Biology subjects

Tomchik, S. M.

Publications and source records attributed to Tomchik, S. M..

5 recordsLinked to original sources

bioRxiv2026

Loss of neurofibromin alters adult metabolism via effects during a developmental critical period

Metabolic alterations commonly accompany neurodevelopmental disorders and may contribute to their pathophysiology. Neurofibromatosis type 1 (OMIM 162200) is a genetic disorder that results from mutations in the NF1 gene and its encoded neurofibromin protein (Nf1). The disorder is multisystemic, affecting multiple aspects of development, physiology, and brain function. In addition, recent evidence suggests that Nf1 deficiency alters metabolic function in both humans and animal models. Whether the metabolic alterations result from changes in neurodevelopment is not known. Here we approach this question in Drosophila melanogaster, which expresses a conserved NF1 gene, exhibits phenotypes reminiscent of the human disease, and shares key developmental mechanisms with humans. Flies with nf1 mutations or RNAi-mediated knockdown exhibit altered metabolism in adulthood. Conditional Nf1 inactivation revealed that the adult metabolic phenotype resulted from loss of Nf1 in neurons during a developmental critical period (third instar larva/pupa), which corresponded to the period of nervous system maturation. Prior to the developmental critical period, nf1 mutants did not exhibit metabolic difference - rather, the metabolic alterations appeared only after the critical period. This suggests that the adult phenotype results from the onset of the developmental alteration during the critical period. High-resolution respirometry on adult mitochondria revealed no differences in complex I/II function or fatty acid oxidation between nf1 mutants and controls, suggesting that the metabolic alterations localize upstream of the electron transport chain at the cellular level. Overall, these data suggest that loss of Nf1 alters adult metabolism via effects during a critical period of nervous system development.

neuroscience↗

bioRxiv2025

Metabolic and behavioral effects of neurofibromin result from differential recruitment of MAPK and mTOR signaling

Neurofibromatosis type 1 results from mutations in the Neurofibromin 1 gene and its encoded neurofibromin protein. This condition produces multiple symptoms, including tumors, behavioral alterations, and metabolic changes. Molecularly, neu-rofibromin mutations affect Ras activity, influencing multiple downstream signaling pathways, including MAPK (Raf/MEK/ERK) and PI3K/Akt/mTOR signaling. This pleiotropy raises the question of which pathways could be targeted to treat the disease symptoms, and whether different phenotypes driven by neurofibromin mutations exhibit similar or diverging dependence on the signaling pathways downstream of Ras. To test this, we examined metabolic and behavioral alterations in the genetically tractable Drosophila neurofibromatosis type 1 model. In vivo genetic analysis revealed that behavioral effects of neurofibromin were mediated by MEK signaling, with no necessity for Akt. In contrast, metabolic effects of neurofibromin were mediated by coordinated actions of MEK/ERK and Akt/mTOR/S6K/4E-BP signaling. At the systemic level, neurofibromin dysregulated metabolism via molecular effects of Nf1 in interneurons and muscle. These changes were accompanied by altered muscle mitochondria morphology, with no concomitant changes in neuronal ultrastructure or neuronal mitochondria. Overall, this suggests that neurofibromin mutations affect multiple signaling cascades downstream of Ras, which differentially affect metabolic and behavioral neurofibromatosis type 1 phenotypes.

neuroscience↗

bioRxiv2024

Neurofibromin deficiency alters the patterning and prioritization of motor behaviors in a state-dependent manner

