Biology subjects

Megighian, A.

Publications and source records attributed to Megighian, A..

10 recordsLinked to original sources

bioRxiv2026

Repellent olfactory cues influence the optomotor response modulation in Drosophila melanogaster

Animals need to precisely perceive and integrate the environmental cues to orient and select the appropriate motor responses required for navigating. This is the case, for instance, of the optokinetic reflex (OKR) and the optomotor response (OMR) in Drosophila melanogaster, where optic flow stimulation modulates the head or the body and legs motor activity respectively. Despite large bodies of literature on both the OKR and the OMR, there is still a limited understanding, in flies, of the impact on these responses of concomitant, and potentially conflicting, sensory inputs. To investigate this aspect, we used fruit flies walking on a sphere, presented with optic flow stimulation leading to the OMR together with the simultaneous exposure to olfactory stimulation, either using established repellent or masking compounds. We analysed the effect of different substances, and of their concentration, on the dynamics of the flies response to moving gratings, evaluating the fly walking path as well as average speed and duration. This analysis revealed several alterations between the compounds tested, in agreement with reported data on the simpler OKR. In conclusion, we show that concomitant exposure to repellents and maskers may consistently affect fundamental processes (the OKR and OMR) available to insects for informing themselves while navigating through the environment.

animal behavior and cognition↗

bioRxiv2025

Targeting Neuromuscular Junction Regeneration is a Therapeutic Strategy in ALS

Instability and denervation of the neuromuscular junction (NMJ) are early events in Amyotrophic Lateral Sclerosis (ALS), likely reflecting a progressive decline in the regenerative capacity of motor neurons (MNs) and their environment. To investigate this, we evaluated NMJ regeneration throughout disease progression in SOD1G93A mice following reversible axon terminal degeneration induced by -Latrotoxin. In parallel, we monitored the expression of CXCR4, a GPCR upregulated during axonal regeneration, and tested whether its pharmacological activation could mitigate ALS- related functional decline. We found that NMJ regenerative capacity is largely preserved during pre- and early symptomatic stages, and remains active in subsets of NMJs even at later stages. CXCR4 is expressed at axon terminals from early disease stages, declining only at end stage. Its expression is conserved across ALS models, including SOD1G93A pigs, hiPSC-derived MN with ALS mutations, and biopsies from sporadic ALS patients. CXCR4 stimulation improved motor function, NMJ innervation, MN survival, and respiratory performance in ALS mice, and axon outgrowth in iPSC-derived MN. These findings identify the NMJ and CXCR4 as viable therapeutic targets in ALS.

neuroscience↗

bioRxiv2025

Motor history influences behavioral strategy more than response outcome in Drosophila melanogaster

In an ever-changing environment, animals continuously implement decision-making processes. This mechanism primarily relies on gathering sensory information through evidence accumulation, which enables the optimization of strategies in uncertain conditions. According to this scheme, the higher the evidence level, the greater the level of accuracy. However, it is not yet clear which, apart from direct sensory inputs, are the other factors that potentially impact strategy selection and their corresponding temporal operating windows in invertebrates. Moreover, it is not guaranteed that maximal accuracy could be the only parameter dictating the decision-making process. To address these questions, we employed a visual stimulation paradigm based on the random dot motion kinetogram (RDMk) with varying coherence levels, applied to tethered Drosophila melanogaster. In this scenario, flies tend to turn their heads according to the optic flows strength and direction. We observed stereotyped head saccadic-like movements across all the RDMk coherence levels, with greater coherence leading to a higher total saccade number and an increased proportion of correct turns. Importantly, logistic regression analysis revealed that, besides sensory inputs, the behavioral outcome and, consequently, the maximal accuracy, are influenced by other factors, in particular the past motor activity. In conclusion, our data support a scenario where accuracy and reaction time are balanced to reach an optimal response condition.

animal behavior and cognition↗

bioRxiv2024

Low Intestinal Doses of Botulinum Neurotoxins types A and B favour infection by Salmonella and Shigella without the flaccid paralysis of botulism

Botulism is a life-threatening disease characterized by a descending flaccid paralysis caused by a protein neurotoxin (BoNT) released by different anaerobic bacterial species of the genus Clostridium. The paralysis results from blockade of neurotransmitter release from the terminals of peripheral cholinergic, skeletal and autonomic neurons exerted by BoNT through the cleavage of SNARE proteins, which are essential for neuroexocytosis. Here, we investigated the effect of different doses of BoNT serotypes A and B, the serotypes most commonly associated with human botulism, on enteric nervous system neurons which play an important role in gut health and physiology. We found that BoNT/A and BoNT/B enter cholinergic neurons where they cleave SNARE proteins even at doses that do not cause signs of flaccid neuroparalysis. However, these low BoNT doses favour the invasion and infection of the mouse body by Salmonella thyphimurium and Shigella flexneri. This may have significant animal health implications.

neuroscience↗

bioRxiv2024

Optokinetic response in D. Melanogaster reveals the nature of common repellent odorants.

