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Publications (111)
Glucose is the primary source of energy for the brain. However, it remains controversial whether, upon neuronal activation, glucose is primarily used by neurons for ATP production, or if it is partially oxidized in astrocytes, as proposed by the astrocyte-neuron lactate shuttle model for glutamatergic neurons. Thus, an in vivo picture of glucose me...
Visual learning in animals is a remarkable cognitive ability that plays a crucial role in their survival and adaptation. Therefore, the ability to learn is highly conserved among animals. Despite lacking a centralized nervous system like vertebrates, invertebrates have demonstrated remarkable learning abilities. Here, we describe a simple behaviora...
The Amyloid Precursor Protein (APP) is linked to Alzheimer s disease. Appl is the single Drosophila APP ortholog and is expressed in all neurons throughout development. Appl was previously shown to modulate, cell-autonomously, axon outgrowth in the mushroom bodies (MBs), the fly olfactory memory center. Furthermore, Appl knockdown in the MBs result...
Astrocytes interact with neurons during cognitive processes. In particular, astrocytes help neurons to fight oxidative stress, a needed function since active neurons are prone to reactive oxygen species (ROS) damage due to their high mitochondrial activity and relatively poor antioxidant defenses. ROS also play major physiological functions, but it...
Sensitivity to numbers is a crucial cognitive ability. The lack of experimental models amenable to systematic genetic and neural manipulation has precluded discovering neural circuits required for numerical cognition. Here, we demonstrate that Drosophila flies spontaneously prefer sets containing larger numbers of objects. This preference is determ...
During neuronal circuit formation, local control of axonal organelles ensures proper synaptic connectivity. Whether this process is genetically encoded is unclear and if so, its developmental regulatory mechanisms remain to be identified. We hypothesized that developmental transcription factors regulate critical parameters of organelle homeostasis...
Left-Right (LR) asymmetry of the nervous system is widespread across animals and is thought to be important for cognition and behaviour. But in contrast to visceral organ asymmetry, the genetic basis and function of brain laterality remain only poorly characterized. In this study, we performed RNAi screening to identify genes controlling brain asym...
FTSJ1 is a conserved human 2'-O-methyltransferase (Nm-MTase) that modifies several tRNAs at position 32 and the wobble position 34 in the anticodon loop. Its loss of function has been linked to X-linked intellectual disability (XLID), and more recently to cancers. However, the molecular mechanisms underlying these pathologies are currently unclear....
During starvation, mammalian brains can adapt their metabolism, switching from glucose to alternative peripheral fuel sources. In the Drosophila starved brain, memory formation is subject to adaptative plasticity, but whether this adaptive plasticity relies on metabolic adaptation remains unclear. Here we show that during starvation, neurons of the...
Brain function relies almost solely on glucose as an energy substrate. The main model of brain metabolism proposes that glucose is taken up and converted into lactate by astrocytes to fuel the energy-demanding neuronal activity underlying plasticity and memory. Whether direct neuronal glucose uptake is required for memory formation remains elusive....
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Reproduction induces increased food intake across females of many animal species1–4, providing a physiologically relevant paradigm for the exploration of appetite regulation. Here, by examining the diversity of enteric neurons in Drosophila melanogaster, we identify a key role for gut-innervating neurons with sex- and reproductive state-specific ac...
How does the concerted activity of neuronal populations shape behavior? Impediments to address this question are primarily due to critical experimental barriers. An integrated perspective on large scale neural information processing requires an in vivo approach that can combine the advantages of exhaustively observing all neurons dedicated to a giv...
In Drosophila, the mushroom bodies (MB) constitute the central brain structure for olfactory associative memory. As in mammals, the cAMP/PKA pathway plays a key role in memory formation. In the MB, Rutabaga adenylate cyclase acts as a coincidence detector during associative conditioning to integrate calcium influx resulting from acetylcholine stimu...
Amyloid precursor protein (APP), the precursor of amyloid beta peptide, plays a central role in Alzheimer’s disease (AD), a pathology characterized by memory decline and synaptic loss upon aging. Understanding the physiological role of APP is fundamental in deciphering the progression of AD, and several studies suggest a synaptic function via prote...
Perseverance in foraging is a high-risk/high-gain strategy. In this issue of Neuron, Sayin et al. (2019) decipher the neuronal circuit that arbitrates this choice in Drosophila. The fly's remarkable tenacity illuminates the interaction between working memory and decision making.
