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Amyotrophic lateral sclerosis (ALS) consists of a group of adult-onset fatal and incurable neurodegenerative disorders characterized by the progressive death of motor neurons (MNs) throughout the central nervous system (CNS). At first, ALS was considered to be an MN disease, caused by cell-autonomous mechanisms acting specifically in MNs. Accordingly, data from ALS patients and ALS animal models revealed alterations in excitability in multiple neuronal populations, including MNs, which were associated with a variety of cellular perturbations such as protein aggregation, ribonucleic acid (RNA) metabolism defects, calcium dyshomeostasis, modified electrophysiological properties, and autophagy malfunctions. However, experimental evidence rapidly demonstrated the involvement of other types of cells, including glial cells, in the etiopathogenesis of ALS through non-cell autonomous mechanisms. Surprisingly, the contribution of pre-motor interneurons (INs), which regulate MN activity and could therefore critically modulate their excitability at the onset or during the progression of the disease, has to date been severely underestimated. In this article, we review in detail how spinal pre-motor INs are affected in ALS and their possible involvement in the etiopathogenesis of the disease.

Gonadotropin-releasing hormone (GnRH) neurons are the final target of a complex network regulating reproduction. The balance between excitatory and inhibitory inputs is essential for rhythmic GnRH secretion, including pulses and surges, yet the underlying mechanisms remain unresolved. Here, using adult animals of both sexes, we test the hypothesis that excitatory kisspeptin and inhibitory neuronal nitric oxide (NO) synthase (nNOS)-derived inputs orchestrate GnRH release within a microcircuit of kisspeptin, nNOS and GnRH neurons (the “KiNG” network). We focus on nNOS neurons of the organum vasculosum of the lamina terminalis (OV) and the median preoptic nucleus (MePO), which interact with kisspeptin and exhibit cycle-dependent kisspeptin receptor (Kiss1r) expression. Using a highly-sensitive NO/cGMP biosensor together with electrophysiological, genetic, chemogenetic and pharmacological approaches we demonstrate that kisspeptin induces NO-dependent cGMP production in the OV/MePO, including in GnRH neurons, which in turn fine-tunes the GnRH/LH response, providing mechanistic insights into how the KiNG network shapes pulse and surge generation. LH secretion rhythms are coordinated by neuronal signaling in the hypothalamus. Here, authors show that kisspeptin-activated nNOS–NO signaling inhibits GnRH neurons, establishing a dual activation–inhibition mechanism to generate LH pulses and surges.

In freshwater environments, the relative contributions of top-down and bottom-up effects on invertebrate communities in relation to productivity are largely ecosystem dependent. Artificial wetlands are increasingly developed to compensate for the loss of natural wetlands; however, their trophic processes remain poorly studied. The present study aimed to evaluate the respective contributions of bottom-up and top-down processes in structuring benthic food webs of three artificial wetlands with varying levels of benthic primary productivity. We found that phototrophic-based food webs in our artificial wetlands were controlled from the bottom-up by primary productivity and algal biomass developing at the water–sediment interface. No significant top-down control of herbivore species by invertebrate predators was detected even in the wetland with the highest productivity. Increased richness of invertebrate grazers and scrapers with benthic primary productivity and algal biomass might have dampened the trophic cascade from predators to primary producers. In contrast with the phototrophic-based food web, analyses performed on the detritus-based food web showed that deposit-feeder invertebrate abundance was not correlated with the quantity of organic matter in sediments, suggesting no bottom-up effect of sedimentary organic matter content on deposit-feeders. More surprisingly, deposit-feeders, especially aquatic oligochaetes, seemed to influence the detritus-based food webs by stimulating organic matter processing and bacterial growth through bioturbation. The present study highlights the occurrence of contrasting trophic processes between phototrophic-based and detritus-based food webs which can have implications on ecosystem functions, such as nutrient cycling and energy fluxes.

The opening of ligand‐gated ion channels in response to agonist binding is a fundamental process in biology. In ATP‐gated P2X receptors, little is known about the molecular events that couple ATP binding to channel opening. In this paper, we identify structural changes of the ATP site accompanying the P2X2 receptor activation by engineering extracellular zinc bridges at putative mobile regions as revealed by normal mode analysis. We provide evidence that tightening of the ATP sites shaped like open ‘jaws’ induces opening of the P2X ion channel. We show that ATP binding favours jaw tightening, whereas binding of a competitive antagonist prevents gating induced by this movement. Our data reveal the inherent dynamic of the binding jaw, and provide new structural insights into the mechanism of P2X receptor activation. P2X receptors are ATP‐gated ion channels involved in many processes, including synaptic transmission and sensory signalling, but their gating mechanism is still ill understood. This study reveals that extracellular ATP opens the channel by tightening nucleotide‐binding sites that are shaped like open ‘jaws’

