Impaired neuronal plasticity and cognitive decline are cardinal features of Alzheimer's disease and related Tauopathies. Aberrantly modified Tau protein and neurotransmitter imbalance, predominantly involving acetylcholine, have been linked to these symptoms. In Drosophila, we have shown that dTau loss specifically enhances associative long-term olfactory memory, impairs foot shock habituation, and deregulates proteins involved in the regulation of neurotransmitter levels, particularly acetylcholine.
View Article and Find Full Text PDFNeurofibromatosis 1 (NF1) is a multisymptomatic disorder with highly variable presentations, which include short stature, susceptibility to formation of the characteristic benign tumors known as neurofibromas, intense freckling and skin discoloration, and cognitive deficits, which characterize most children with the condition. Attention deficits and Autism Spectrum manifestations augment the compromised learning presented by most patients, leading to behavioral problems and school failure, while fragmented sleep contributes to chronic fatigue and poor quality of life. Neurofibromin (Nf1) is present ubiquitously during human development and postnatally in most neuronal, oligodendrocyte, and Schwann cells.
View Article and Find Full Text PDFTauopathies including Alzheimer's disease, are characterized by progressive cognitive decline, neurodegeneration, and intraneuronal aggregates comprised largely of the axonal protein Tau. It has been unclear whether cognitive deficits are a consequence of aggregate accumulation thought to compromise neuronal health and eventually lead to neurodegeneration. We use the tauopathy model and mixed-sex populations to reveal an adult onset pan-neuronal Tau accumulation-dependent decline in learning efficacy and a specific defect in protein synthesis-dependent memory (PSD-M), but not in its protein synthesis-independent variant.
View Article and Find Full Text PDFThe ability to learn from the consequences of one's actions, extracting useful information from threatening, painful or rewarding encounters and developing the skill of predicting probable events from pre-experienced stimuli, is essential for survival and reproductive success [...
View Article and Find Full Text PDFAccumulation of highly post-translationally modified tau proteins is a hallmark of neurodegenerative disorders known as tauopathies, the most common of which is Alzheimer's disease. Although six tau isoforms are found in the human brain, the majority of animal and cellular tauopathy models utilize a representative single isoform. However, the six human tau isoforms present overlapping but distinct distributions in the brain and are differentially involved in particular tauopathies.
View Article and Find Full Text PDFHabituation is a conserved adaptive process essential for incoming information assessment, which drives the behavioral response decrement to recurrent inconsequential stimuli and does not involve sensory adaptation or fatigue. Although the molecular mechanisms underlying the process are not well understood, habituation has been reported to be defective in a number of disorders including schizophrenia. We demonstrate that loss of , the homolog of a gene whose transcriptional downregulation has been linked to schizophrenia, results in defective habituation to recurrent footshocks in mixed sex populations.
View Article and Find Full Text PDFMemories are lasting representations over time of associations between stimuli or events. In general, the relatively slow consolidation of memories requires protein synthesis with a known exception being the so-called Anesthesia Resistant Memory (ARM) in Drosophila. This protein synthesis-independent memory type survives amnestic shocks after a short, sensitive window post training, and can also emerge after repeated cycles of training in a negatively reinforced olfactory conditioning task, without rest between cycles (massed conditioning-MC).
View Article and Find Full Text PDFMemory consolidation is a time-dependent process occurring over hours, days, or longer in different species and requires protein synthesis. An apparent exception is a memory type in elicited by a single olfactory conditioning episode, which ostensibly consolidates quickly, rendering it resistant to disruption by cold anesthesia a few hours post-training. This anesthesia-resistant memory (ARM), is independent of protein synthesis.
View Article and Find Full Text PDFHoneybees (Apis mellifera) continue to succumb to human and environmental pressures despite their crucial role in providing essential ecosystem services. Owing to their foraging and honey production activities, honeybees form complex relationships with species across all domains, such as plants, viruses, bacteria and other hive pests, making honey a valuable biomonitoring tool for assessing their ecological niche. Thus, the application of honey shotgun metagenomics (SM) has paved the way for a detailed description of the species honeybees interact with.
View Article and Find Full Text PDFActa Neuropathol Commun
April 2022
Tau accumulation is clearly linked to pathogenesis in Alzheimer's disease and other Tauopathies. However, processes leading to Tau fibrillization and reasons for its pathogenicity remain largely elusive. Mical emerged as a novel interacting protein of human Tau expressed in Drosophila brains.
View Article and Find Full Text PDFCognitive dysfunction is among the hallmark symptoms of Neurofibromatosis 1, and accordingly, loss of the ortholog of Neurofibromin 1 (dNf1) precipitates associative learning deficits. However, the affected circuitry in the adult CNS remained unclear and the compromised mechanisms debatable. Although the main evolutionarily conserved function attributed to Nf1 is to inactivate Ras, decreased cAMP signaling on its loss has been thought to underlie impaired learning.
View Article and Find Full Text PDFHyperphosphorylated Tau protein is the main component of the neurofibrillary tangles, characterizing degenerating neurons in Alzheimer's disease and other Tauopathies. Expression of human Tau protein in Drosophila CNS results in increased toxicity, premature mortality and learning and memory deficits. Herein we use novel transgenic lines to investigate the contribution of specific phosphorylation sites previously implicated in Tau toxicity.