Can mating influence cognitive functions such as learning and memory in a permanent way? We have addressed this question using a combined behavioral and in vivo imaging approach, finding that aversive long-term memory performance strongly increases in Drosophila females in response to sperm transfer following mating. A peptide in the male sperm, th...
Physiology and metabolism are often sexually dimorphic, but the underlying mechanisms remain incompletely understood. Here, we use the intestine of Drosophila melanogaster to investigate how gut-derived signals contribute to sex differences in whole-body physiology. We find that carbohydrate handling is male-biased in a specific portion of the inte...
Table S1. List of Transgenic Lines Used for Anatomical Experiments, Related to STAR Methods
Note for Figure 3, all genotypes are labeled in the figure. For behavioral experiments the genotypes are labeled in the figure.
Table S2. Detailed List of All Odors Used for Behavioral and Calcium Imaging Experiments, Related to STAR Methods
Table S3. Full Chemical Name of Each Odorant, Shorthand Nomenclature, Concentration, CAS Number, and Diluent, Related to STAR Methods
The first column contains the full chemical name of each odorant, followed by the short-hand nomenclature used in Figure 6B (Paper Abbreviation), the concentration, CAS number and diluent.
Data S1. SWC Files Containing the EM and Light Microscopy Reconstructions of the Different Neurons Used in This Study
It was proposed that the Drosophila amnesiac gene (amn) is required for consolidation of aversive memory in the dorsal paired medial (DPM) neurons, a pair of large neurons that broadly innervate the mushroom bodies (MB), the fly center for olfactory learning and memory (Waddell et al., 2000). Yet, a conditional analysis showed that it was not possi...
The behavioral response to a sensory stimulus may depend on both learned and innate neuronal representations. How these circuits interact to produce appropriate behavior is unknown. In Drosophila, the lateral horn (LH) and mushroom body (MB) are thought to mediate innate and learned olfactory behavior, respectively, although LH function has not bee...
Memory consolidation is a crucial step for long-term memory (LTM) storage. However, we still lack a clear picture of how memory consolidation is regulated at the neuronal circuit level. Here, we took advantage of the well-described anatomy of the Drosophila olfactory memory center, the mushroom body (MB), to address this question in the context of...
A key function of the brain is to filter essential information and store it in the form of stable, long-term memory (LTM). We demonstrate here that the Dunce (Dnc) phosphodiesterase, an important enzyme that degrades cAMP, acts as a molecular switch that controls LTM formation in Drosophila. We show that, during LTM formation, Dnc is inhibited in t...
Video displaying whole-brain expression of SPNsplit-Gal4 driving mcd8::GFP (green) and anti-nc82 neuropil counterstaining (magenta). The expression pattern is exclusively restricted to the SPN.
Video S5. Double Labeling of SPN and MP1 at the MB Peduncle (Driver Combination 2), Related to Figure 4
Video displaying SPN expression at the level of the MB peduncle using VT026326-Gal4>UAS-tdTomato (magenta), with MP1 expression using 30E11-LexA>Aop-mCD8::GFP (green). The SPN projection co-localizes with the MP1 projections covering the posteri...
3D reconstruction of the SPN in SPNsplit-Gal4>UAS-mcd8::GFP-labeled brains, with anti-nc82 neuropil counterstaining to visualize brain regions.
Video S4. Double Labeling of SPN and MP1 at the MB Peduncle (Driver Combination 1), Related to Figure 4
Video displaying SPN expression at the level of the MB peduncle using VT026326-LexA>Aop-mCD8::GFP (magenta), with MP1 expression using NP0047-Gal4>UAS-RFP (green). The SPN projections co-localize with the MP1 projections covering the posterior p...
Video S6. Labeling of the SPN and GRASP Signals with MP1 at the MB Peduncle, Related to Figure 4
Video displaying SPN expression at the level of the MB peduncle using VT026326>UAS-tdTomato (magenta) and GRASP signals, showing reconstituted GFP between VT026326-Gal4 (SPN) and 30E11 (MP1). The GRASP signals specifically localize on the SPN projectio...
Video S1. Whole-Brain Labeling of the SPN Driver GH298-Gal4 (1.1), VT026326-Gal4 (1.2), and Their Intersection (1.3), Related to Figure 1
Video 1.1 displays whole-brain expression of GH298-Gal4 driving mcd8::GFP (green) and anti-nc82 neuropil counterstaining (magenta). Video 1.2 displays whole-brain expression of VT026326-Gal4 driving mcd8::GFP (g...