Glutamate delta (GluD) receptors belong to the ionotropic glutamate receptor family, yet they don’t bind glutamate and are considered orphan. Progress in defining the ion channel function of GluDs in neurons has been hindered by a lack of pharmacological tools. Here, we used a chemo-genetic approach to engineer specific and photo-reversible pharmacology in GluD2 receptor. We incorporated a cysteine mutation in the cavity located above the putative ion channel pore, for site-specific conjugation with a photoswitchable pore blocker. In the constitutively open GluD2 Lurcher mutant, current could be rapidly and reversibly decreased with light. We then transposed the cysteine mutation to the native receptor, to demonstrate with high pharmacological specificity that metabotropic glutamate receptor signaling triggers opening of GluD2. Our results assess the functional relevance of GluD2 ion channel and introduce an optogenetic tool that will provide a novel and powerful means for probing GluD2 ionotropic contribution to neuronal physiology. Neurotransmitters are chemicals released by the body that trigger activity in neurons. Receptors on the surface of neurons detect these neurotransmitters, providing a link between the inside and the outside of the cell. Glutamate is one of the major neurotransmitters and is involved in virtually all brain functions. Glutamate binds to two different types of receptors in neurons. Ionotropic receptors have pores known as ion channels, which open when glutamate binds. This is a fast-acting response that allows sodium ions to flow into the neuron, triggering an electrical signal. Metabotropic receptors, on the other hand, trigger a series of events inside the cell that lead to a response. Metabotropic receptors take more time than ionotropic receptors to elicit a response in the cell, but their effects last much longer. One type of receptor, known as the GluD family, is very similar to ionotropic glutamate receptors but does not directly respond to glutamate. Instead, the ion channel of GluD receptors opens after being activated by glutamate metabotropic receptors. GluD receptors are produced throughout the brain and play roles in synapse formation and activity, but the way they work remains unclear. An obstacle to understanding how GluD receptors work is the lack of molecules that can specifically block these receptors’ ion channel activity. Lemoine et al. have developed a tool that enables control of the ion channel in GluD receptors using light. Human cells grown in the lab were genetically modified to produce a version of GluD2 (a member of the GluD family) with a light-sensitive molecule attached. In darkness or under green light, the light-sensitive molecule blocks the channel and prevents ions from passing through. Under violet light, the molecule twists, and ions can flow through the channel. With this control over the GluD2 ion channel activity, Lemoine et al. were able to validate previous research showing that the activation of metabotropic glutamate receptors can trigger GluD2 to open. The next step will be to test this approach in neurons. This will help researchers to understand what role GluD ion channels play in neuron to neuron communication.

Although patterns of seedling selection by herbivores are strongly influenced by plant age and the expression of anti-herbivore defence, it is unclear how these characteristics interact to influence seedling susceptibility to herbivory. We tracked ontogenetic changes in a range of secondary metabolites (total phenolics, alkaloids and cyanogenic glycosides) commonly associated with seedling defence for nine sympatric British grassland species. Although there was marked variation in concentrations of secondary metabolites between different species, we found a consistent increase in the deployment of phenolics, alkaloids and cyanogenics with seedling age for six of the seven dicotyledonous species examined. The two grass species by contrast exhibited low levels of secondary metabolites across all developmental stages, possibly due to an investment in structural (silica phytoliths) defence. Our results corroborate species-specific patterns of seedling herbivory observed in field studies, and offer some explanation for the relatively high sensitivity to herbivore attack frequently observed for relatively young seedlings compared with their older conspecifics. Our results also support predictions made by the growth-differentiation balance hypothesis regarding ontogenetic changes in resource allocation to anti-herbivore defence for a range of potential chemical defences and across a range of sympatric plant species presumably subject to broadly similar selective pressures at the regeneration stage.

Long-term exposure to nicotine alters brain circuits and induces profound changes in decision-making strategies, affecting behaviors both related and unrelated to drug seeking and consumption. Using an intracranial self-stimulation reward-based foraging task, we investigated in mice the impact of chronic nicotine on midbrain dopamine neuron activity and its consequence on the trade-off between exploitation and exploration. Model-based and archetypal analysis revealed substantial inter-individual variability in decision-making strategies, with mice passively exposed to nicotine shifting toward a more exploitative profile compared to non-exposed animals. We then mimicked the effect of chronic nicotine on the tonic activity of dopamine neurons using optogenetics, and found that photo-stimulated mice adopted a behavioral phenotype similar to that of mice exposed to chronic nicotine. Our results reveal a key role of tonic midbrain dopamine in the exploration/exploitation trade-off and highlight a potential mechanism by which nicotine affects the exploration/exploitation balance and decision-making. Chronic nicotine exposure impacts various components of decision-making processes, such as exploratory behaviors. Here, the authors identify the cellular mechanism and show that chronic nicotine exposure increases the tonic activity of VTA dopaminergic neurons and reduces exploration in mice.