Animals ability to orient and navigate relies on selecting an appropriate motor response based on the perception and integration of the environmental information. This is the case, for instance, of the optokinetic response (OKR) in Drosophila melanogaster, where optic flow visual stimulation modulates the walking or flying patterns. Despite a large body of literature on the OKR, theres still a limited understanding of the impact on OKR of concomitant, potentially conflicting, inputs. To evaluate the impact of this multimodal integration, we combined in D. melanogaster, while flying in a tethered condition, the optic flow stimulation leading to OKR with the simultaneous presentation of olfactory cues, based on repellent or masking compounds typically used against noxious insect species. First, this approach al lowed us to directly quantify the effect of several substances and their concentration, on the dynamics of the flies OKR in response to moving gratings by evaluating the number of saccades and the velocity of its slow phase. Subsequently, this analysis was capable of easily revealing the actual effect, i.e. masking vs repellent, of the compound tested. In conclusion, we show that D. melanogaster, a cost-affordable species, represents a viable option for studying the effects of several compounds on the navigational abilities of insects.

animal behavior and cognition↗

bioRxiv2023

Agonists of melatonin receptors strongly promote the functional recovery from the neuroparalysis induced by neurotoxic snakes

Snake envenoming is a major, but neglected, tropical disease. Among venomous snakes, those inducing neurotoxicity such as kraits (Bungarus genus) cause a potentially lethal peripheral neuroparalysis with respiratory deficit in a large number of people each year. In order to prevent the development of a deadly respiratory paralysis, hospitalization with pulmonary ventilation and use of antivenoms are the primary therapies currently employed. However, hospitals are frequently out of reach for envenomated patients and there is a general consensus that additional, non-expensive treatments, deliverable even long after the snake bite, are needed. Traumatic or toxic degenerations of peripheral motor neurons cause a neuroparalysis that activates a pro-regenerative intercellular signaling program taking place at the neuromuscular junction (NMJ). We recently reported that the intercellular signaling axis melatonin-melatonin receptor 1 (MT1) plays a major role in the recovery of function of the NMJs after degeneration of motor axon terminals caused by massive Ca2+ influx. Here we show that the small chemical MT1 agonists: Ramelteon and Agomelatine, already licensed for the treatment of insomnia and depression, respectively, are strong promoters of the neuroregeneration after paralysis induced by krait venoms in mice, which is also Ca2+ mediated. The venom from a Bungarus species representative of the large class of neurotoxic snakes (including taipans, coral snakes, some Alpine vipers in addition to other kraits) was chosen. The functional recovery of the NMJ was demonstrated using electrophysiological, imaging and lung ventilation detection methods. According to the present results, we propose that Ramelteon and Agomelatine should be tested in human patients bitten by neurotoxic snakes acting presynaptically to promote their recovery of health. Noticeably, these drugs are commercially available, safe, non-expensive, have a long bench life and can be administered long after a snakebite even in places far away from health facilities. SynopsisSnakebite envenomings cause important tropical human diseases that often include a lethal muscle paralysis. Current treatments consist in hospitalization and antivenoms, which are not always quickly accessible to victims. In fact, these snakebites take place mainly in rural and low income countries. In this work, researchers discovered, in mice, a novel function of melatonin and of its type 1 receptor in promoting functional recovery after snake-induced peripheral neuroparalysis with nerve terminal degeneration. In particular, researchers found that drugs approved for the treatment of insomnia (Ramelteon) and depression (Agomelatine), activate melatonin receptor and promote the functional recovery after a krait venom induced paralysis. These drugs are on sell in pharmacies, are safe and stable, and are ready to be tried for promoting the recovery from peripheral neuroparalysis in human victims bitten by neurotoxic snakes, even without hospitalization.