Non-caloric artificial sweeteners (NAS) are widely used in modern human food, raising the question about their health impact. Here we have asked whether NAS consumption is a neutral experience at neural and behavioral level, or if NAS can be interpreted and remembered as negative experience. We used behavioral and imaging approaches to demonstrate...
Neprilysins are Type II metalloproteinases known to degrade and inactivate a number of small peptides, in particular the mammalian amyloid-β peptide (Aβ). In Drosophila, several neprilysins expressed in the brain are required for middle-term (MTM) and long-term memory(LTM) in the dorsal paired medial (DPM) neurons, a pair of large neurons that broa...
Many animals can show either learned or innate behavioural responses to a given stimulus. However, how innate and memory circuits interact to produce an appropriate behavioural response is unknown. The Drosophila olfactory system is an excellent model to study how sensory stimuli are processed, stored and transformed into behaviour. Its numerical s...
Efficient energy use has constrained the evolution of nervous systems. However, it is unresolved whether energy metabolism may resultantly regulate major brain functions. Our observation that Drosophila flies double their sucrose intake at an early stage of long-term memory formation initiated the investigation of how energy metabolism intervenes i...
Supplementary Figures and Supplementary Table.
Expression pattern of the VT30559 driver in the whole brain. This is a full confocal stack at 20X magnification of a fly expressing mCD8::GFP (immunostained in green) through the VT30559 GAL4 driver. The brain neuropil is counterstained by anti-nc82 immunochemistry (red).
Detailed expression pattern of the VT30559 driver in MB. This is a full confocal stack at 40X magnification focused on MB region of a fly expressing mCD8::GFP (immunostained in green) through the VT30559 GAL4 driver. The brain neuropil is counterstained by anti-nc82 immunochemistry (red).
The amyloid precursor protein (APP) is a membrane protein engaged in complex proteolytic pathways. APP and its derivatives have been shown to play a central role in Alzheimer’s disease (AD), a progressive neurodegenerative disease characterized by memory decline. Despite a huge effort from the research community, the primary cause of AD remains unc...
Significance statement:
Neprilysins are endopeptidases known to degrade a number of small peptides. Neprilysin research has essentially focused on their role in Alzheimer's disease and heart failure. Here, we use Drosophila melanogaster to study whether neprilysins are involved in memory. Drosophila can form several types of olfactory memory and t...
The amyloid precursor protein (APP) plays a central role in Alzheimer's disease (AD). APP can undergo two exclusive proteolytic pathways: cleavage by the α-secretase initiates the non-amyloidogenic pathway while cleavage by the β-secretase initiates the amyloidogenic pathway that leads, after a second cleavage by the γ-secretase, to amyloid-β (Aβ)...
Understanding how the various memory components are encoded and how they interact to guide behavior requires knowledge of the underlying neural circuits. Currently, aversive olfactory memory in Drosophila is behaviorally subdivided into four discrete phases. Among these, short- and long-term memories rely, respectively, on the γ and α/β Kenyon cell...
Sensory cues relevant to a food source, such as odors, can be associated with post-ingestion signals related either to food energetic value or toxicity. Despite numerous behavioral studies, a global understanding of the mechanisms underlying these long delay associations remains out of reach. Here, we demonstrate in Drosophila that the long-term as...
The APP plays a central role in AD, a pathology that first manifests as a memory decline. Understanding the role of APP in normal cognition is fundamental in understanding the progression of AD, and mammalian studies have pointed to a role of secreted APPα in memory. In Drosophila, we recently showed that APPL, the fly APP ortholog, is required for...
Significance
A biologically relevant event such as finding food under starvation conditions or being poisoned can drive long-term memory (LTM) in a single training session. Neuronal mechanisms by which such a strong reward or punishment induces stable memory are poorly understood. Here we show that distinct subsets of dopamine neurons signal reward...
Significance of behavioral differences for Fly Bowl assay. For each line, we compared the fraction of time the split-GAL4/dTrpA1 line does each of 14 behaviors to two controls: empty GAL4 crossed to dTrpA1 (pBDPGAL4U/dTrpA1) and split-GAL4/+. Each data point corresponds to the fraction of time that all 20 flies in a given video performed the given...
