Biology subjects

Preat, T.

Publications and source records attributed to Preat, T..

10 recordsLinked to original sources

bioRxiv2025

In vivo autofluorescence lifetime imaging of the Drosophila brain captures metabolic shifts associated with memory formation

Neuronal energy regulation is increasingly recognized as a critical factor underlying brain functions and their pathological alterations, yet the metabolic dynamics that accompany cognitive processes remain poorly understood. As a label-free and minimally invasive technique, fluorescence lifetime imaging (FLIM) of coenzymes NADH and NADPH (collectively referred to as NAD(P)H) offers the possibility to resolve cellular metabolic profiles with high spatial precision. However, NAD(P)H FLIMs capacity to detect subtle variations in neuronal metabolism has not been demonstrated. In this study, we applied NAD(P)H FLIM to map the metabolic profiles of Drosophila neurons in vivo across multiple scales, focusing on the primary centers for associative memory: the mushroom bodies (MBs). At a broad scale, we obtained an overview of the metabolic signatures of the main brain tissue and identified a marked difference between neuropil and cortex areas. At a finer scale, our findings revealed notable heterogeneity in the basal metabolic profiles of distinct MB neuron subtypes. Measurements performed after associative olfactory learning also uncovered a low-magnitude subtype-specific metabolic shift associated with memory formation, suggesting the utility of NAD(P)H FLIM in detecting physiology-driven changes linked to brain function. These results establish a promising framework for studying the spatial heterogeneities and the dynamics of cerebral energy metabolism in vivo.

neuroscience↗

bioRxiv2024

Neuronal fatty acid oxidation fuels memory after intensive learning

Metabolic flexibility allows cells to adapt to different fuel sources, which is particularly important for cells with high metabolic demands. In contrast, neurons, which are major energy consumers, are considered to rely almost solely on glucose and its derivatives to support their metabolism1-3. Here, using Drosophila melanogaster, we show memory formed after intensive massed training is dependent on mitochondrial fatty acid (FA) {beta}-oxidation to produce ATP in neurons of the mushroom bodies (MB), a major integrative center in insects brain. We identify neuronal lipid droplets as the main source of FAs for this type of memory. Furthermore, we demonstrate that this intensive massed training is associated with mitochondria network remodeling in the soma of MB neurons, resulting in increased mitochondrial size. Artificially increasing mitochondria size in adult MB neurons increases ATP production in their soma and, at the behavioral level, strikingly results in improved memory performance after massed training. These findings challenge the prevailing view that neurons are unable to use FAs for energy production, and importantly revealing on the contrary that in vivo neuronal FA oxidation has an essential role in cognitive function, including memory formation.

neuroscience↗

bioRxiv2024

Mitochondrial Ca2+ efflux controls neuronal metabolism and long-term memory across species

While impairing neuronal metabolism limits brain performance, it remains poorly understood whether enhancing metabolism in neurons, in contrast, could boost brain function. We find that reducing the expression of the mitochondrial H+/Ca2+ exchanger Letm1 results in increased Ca2+ retention in the mitochondrial matrix of firing neurons, which overactivates neuronal metabolism in flies and rodents. We find that upscaled metabolic states in active neurons of central memory circuits of flies and mice enable storing long-term memories in training paradigms in which wild-type counterparts of both species fail to remember. Our findings unveil an evolutionarily conserved mechanism that controls mitochondrial metabolism in active neurons and prove its crucial role in governing higher brain functions, such as long-term memory formation. Highlights- Letm1 controls activity-driven mitochondrial Ca2+ efflux in neurons - Increased mitochondrial Ca2+ retention during activity overactivates neuronal metabolism - Activity-driven upscaling of neuronal metabolism facilitates long-term olfactory memory in flies and mice

neuroscience↗

bioRxiv2023

PKCdelta is an activator of neuronal mitochondrial metabolism that mediates the spacing effect on memory consolidation

Relevance-based selectivity and high energy cost are two distinct features of long-term memory (LTM) formation that warrant its default inhibition. Spaced repetition of learning is a highly conserved cognitive mechanism that can lift this inhibition. Here, we questioned how the spacing effect integrates experience selection and energy efficiency at the cellular and molecular levels. We showed in Drosophila that spaced training triggers LTM formation by extending over several hours an increased mitochondrial metabolic activity in neurons of the associative memory center, the mushroom bodies (MBs). We found that this effect is mediated by PKC{delta}, a member of the so-called novel PKC family of enzymes, which uncovers the critical function of PKC{delta} in neurons as a regulator of mitochondrial metabolism for LTM. Additionally, PKC{delta} activation and translocation to mitochondria result from LTM-specific dopamine signaling on MB neurons. By bridging experience-dependent neuronal circuit activity with metabolic modulation of memory-encoding neurons, PKC{delta} signaling binds the cognitive and metabolic constraints underlying LTM formation into a unified gating mechanism.

neuroscience↗

bioRxiv2023

Respective contribution of Appl to mushroom body axon growth and long-term memory in Drosophila

