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Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system (CNS). Excitatory amino acid transporters (EAATs) regulate extracellular glutamate by transporting it into cells, mostly glia, to terminate neurotransmission and to avoid neurotoxicity. EAATs are also chloride (Cl-) channels, but the physiological role of Cl- conductance through EAATs is poorly understood. Mutations of human EAAT1 (hEAAT1) have been identified in patients with episodic ataxia type 6 (EA6). One mutation showed increased Cl- channel activity and decreased glutamate transport, but the relative contributions of each function of hEAAT1 to mechanisms underlying the pathology of EA6 remain unclear. Here we investigated the effects of 5 additional EA6-related mutations on hEAAT1 function in Xenopus laevis oocytes, and on CNS function in a Drosophila melanogaster model of locomotor behavior. Our results indicate that mutations resulting in decreased hEAAT1 Cl- channel activity but with functional glutamate transport can also contribute to the pathology of EA6, highlighting the importance of Cl- homeostasis in glial cells for proper CNS function. We also identified what we believe is a novel mechanism involving an ectopic sodium (Na+) leak conductance in glial cells. Together, these results strongly support the idea that EA6 is primarily an ion channelopathy of CNS glia.

Escape behaviors help animals avoid harm from predators and other threats in the environment. Successful escape relies on integrating information from multiple stimulus modalities (of external or internal origin) to compute trajectories toward safe locations, choose between actions that satisfy competing motivations, and execute other strategies that ensure survival. To this end, escape behaviors must be adaptive. When a Drosophila melanogaster larva encounters a noxious stimulus, such as the focal pressure a parasitic wasp applies to the larval cuticle via its ovipositor, it initiates a characteristic escape response. The escape sequence consists of an initial abrupt bending, lateral rolling, and finally rapid crawling. Previous work has shown that the detection of noxious stimuli primarily relies on class IV multi-dendritic arborization neurons (Class IV neurons) located beneath the body wall, and more recent studies have identified several important components in the nociceptive neural circuitry involved in rolling. However, the neural mechanisms that underlie the rolling-escape sequence remain unclear. Here, we present both functional and anatomical evidence suggesting that bilateral descending neurons within the subesophageal zone of D. melanogaster larva play a crucial role in regulating the termination of rolling and subsequent transition to escape crawling. We demonstrate that these descending neurons (designated SeIN128) are inhibitory and receive inputs from a second-order interneuron upstream (Basin-2) and an ascending neuron downstream of Basin-2 (A00c). Together with optogenetic experiments showing that co-activation of SeIN128 neurons and Basin-2 influence the temporal dynamics of rolling, our findings collectively suggest that the ensemble of SeIN128, Basin-2, and A00c neurons forms a GABAergic feedback loop onto Basin-2, which inhibits rolling and thereby facilitates the shift to escape crawling.

Escape behaviors help animals avoid harm from predators and other threats in the environment. Successful escape relies on integrating information from multiple stimulus modalities (of external or internal origin) to compute trajectories toward safe locations, choose between actions that satisfy competing motivations, and execute other strategies that ensure survival. To this end, escape behaviors must be adaptive. When a Drosophila melanogaster larva encounters a noxious stimulus, such as the focal pressure a parasitic wasp applies to the larval cuticle via its ovipositor, it initiates a characteristic escape response. The escape sequence consists of an initial abrupt bending, lateral rolling, and finally rapid crawling. Previous work has shown that the detection of noxious stimuli primarily relies on class IV multi-dendritic arborization neurons (Class IV neurons) located beneath the body wall, and more recent studies have identified several important components in the nociceptive neural circuitry involved in rolling. However, the neural mechanisms that underlie the rolling-escape sequence remain unclear. Here, we present both functional and anatomical evidence suggesting that bilateral descending neurons within the subesophageal zone of D. melanogaster larva play a crucial role in regulating the termination of rolling and subsequent transition to escape crawling. We demonstrate that these descending neurons (designated SeIN128) are inhibitory and receive inputs from a second-order interneuron upstream (Basin-2) and an ascending neuron downstream of Basin-2 (A00c). Together with optogenetic experiments showing that co-activation of SeIN128 neurons and Basin-2 influence the temporal dynamics of rolling, our findings collectively suggest that the ensemble of SeIN128, Basin-2, and A00c neurons forms a GABAergic feedback loop onto Basin-2, which inhibits rolling and thereby facilitates the shift to escape crawling.