View Article and Find Full Text PDFTauopathies are a heterogeneous group of neurodegenerative dementias involving perturbations in the levels, phosphorylation or mutations of the neuronal microtubule-binding protein Tau. Tauopathies are characterized by accumulation of hyperphosphorylated Tau leading to formation of a range of aggregates including macromolecular ensembles such as Paired Helical filaments and Neurofibrilary Tangles whose morphology characterizes and differentiates these disease states. Why nonphysiological Tau proteins elude the surveillance normal proteostatic mechanisms and eventually form these macromolecular assemblies is a central mostly unresolved question of cardinal importance for diagnoses and potential therapeutic interventions.
View Article and Find Full Text PDFHabituation is the adaptive behavioral outcome of processes engaged in timely devaluation of non-reinforced repetitive stimuli, but the neuronal circuits and molecular mechanisms that underlie them are not well understood. To gain insights into these processes we developed and characterized a habituation assay to repetitive footshocks in mixed sex groups and demonstrated that acute neurotransmission from adult α/β mushroom body (MB) neurons prevents premature stimulus devaluation. Herein we demonstrate that activity of the non-receptor tyrosine kinase dBtk protein is required within these neurons to prevent premature habituation.
View Article and Find Full Text PDFAlthough the involvement of pathological tau in neurodegenerative dementias is indisputable, its physiological roles have remained elusive in part because its abrogation has been reported without overt phenotypes in mice and This was addressed using the recently described and Mi{MIC} mutants and focused on molecular and behavioral analyses. Initially, we show that tau (dTau) loss precipitates dynamic cytoskeletal changes in the adult CNS and translation upregulation. Significantly, we demonstrate for the first time distinct roles for dTau in adult mushroom body (MB)-dependent neuroplasticity as its downregulation within α'β'neurons impairs habituation.
View Article and Find Full Text PDFHabituation is the process whereby perceptual changes alter the value of environmental stimuli, enabling salience filtering. This behavioral response decrement is a form of non-associative learning, where the subject learns about the stimulus and does not involve sensory adaptation, sensory or motor fatigue. The range of behavioral responses in led to the development of a number of habituation paradigms addressing various sensory modalities.
View Article and Find Full Text PDFWe used Drosophila melanogaster as an experimental model to express mouse and pig BM88/CEND1 (cell cycle exit and neuronal differentiation 1) in order to investigate its potential functional effects on Drosophila neurogenesis. BM88/CEND1 is a neuron-specific protein whose function is implicated in triggering cells to exit from the cell cycle and differentiate towards a neuronal phenotype. Transgenic flies expressing either mouse or pig BM88/CEND1 in the nervous system had severe neuronal phenotypes with variable expressivity at various stages of embryonic development.
View Article and Find Full Text PDFExpert Opin Drug Discov
March 2019
Drosophila melanogaster offers a powerful expedient and economical system with facile genetics. Because of the high sequence and functional conservation with human disease-associated genes, it has been cardinal in deciphering disease mechanisms at the genetic and molecular level. Drosophila are amenable to and respond well to pharmaceutical treatment which coupled to their genetic tractability has led to discovery, repositioning, and validation of a number of compounds.
View Article and Find Full Text PDFUnlabelled: Habituation is the process that enables salience filtering, precipitating perceptual changes that alter the value of environmental stimuli. To discern the neuronal circuits underlying habituation to brief inconsequential stimuli, we developed a novel olfactory habituation paradigm, identifying two distinct phases of the response that engage distinct neuronal circuits. Responsiveness to the continuous odor stimulus is maintained initially, a phase we term habituation latency and requires Rutabaga Adenylyl-Cyclase-depended neurotransmission from GABAergic Antennal Lobe Interneurons and activation of excitatory Projection Neurons (PNs) and the Mushroom Bodies.
View Article and Find Full Text PDFAccumulation of normal or mutant human Tau isoforms in Central Nervous System (CNS) neurons of vertebrate and invertebrate models underlies pathologies ranging from behavioral deficits to neurodegeneration that broadly recapitulate human Tauopathies. Although some functional differences have begun to emerge, it is still largely unclear whether normal and mutant Tau isoforms induce differential effects on the synaptic physiology of CNS neurons. We use the oligosynaptic Giant Fiber System in the adult Drosophila CNS to address this question and reveal that 3R and 4R isoforms affect distinct synaptic parameters.
View Article and Find Full Text PDFMEF2 (myocyte enhancer factor 2) transcription factors are found in the brain and muscle of insects and vertebrates and are essential for the differentiation of multiple cell types. We show that in the fruit fly , MEF2 is essential for the formation of mushroom bodies in the embryonic brain and for the normal development of wings in the adult. In embryos mutant for , there is a striking reduction in the number of mushroom body neurons and their axon bundles are not detectable.
View Article and Find Full Text PDFIn addition to mechanisms promoting protein-synthesis-dependent long-term memory (PSD-LTM), the process appears to also be specifically constrained. We present evidence that the highly conserved receptor tyrosine kinase dAlk is a novel PSD-LTM attenuator in Reduction of dAlk levels in adult α/β mushroom body (MB) neurons during conditioning elevates LTM, whereas its overexpression impairs it. Unlike other memory suppressor proteins and miRNAs, dAlk within the MBs constrains PSD-LTM specifically but constrains learning outside the MBs as previously shown.
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