1. Positive interactions driven by ecosystem engineers have been determined to be important community forces in stressed environments. By ameliorating habitat conditions, ecosystem engineering can create available ecological niches for other species. In poorly oxygenated sediments of freshwater wetlands, small invertebrates such as tubificid worms and chironomid larvae are known to function as active bioturbators; however, their effects on the growth and physiology of organisms which are constrained by low oxygénation of sediments have never been studied. 2. We examined whether the common bioturbator, Tubifex tubifex, significantly influences the growth and the physiological state of two plant species, Elodea canadensis and Myriophyllum spicatum, in experimental systems simulating a water-sediment interface of wetlands. We also quantified the influence of plant-animal interactions on biogeochemical processes (fluxes of oxygen and nitrogen at the water-sediment interface) and microbial compartment in sediments. 3. Tubificid worms stimulated growth of aboveground and belowground biomasses of the two plants through reduction in the anoxic stress in sediments. Myriophyllum spicatum, which was the best adapted to sedimentary anaerobic conditions, essentially increased its biomass whereas E. canadensis, less adapted to anaerobic conditions, shifted its root metabolism from anaerobic to aerobic. 4. Biogeochemical processes were not significantly influenced by plant-animal interactions: (i) oxygen flux from overlying water to sediments probably reached a threshold that could not be raised by the increased plant biomass induced by worms and (ii) nitrogen fluxes were essentially linked to bioturbation activities of worms. 5. Our study confirmed that the reduction in constraining variables by physical habitat modifications (ecosystem engineering) may play a crucial role in community and ecosystem processes. The fact that positive interactions measured between ecosystem engineers and plant species in anoxic wetland sediments were highly dependent on the ecophysiology of plant species suggests an extension of this first study to a wide range of macrophytes in order to determine the main plant functional traits driving plant-animal interactions in wetland sediments.

Dopamine (DA) neurons of the ventral tegmental area (VTA) integrate cholinergic inputs to regulate key functions such as motivation and goal-directed behaviors. Yet the temporal dynamic range and mechanism of action of acetylcholine (ACh) on the modulation of VTA circuits and reward-related behaviors are not known. Here, we used a chemical-genetic approach for rapid and precise optical manipulation of nicotinic neurotransmission in VTA neurons in living mice. We provide direct evidence that the ACh tone fine-tunes the firing properties of VTA DA neurons through β2-containing (β2*) nicotinic ACh receptors (nAChRs). Furthermore, locally photo-antagonizing these receptors in the VTA was sufficient to reversibly switch nicotine reinforcement on and off. By enabling control of nicotinic transmission in targeted brain circuits, this technology will help unravel the various physiological functions of nAChRs and may assist in the design of novel therapies relevant to neuropsychiatric disorders. Acetylcholine is one of the most abundant chemicals in the brain, with key roles in learning, memory and attention. Neurons throughout the brain use acetylcholine to exchange messages. Acetylcholine binds to two different classes of receptors on neurons: nicotinic and muscarinic. As the name suggests, nicotinic receptors also respond to nicotine, the main addictive substance in tobacco, while muscarinic receptors respond to muscarine, present in certain poisonous mushrooms. Nicotinic and muscarinic receptors each consist of many different subtypes. But standard pharmacology techniques cannot discriminate between the effects of acetylcholine binding to these different subtypes. Likewise, they cannot distinguish between acetylcholine binding to the same receptor subtype on different neurons. Durand-de Cuttoli, Mondoloni et al. have now developed a new nanotechnology that uses light to target specific acetylcholine receptor subtypes in freely moving mice. The technology was tested in a brain region called the VTA, which is part of the brain’s reward system. Experiments showed that when acetylcholine binds to a specific subtype of nicotinic receptors on VTA neurons – called β2-containing receptors – it makes the neurons release the brain's reward signal, dopamine. Switching these receptors on and off changed how the mice responded to nicotine. With the receptors switched on, mice preferred locations associated with nicotine. Switching the receptors off removed this preference. Nicotine may thus be addictive in part because it triggers VTA neurons to release dopamine via its actions on β2-containing nicotinic receptors. This new technology will help reveal the mechanisms of action of acetylcholine and nicotine. Blocking the effects of nicotine at a specific time and place in the mouse brain may uncover the receptors and brain regions that drive nicotine consumption. Smoking remains a major cause of preventable death worldwide. This new approach could help us develop strategies to prevent or treat addiction.

The powerful optogenetic pharmacology method allows the optical control of neuronal activity by photoswitchable ligands tethered to channels and receptors. However, this approach is technically demanding, as it requires the design of pharmacologically active ligands. The development of versatile technologies therefore represents a challenging issue. Here, we present optogating, a method in which the gating machinery of an ATP-activated P2X channel was reprogrammed to respond to light. We found that channels covalently modified by azobenzene-containing reagents at the transmembrane segments could be reversibly turned on and off by light, without the need of ATP, thus revealing an agonist-independent, light-induced gating mechanism. We demonstrate photocontrol of neuronal activity by a light-gated, ATP-insensitive P2X receptor, providing an original tool devoid of endogenous sensitivity to delineate P2X signaling in normal and pathological states. These findings open new avenues to specifically activate other ion channels independently of their natural stimulus.