The locomotor repertoire of an individual can encompass a range of distinct motor patterns, all of which are encoded and coordinated by the nervous system. Despite diversity in these behaviours, each locomotor mode is enabled by a limited, common musculature. How neural circuits are organised to facilitate discrete patterns of locomotion is not well understood. Drosophila larvae invoke distinct locomotor patterns for either exploratory or nocifensive behaviours. Here we use optogenetics to perform a high-throughput behavioural screen of ventral nerve cord interneurons for their involvement in the performance of nocifensive behaviour. We identified a set of inhibitory premotor neurons (A02e neurons) which were sufficient to delay the onset of nocifensive behaviour. Behavioural characterisation of the A02e neurons revealed activity-dependent modulation of larval posture during escape behaviours, but not basal locomotor behaviours. Further, A02e-related premotor neurons, which recruit heterogeneous motor cohorts, showed differences in the modulation of both exploratory and nocifensive behaviours. Our results suggest that certain premotor neurons are differentially recruited between nocifensive and basal behaviours. Based on the neurons assayed we predict that the somatic lateral and dorsal muscles, but not ventral muscles, are particularly important for the initiation of larval escape behaviours. Therefore, whether a premotor neuron is necessary for the performance of a discrete behaviour, depends on the motor cohorts it innervates.

Abstract All animal behaviour must ultimately be governed by physical laws. As a basis for understanding the physics of behaviour in a simple system, we here develop an effective theory for the motion of the larval form of the fruitfly Drosophila melanogaster, and compare it against a quantitative analysis of the real animal’s behaviour. We first define a set of fields which quantify stretching, bending, and twisting along the larva’s antero- posterior axis, and then perform a search in the space of possible theories that could govern the long-wavelength physics of these fields, using a simplified approach inspired by the renormalisation group. Guided by symmetry considerations and stability requirements, we arrive at a unique, analytically tractable free-field theory with a minimum of free parameters. Unexpectedly, we are able to explain a wide-spectrum of features of Drosophila larval behaviour by applying equilibrium statistical mechanics: our theory closely predicts the animals’ postural modes (eigenmaggots), as well as distributions and trajectories in the postural mode space across several behaviours, including peristaltic crawling, rolling, self-righting and unbiased substrate exploration. We explain the low-dimensionality of postural dynamics via Boltzmann suppression of high frequency modes, and also propose and experimentally test, novel predictions on the relationships between different forms of body deformation and animal behaviour. We show that crawling and rolling are dominated by similar symmetry properties, leading to identical dynamics/statistics in mode space, while rolling and unbiased exploration have a common dominant timescale. Furthermore, we are able to demonstrate that self-righting behaviour occurs continuously throughout substrate exploration, owing to the decoupling of stretching, bending, and twisting at low energies. Together, our results demonstrate that relatively simple effective physics can be used to explain and predict a wide range of animal behaviours. Competing Interest Statement The authors have declared no competing interest. Footnotes * Manuscript restructured to improve clarity; incorporation of experimental data on rolling and self-righting behaviours; added a short argument on neuromuscular forcing effects within the main paper.

Escape behaviors help animals avoid harm from predators and other threats in the environment. Successful escape relies on integrating information from multiple stimulus modalities (of external or internal origin) to compute trajectories toward safe locations, choose between actions that satisfy competing motivations, and execute other strategies that ensure survival. To this end, escape behaviors must be adaptive. When a Drosophila melanogaster larva encounters a noxious stimulus, such as the focal pressure a parasitic wasp applies to the larval cuticle via its ovipositor, it initiates a characteristic escape response. The escape sequence consists of an initial abrupt bending, a corkscrew-like rolling, and finally rapid crawling. Previous work has shown that the detection of noxious stimuli primarily relies on class IV multi dendritic arborization neurons (Class IV neurons) located beneath the body wall, and more recent studies have identified several important components in the nociceptive neural circuitry involved in rolling. However, the neural mechanisms that underlie the rolling-escape sequence remain unclear. Here we present both functional and anatomical evidence suggesting that bilateral descending neurons within the subesophageal zone of D. melanogaster larva play a crucial role in regulating the termination of rolling and subsequent transition to escape crawling. We demonstrate that these descending neurons (designated SeIN128) are inhibitory and receive inputs from a second-order interneuron upstream (Basin-2) and an ascending neuron downstream of Basin-2 (A00c). Together with optogenetic experiments showing that joint stimulation of SeIN128 neurons and Basin-2 influence the temporal dynamics of rolling, our findings collectively suggest that the ensemble of SeIN128, Basin-2, and A00c neurons forms a GABAergic feedback loop onto Basin-2, which inhibits rolling and thereby facilitates the shift to escape crawling.Competing Interest StatementThe authors have declared no competing interest.Footnotes* Supplemental files uploaded.

Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system (CNS). Excitatory Amino Acid Transporters (EAATs) regulate extracellular glutamate by transporting it into cells, mostly glia, to terminate neurotransmission and to avoid neurotoxicity. EAATs are also chloride (Cl-) channels, but the physiological role of Cl- conductance through EAATs is poorly understood. Mutations of human EAAT1 (hEAAT1) have been identified in patients with episodic ataxia type 6 (EA6). One mutation showed increased Cl- channel activity and decreased glutamate transport, but the relative contributions of each function of hEAAT1 to mechanisms underlying the pathology of EA6 remain unclear. Here we investigated the effects of five additional EA6-related mutations on hEAAT1 function in Xenopus laevis oocytes, and on CNS function in a Drosophila melanogaster model of locomotor behavior. Our results indicate that mutations with decreased hEAAT1 Cl- channel activity and functional glutamate transport can also contribute to the pathology of EA6, highlighting the importance of Cl- homeostasis in glial cells for proper CNS function. We also identified a novel mechanism involving an ectopic sodium (Na+) leak conductance in glial cells. Together, these results strongly support the idea that EA6 is primarily an ion channelopathy of CNS glia. Competing Interest Statement The authors have declared no competing interest.

Reframing beliefs about illness, along with specialist rehabilitation, can help recovery in people with severe ME/CFS, write Alastair Miller, Fiona Symington, Paul Garner, and Maria Pedersen

Alagille syndrome is a rare genetic disease that often presents with severe cholestasis and pruritus. There are no approved drugs for management. Maralixibat, an apical, sodium-dependent, bile acid transport inhibitor, prevents enterohepatic bile acid recirculation. We evaluated the safety and efficacy of maralixibat for children with cholestasis in Alagille syndrome. ICONIC was a placebo-controlled, randomised withdrawal period (RWD), phase 2b study with open-label extension in children (aged 1–18 years) with Alagille syndrome (NCT02160782). Eligible participants had more than three times the normal serum bile acid (sBA) levels and intractable pruritus. After 18 weeks of maralixibat 380 μg/kg once per day, participants were randomly assigned (1:1) to continue maralixibat or receive placebo for 4 weeks. Subsequently, all participants received open-label maralixibat until week 48. During the long-term extension (204 weeks reported), doses were increased up to 380 μg/kg twice per day. The primary endpoint was the mean sBA change during the RWD in participants with at least 50% sBA reduction by week 18. Cholestastic pruritus was assessed using observer-rated, patient-rated, and clinician-rated 0–4 scales. The safety population was defined as all participants who had received at least one dose of maralixibat. This trial was registered with ClinicalTrials.gov, NCT02160782, and is closed to recruitment. Between Oct 28, 2014, and Aug 14, 2015, 31 participants (mean age 5·4 years [SD 4·25]) were enrolled and 28 analysed at week 48. Of the 29 participants who entered the randomised drug withdrawal period, ten (34%) were female and 19 (66%) were male. In the RWD, participants switched to placebo had significant increases in sBA (94 μmol/L, 95% CI 23 to 164) and pruritus (1·7 points, 95% CI 1·2 to 2·2), whereas participants who continued maralixibat maintained treatment effect. This study met the primary endpoint (least square mean difference –117 μmol/L, 95% CI –232 to –2). From baseline to week 48, sBA (–96 μmol/L, –162 to –31) and pruritus (–1·6 pts, –2·1 to –1·1) improved. In participants who continued to week 204 (n=15) all improvements were maintained. Maralixibat was generally safe and well tolerated throughout. The most frequent adverse events were gastrointestinal related. Most adverse events were self-limiting in nature and mild-to-moderate in severity. In children with Alagille syndrome, maralixibat is, to our knowledge, the first agent to show durable and clinically meaningful improvements in cholestasis. Maralixibat might represent a new treatment paradigm for chronic cholestasis in Alagille syndrome. Mirum Pharmaceuticals.

Although different detergents can give rise to detergent-resistant membranes of different composition, it is unclear whether this represents domain heterogeneity in the original membrane. We compared the mechanism of action of five detergents on supported lipid bilayers composed of equimolar sphingomyelin, cholesterol, and dioleoylphosphatidylcholine imaged by atomic force microscopy, and on raft and nonraft marker proteins in live cells imaged by confocal microscopy. There was a marked correlation between the detergent solubilization of the cell membrane and that of the supported lipid bilayers. In both systems Triton X-100 and CHAPS (3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate) distinguished between the nonraft liquid-disordered (l d) and raft liquid ordered (l o) lipid phases by selectively solubilizing the l d phase. A higher concentration of Lubrol was required, and not all the l d phase was solubilized. The solubilization by Brij 96 occurred by a two-stage mechanism that initially resulted in the solubilization of some l d phase and then progressed to the solubilization of both l d and l o phases simultaneously. Octyl glucoside simultaneously solubilized both l o and l d phases. These data show that the mechanism of membrane solubilization is unique to an individual detergent. Our observations have significant implications for using different detergents to isolate membrane rafts from biological systems.