pharmacology and toxicology↗

bioRxiv2020

Hierarchical Spatial Search Strategies in Drosophila

Humans rely on multiple systems of sensory information to make decisions. However, strategies that shorten decision-making time by taking into account fewer but more essential elements of information are preferred to strategies involving complex analyses. These "shortcuts to decision" are also termed "heuristics". The identification of heuristic principles in species phylogenetically distant to humans would shed light on the evolutionary origin of speed-accuracy trade-offs and offer the possibility to investigate the brain representations of such trade-offs, urgency, and uncertainty. During experiments on spatial learning, we acknowledged that the search strategies of the invertebrate Drosophila melanogaster, the common fruit fly, resembled a spatial heuristic. Here we show that the fruit fly applies a heuristic termed the "Nearest Neighbour Rule" to avoid bitter taste (a negative stimulation). That is, the fly visits the salient location closest to its current position to hopefully stop the negative stimulation. Only if this strategy proves unsuccessful, the animal uses other learned associations to avoid bitter taste. The acknowledgement of a heuristic in D. melanogaster supports the view that invertebrates can leverage on economic principles when making choices and that the existence of heuristics in evolution dates to at least 600 million years ago.

neuroscience↗

bioRxiv2019

Searching for relief: Drosophila melanogaster navigation in a virtual bitter maze

Animals use pain-relief learning to discern which actions can diminish or abolish noxious stimuli. If relief from pain is provided in a specific location, place learning is the mechanism used to pinpoint that location in space. Little is known about how physiological and non-directly damaging stimuli can alter visual-based searching behaviour in animals. Here we show how the optogenetically-induced activation of bitter-sensing neurons urges Drosophila melanogaster to seek relief from bitter taste stimulation and that this distressful, but ecologically relevant stimulus, innately wired to the threat of intoxication, is sufficient to elicit pain-relief-like behavioural responses. Specifically, freely walking flies inside an open circular arena are trained to seek relief from the unpleasant stimulation by searching for a safe area alternatively positioned in the proximity of a pair of identical, diametrically opposed, visual markers. Moreover, and perhaps more importantly, under this paradigm flies develop visual place learning manifested by their seeking relief in the zone associated with bitter relief during the last trial of training, even when exposed to constant bitter stimulation with no relief provided. An important implication is that this form of learning does not lead to operant conditioning generalization. We further propose that kinematic indexes, such as the spatially-specific reduction of locomotor velocity, may provide immediate evidence of relief-based place learning and spatial memory.

animal behavior and cognition↗

bioRxiv2019

TDP-43 regulates the expression levels of Disc-large in skeletal muscles to promote the assemble of the neuromuscular synapses in Drosophila

BackgroundAlterations in the intracellular distribution of TDP-43 were observed in the skeletal muscles of patients suffering from ALS. However, it is not clear whether these modifications play an active role in the disease or represent a physiological adaptation to muscles homeostasis.\n\nResultTo answer these questions, we modulated the activity of this protein in Drosophila muscles and observed that TDP-43 was required in these tissues to promote the formation and growth of the neuromuscular synapses. Moreover, we identified that TDP-43 regulates the expression levels of Disc-large (Dlg) and demonstrated that the modulation of Dlg activity, in skeletal muscles or motoneurons, was sufficient to recover the TDP-43-null locomotive and synaptic defects in flies. Additionally, we found that similar mechanisms are conserved in human cell lines and present in tissues derived from ALS patients.\n\nConclusionsOur results uncover the physiological role of TDP-43 in skeletal muscles as well as the mechanisms behind the autonomous and non-autonomous behavior of this protein in the organization of the neuromuscular synapses.

neuroscience↗

bioRxiv2018

Mechanisms of selection for the control of action in Drosophila melanogaster

In the last few years several studies have investigated the neural mechanisms underlying spatial orientation in Drosophila melanogaster. Convergent results suggest that this mechanism is associated with specific neural circuits located within the Central Complex (CC). Furthermore such circuits appear to be associated with visual attention, specifically with selective attention processes implicated in the control of action. Our aim was to understand how wild-type flies react to the abrupt appearance of a visual distractor during an ongoing locomotor action. Thus, we adapted the well-known Buridan paradigm, used to study walking behaviour in flies, so we could specifically address the mechanisms involved in action selection. We found that flies tended to react in one of two ways when confronted with a visual distractor during ongoing locomotion. Flies either: (i) committed to a new path situated midway between the original target and the distractor, consistent with a novelty effect; or (ii) remained on the original trajectory with a slight deviation in direction of the distractor. We believe that these results provide the first indication of how flies react, from the motor point of view, in a bi-stable context requiring the presence of selection-for-action mechanisms. Some considerations on the neural circuits underlying such behavioural responses are advanced.

animal behavior and cognition↗