Animals discriminate stimuli, learn their predictive value and use this knowledge to modify their behavior. In Drosophila, the mushroom body (MB) plays a key role in these processes. Sensory stimuli are sparsely represented by ∼2000 Kenyon cells, which converge onto 34 output neurons (MBONs) of 21 types. We studied the role of MBONs in several asso...
One of the challenges facing memory research is to combine network- and cellular-level descriptions of memory encoding. In this context, Drosophila offers the opportunity to decipher, down to single-cell resolution, memory-relevant circuits in connection with the mushroom bodies (MBs), prominent structures for olfactory learning and memory. Althoug...
Hunger and Memory
During starvation, are all brain functions slowed down, or are specific functions disabled to save energy? Plaçais and Preat (p. 440 ) investigated how the brain of Drosophila deals with severe resource limitation. The brain cut selected expenses to reduce the threat to survival and switched off the formation of aversive long-term...
Several lines of evidence indicate that sleep plays a critical role in learning and memory. The aim of this study was to evaluate anesthesia resistant memory following sleep deprivation in Drosophila.
Four to 16 h after aversive olfactory training, flies were sleep deprived for 4 h. Memory was assessed 24 h after training. Training, sleep deprivati...
Animals approach stimuli that predict a pleasant outcome. After the paired presentation of an odour and a reward, Drosophila melanogaster can develop a conditioned approach towards that odour. Despite recent advances in understanding the neural circuits for associative memory and appetitive motivation, the cellular mechanisms for reward processing...
The remodelling of neurons during their development is considered necessary for their normal function. One fundamental mechanism involved in this remodelling process in both vertebrates and invertebrates is axon pruning. A well-documented case of such neuronal remodelling is the developmental axon pruning of mushroom body γ neurons that occurs duri...
Four lines were selected from a collection of 33 lines prepared by P insertion mutagenesis using a single-copy P-element system; the males of these four lines showed memory defects after acquisition of conditioned reflex suppression of courting. In two lines (P171 and P95), the dynamics of retention of the conditioned reflex in the repeated impregn...
A fundamental duty of any efficient memory system is to prevent long-lasting storage of poorly relevant information. However, little is known about dedicated mechanisms that appropriately trigger production of long-term memory (LTM). We examined the role of Drosophila dopaminergic neurons in the control of LTM formation and found that they act as a...
A central goal of neuroscience is to understand how neural circuits encode memory and guide behavior changes. Many of the molecular mechanisms underlying memory are conserved from flies to mammals, and Drosophila has been used extensively to study memory processes. To identify new genes involved in long-term memory, we screened Drosophila enhancer-...
It is broadly accepted that long-term memory (LTM) is formed sequentially after learning and short-term memory (STM) formation, but the nature of the relationship between early and late memory traces remains heavily debated [1-5]. To shed light on this issue, we used an olfactory appetitive conditioning in Drosophila, wherein starved flies learned...
Aversive olfactory memory is formed in the mushroom bodies in Drosophila melanogaster. Memory retrieval requires mushroom body output, but the manner in which a memory trace in the mushroom body drives conditioned avoidance of a learned odor remains unknown. To identify neurons that are involved in olfactory memory retrieval, we performed an anatom...
Cytokine signaling through the JAK/STAT pathway regulates multiple cellular responses, including cell survival, differentiation, and motility. Although significant attention has been focused on the role of cytokines during inflammation and immunity, it has become clear that they are also implicated in normal brain function. However, because of the...
The amyloid precursor protein (APP) plays an important role in Alzheimer's disease (AD), a progressive neurodegenerative pathology that first manifests as a decline of memory. While the main hypothesis for AD pathology centers on the proteolytic processing of APP, very little is known about the physiological function of the APP protein in the adult...
Ceramidases catalyze the conversion of ceramide to sphingosine. They are acylaminohydrolases that catalyze the deacylation of the amide-linked saturated fatty acid from ceramide to generate sphingosine. They also catalyze the reverse reaction of ceramide biosynthesis using sphingosine and fatty acid. In mammals, different proteins catalyze these re...
The neuromodulatory function of dopamine (DA) is an inherent feature of nervous systems of all animals. To learn more about the function of neural DA in Drosophila, we generated mutant flies that lack tyrosine hydroxylase, and thus DA biosynthesis, selectively in the nervous system. We found that DA is absent or below detection limits in the adult...