The Amyloid Precursor Protein (APP) is associated with Alzheimers disease. Appl is the single Drosophila APP ortholog and is expressed in all neurons throughout development. Appl was previously shown to cell-autonomously modulate axon outgrowth in the mushroom bodies (MBs), the fly olfactory memory center. However, we found that Appld, the only reported null allele, affects the normal function of vnd, the gene just proximal to Appl. To decipher developmental defects specifically due to a loss of only Appl function, we generated a precise Appl null allele (ApplC2.1) by CRISPR/Cas9 genomic engineering. With ApplC2.1, we confirmed the partial requirement for Appl in MB axon outgrowth. We also produced new CRISPR vnd alleles removing either vnd-B or vnd-A function. We report here that vnd is also required for MB {beta}-branch axon outgrowth and to a much greater extent than Appl itself. Moreover, vnd is expressed in neurons close to, but not within, the MB during development and is required non-cell-autonomously for MB axon outgrowth

neuroscience↗

bioRxiv2023

Long-term memory formation depends on an astrocyte-to-neuron H2O2 signaling

Astrocytes interact with neurons during cognitive processes1. In particular, astrocytes help neurons to fight oxidative stress2, a needed function since active neurons are prone to reactive oxygen species (ROS) damage due to their high mitochondrial activity and relatively poor antioxidant defenses3. ROS also play major physiological functions4,5, but it remains unknown how neuronal ROS signaling is activated during memory formation and if astrocytes play a role in that process. We discovered in Drosophila an astrocyte-to-neuron H2O2 signaling cascade essential for long-term memory formation. Stimulation of astrocytes by acetylcholine induces an intracellular calcium increase that triggers the formation of extracellular O2{degrees}- by astrocytic NADPH oxidase. Superoxide dismutase 3 secreted by astrocytes converts O2{degrees}- into H2O2, which is imported into neurons of the olfactory memory center (the mushroom body), as revealed by in vivo H2O2 imaging using an ultrasensitive sensor. Importantly, SOD3 activity requires Cu2+, which we show is delivered by the neuronal Amyloid Precursor Protein. Furthermore, we found that human amyloid-{beta} peptide, involved in Alzheimers disease, inhibits the astrocytic cholinergic receptor and hampers memory formation by preventing H2O2 import into neurons. These findings could have major implications for the understanding of Alzheimers disease etiology, as soluble synaptic A{beta}42 correlates better with the pattern of cognitive decline in AD than amyloid plaques6, and since early pathology in cholinergic neurons of the basal forebrain predicts memory defects7,8.

neuroscience↗

bioRxiv2023

Developmental transcriptional control of mitochondrial homeostasis is required for activity-dependent synaptic connectivity

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 that contribute to circuit wiring. We combined cell type-specific transcriptomics with a genetic screen to discover such factors. We identified Telomeric Zinc finger-Associated Protein (TZAP) as a temporal developmental regulator of neuronal mitochondrial homeostasis genes, including Pink1. In Drosophila, loss of dTzap function during visual circuit development leads to loss of activity-dependent synaptic connectivity, that can be rescued by Pink1 expression. At the cellular level, loss of dTzap/TZAP leads to defects in mitochondrial morphology, attenuated calcium uptake and reduced synaptic vesicle release in fly and mammalian neurons. Our findings highlight developmental transcriptional regulation of mitochondrial homeostasis as a key factor in activity-dependent synaptic connectivity.

neuroscience↗

bioRxiv2022

Glycolysis-derived alanine from glia fuels neuronal mitochondria for memory in Drosophila

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 metabolism during cognitive processes is missing. Here, we uncover in Drosophila a glia-to-neuron alanine transfer that sustains memory formation. Following associative conditioning, glycolysis in glial cells produces alanine, which is back-converted into pyruvate in mushroom body cholinergic neurons to uphold their increased mitochondrial needs. Alanine, as a mediator of glia-neuron coupling, could be an alternative to lactate in cholinergic systems. In parallel, a dedicated glial glucose transporter imports glucose specifically for long-term memory, by directly transferring it to neurons for use by the pentose phosphate pathway. Our results demonstrate in vivo the compartmentalization of glucose metabolism between neurons and glial cells during memory formation.

neuroscience↗

bioRxiv2022

Numerical discrimination in Drosophila melanogaster

Sensitivity to numbers is a crucial and evolutionarily conserved cognitive ability. The lack of experimental models amenable to systematic genetic and neural manipulation has precluded discovering circuits required for numerical cognition. Here, we demonstrate that in a two-choice task Drosophila fruit flies spontaneously prefer sets containing more objects. This preference is determined by the ratio between the two numerical quantities tested, a characteristic signature of numerical cognition across species. Individual flies maintained their numerical choice over consecutive days. Using a numerical visual conditioning paradigm, we found that flies are capable of associating sucrose with numerical quantities and can be trained to reverse their spontaneous preference for large quantities. Finally, we show that silencing LC11 neurons reduces the preference for more objects, thus identifying a neuronal substrate for numerical cognition in invertebrates. This discovery paves the way for the systematic analysis of the behavioral and neural mechanisms underlying sensitivity to numerosity.

neuroscience↗

bioRxiv2017

Memory retrieval recruits both innate and learned olfactoryprocessing centres in Drosophila

Animals can show either learned or innate behavioral responses to a given stimulus. How these circuits interact to produce an appropriate behavioral response is unknown. In the Drosophila olfactory system, the lateral horn (LH) and the mushroom body (MB) are thought to mediate innate and learned olfactory behavior respectively, although the function of the LH has not been directly tested. Here we identify two LH cell-types (PD2a1/b1) that receive input from an MB output neuron required for recall of aversive olfactory memories. In contrast to the model above we find that PD2a1/b1 are required for aversive memory retrieval. PD2a1/b1 activity is modulated by training, indicating that memory information is passed to the innate olfactory processing centre. We map the connectivity of PD2a1/b1 to other olfactory neurons with connectomic data. This provides a circuit mechanism by which learned and unlearned olfactory information can interact to produce appropriate behavior.

neuroscience↗