Genetic disorders such as neurofibromatosis type 1 increase vulnerability to cognitive and behavioral disorders, such as autism spectrum disorder and attention-deficit/hyperactivity disorder. Neurofibromatosis type 1 results from loss-of-function mutations in the neurofibromin gene and subsequent reduction in the neurofibromin protein (Nf1). While the mechanisms have yet to be fully elucidated, loss of Nf1 may alter neuronal circuit activity leading to changes in behavior and susceptibility to cognitive and behavioral comorbidities. Here we show that mutations decreasing Nf1 expression alter motor behaviors, impacting the patterning, prioritization, and behavioral state dependence in a Drosophila model of neurofibromatosis type 1. Loss of Nf1 increases spontaneous grooming in a nonlinear spatial and temporal pattern, differentially increasing grooming of certain body parts, including the abdomen, head, and wings. This increase in grooming could be overridden by hunger in food-deprived foraging animals, demonstrating that the Nf1 effect is plastic and internal state-dependent. Stimulus-evoked grooming patterns were altered as well, with nf1 mutants exhibiting reductions in wing grooming when coated with dust, suggesting that hierarchical recruitment of grooming command circuits was altered. Yet loss of Nf1 in sensory neurons and/or grooming command neurons did not alter grooming frequency, suggesting that Nf1 affects grooming via higher-order circuit alterations. Changes in grooming coincided with alterations in walking. Flies lacking Nf1 walked with increased forward velocity on a spherical treadmill, yet there was no detectable change in leg kinematics or gait. Thus, loss of Nf1 alters motor function without affecting overall motor coordination, in contrast to other genetic disorders that impair coordination. Overall, these results demonstrate that loss of Nf1 alters the patterning and prioritization of repetitive behaviors, in a state-dependent manner, without affecting motor coordination.

neuroscience↗

bioRxiv2021

Associative learning drives longitudinally-graded presynaptic plasticity of neurotransmitter release along axonal compartments

Anatomical and physiological compartmentalization of neurons is a mechanism to increase the computational capacity of a circuit, and a major question is what role axonal compartmentalization plays. Axonal compartmentalization may enable localized, presynaptic plasticity to alter neuronal output in a flexible, experience-dependent manner. Here we show that olfactory learning generates compartmentalized, bidirectional plasticity of acetylcholine release that varies across the longitudinal compartments of Drosophila mushroom body (MB) axons. The directionality of the learning-induced plasticity depends on the valence of the learning event (aversive vs. appetitive), varies linearly across proximal to distal compartments following appetitive conditioning, and correlates with learning-induced changes in downstream mushroom body output neurons (MBONs) that modulate behavioral action selection. Potentiation of acetylcholine release was dependent on the CaV2.1 calcium channel subunit cacophony. In addition, contrast between the positive conditioned stimulus and other odors required the inositol triphosphate receptor (IP3R), which was required to maintain responsivity to odors in untrained conditions. Downstream from the mushroom body, a set of MBONs that receive their input from the {gamma}3 MB compartment were required for normal appetitive learning, suggesting that they represent a key node through which discriminative effects influence appetitive memory and decision-making. These data demonstrate that learning drives valence-correlated, compartmentalized, bidirectional potentiation and depression of synaptic neurotransmitter release, which rely on distinct mechanisms and are distributed across axonal compartments in a learning circuit.

neuroscience↗

bioRxiv2019

Neurofibromin regulates metabolic rate via neuronal mechanisms in Drosophila

Neurofibromatosis type 1 (NF1) is a genetic disorder predisposing patients to a range of features, the most characteristic of which include areas of abnormal skin pigmentation and benign tumors associated with peripheral nerves, termed neurofibromas. Less common, but more serious symptoms also include malignant peripheral nerve sheath tumors, other malignancies, and learning disabilities. The NF1 gene encodes neurofibromin, a large protein that functions as a negative regulator of Ras signaling and mediates pleiotropic cellular and organismal function. Recent evidence suggests NF1 may regulate metabolism, though the mechanisms are unknown. Here we show that the Drosophila ortholog of NF1, dNf1 regulates metabolic homeostasis in fruit flies by functioning within a discrete brain circuit. Loss of dNf1 increases metabolic rate and feeding, enhances starvation susceptibility, and decreases lipid stores while increasing lipid turnover rate. The increase in metabolic rate is independent of locomotor activity (grooming), and maps to a subset of neurons in the ventral nervous system. The feeding and metabolic rate effects are due to loss of dNf1 in the same set of neurons, suggesting that increased feeding may be a compensatory effect driven by the increase in metabolic rate and lipid turnover. Finally, we show that the Ras GAP-related domain of neurofibromin is required for normal metabolism, demonstrating that Ras signaling downstream of dNf1 mediates the metabolic effects. These data demonstrate that dNf1 regulates metabolic rate via neuronal mechanisms, suggest that cellular and systemic metabolic alterations may represent a pathophysiological mechanism in NF1, and provide a platform for investigating the cellular role of neurofibromin in metabolic homeostasis.

neuroscience↗