical synapse configuration, exert state-dependent inhibition and potentiation of A motor neuron’s intrinsic activity to regulate backward locomotion. Thus, motor neurons themselves derive rhythms, which are dually regulated by the descending interneurons to control the reversal motor state. These and previous findings exemplify compression: essential circuit properties are conserved but executed by fewer numbers and layers of neurons in a small locomotor network.

Animal behaviors are commonly organized into long-lasting states that coordinately impact the generation of diverse motor outputs such as feeding, locomotion, and grooming. However, the neural mechanisms that coordinate these distinct motor programs remain poorly understood. Here, we examine how the distinct motor programs of the nematode C. elegans are coupled together across behavioral states. We describe a new imaging platform that permits automated, simultaneous quantification of each of the main C. elegans motor programs over hours or days. Analysis of these whole-organism behavioral profiles shows that the motor programs coordinately change as animals switch behavioral states. Utilizing genetics, optogenetics, and calcium imaging, we identify a new role for dopamine in coupling locomotion and egg-laying together across states. These results provide new insights into how the diverse motor programs throughout an organism are coordinated and suggest that neuromodulators like dopamine can couple motor circuits together in a state-dependent manner.

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Mutations in pre-synaptic voltage-gated calcium channels can lead to familial hemiplegic migraine type 1 (FHM1). While mammalian studies indicate that the migraine brain is hyperexcitable due to enhanced excitation or reduced inhibition, the molecular and cellular mechanisms underlying this excitatory/inhibitory (E/I) imbalance are poorly understood. We identified a gain-of-function (gf) mutation in the Caenorhabditis elegans CaV2 channel α1 subunit, UNC-2, which leads to increased calcium currents. unc-2(zf35gf) mutants exhibit hyperactivity and seizure-like motor behaviors. Expression of the unc-2 gene with FHM1 substitutions R192Q and S218L leads to hyperactivity similar to that of unc-2(zf35gf) mutants. unc-2(zf35gf) mutants display increased cholinergic and decreased GABAergic transmission. Moreover, increased cholinergic transmission in unc-2(zf35gf) mutants leads to an increase of cholinergic synapses and a TAX-6/calcineurin-dependent reduction of GABA synapses. Our studies reveal mechanisms through which CaV2 gain-of-function mutations disrupt excitation-inhibition balance in the nervous system.

Background: Bronchiectasis is a chronic infectious respiratory disease with diverse causes and ethnic or geographic differences. However, few large-scale studies of its etiology have been conducted in Asia. This study aimed to determine the etiology and clinical features of bronchiectasis in Taiwan.Methods: This longitudinal cohort study investigated the etiology and clinical features of newly diagnosed noncystic fibrosis bronchiectasis patients from January 2002 to December 2016. The clinical, functional and microbiological data of patients were retrieved from the Chang Gung Research Database, which includes seven medical facilities throughout Taiwan. The index date was the date of the first bronchiectasis diagnosis. Known diseases that were diagnosed before the index date were regarded as etiologies of bronchiectasis. Results: The cohort comprised 15,729 adult patients with bronchiectasis. Idiopathic (32%) was the most common cause, followed by post-pneumonia (24%). Other causes included post-tuberculosis (12%), chronic obstructive pulmonary disease (14%), asthma (10%), gastroesophageal reflux disease (2%) and rheumatic diseases (2%). At diagnosis, 8487 patients had sputum culture. Pseudomonas aeruginosa (5.3%) was the most common bacteria, followed by non-tuberculosis mycobacteria (3.6%), Haemophilus influenzae (3.4%) and Klebsiella pneumoniae (3.1%), but 6155 (72.1%) had negative sputum cultures. Patients with post-tuberculosis had a higher sputum isolation rate of non-tuberculosis mycobacteria than P. aeruginosa. Patients with post-tuberculosis and post-pneumonia bronchiectasis had a higher frequency of chronic lung infection than other groups (p < 0.05). Clinical characteristics, such as gender, lung function, comorbidities and microbiology, were significantly different between idiopathic and known etiologies.Conclusions: Idiopathic, post-infection and tuberculosis constitute major bronchiectasis etiologies in Taiwan. Clinical characteristics and sputum microbiology were distinct among separate etiology phenotypes.