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Hundreds of dietary supplements have been reported to improve cognitive and emotional function in humans, but few have scientific foundation. A new study from the Waddell group provides fresh insight into how dietary Magnesium supplementation can influence memory performance.
NEAT1-mediated regulation of proteostasis and mRNA localization impacts autophagy dysregulation in Rett syndrome
Abstract Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily caused by loss-of-function mutations in the MECP2 gene, resulting in diverse cellular dysfunctions. Here, we investigated the role of the long noncoding RNA (lncRNA) NEAT1 in the context of MeCP2 deficiency using human neural cells and RTT patient samples. Through single-cell RNA sequencing and molecular analyses, we found that NEAT1 is markedly downregulated in MECP2 knockout (KO) cells at various stages of neural differentiation. NEAT1 downregulation correlated with aberrant activation of the mTOR pathway, abnormal protein metabolism, and dysregulated autophagy, contributing to the accumulation of protein aggregates and impaired mitochondrial function. Reactivation of NEAT1 in MECP2-KO cells rescued these phenotypes, indicating its critical role downstream of MECP2. Furthermore, direct RNA–RNA interaction was revealed as the key process for NEAT1 influence on autophagy genes, leading to altered subcellular localization of specific autophagy-related messenger RNAs and impaired biogenesis of autophagic complexes. Importantly, NEAT1 restoration rescued the morphological defects observed in MECP2-KO neurons, highlighting its crucial role in neuronal maturation. Overall, our findings elucidate lncRNA NEAT1 as a key mediator of MeCP2 function, regulating essential pathways involved in protein metabolism, autophagy, and neuronal morphology.
Dopaminergic systems create reward seeking despite adverse consequences.
Resource-seeking behaviours are ordinarily constrained by physiological needs and threats of danger, and the loss of these controls is associated with pathological reward seeking1. Although dysfunction of the dopaminergic valuation system of the brain is known to contribute towards unconstrained reward seeking2,3, the underlying reasons for this behaviour are unclear. Here we describe dopaminergic neural mechanisms that produce reward seeking despite adverse consequences in Drosophila melanogaster. Odours paired with optogenetic activation of a defined subset of reward-encoding dopaminergic neurons become cues that starved flies seek while neglecting food and enduring electric shock punishment. Unconstrained seeking of reward is not observed after learning with sugar or synthetic engagement of other dopaminergic neuron populations. Antagonism between reward-encoding and punishment-encoding dopaminergic neurons accounts for the perseverance of reward seeking despite punishment, whereas synthetic engagement of the reward-encoding dopaminergic neurons also impairs the ordinary need-dependent dopaminergic valuation of available food. Connectome analyses reveal that the population of reward-encoding dopaminergic neurons receives highly heterogeneous input, consistent with parallel representation of diverse rewards, and recordings demonstrate state-specific gating and satiety-related signals. We propose that a similar dopaminergic valuation system dysfunction is likely to contribute to maladaptive seeking of rewards by mammals.
Compensatory enhancement of input maintains aversive dopaminergic reinforcement in hungry Drosophila.
Hungry animals need compensatory mechanisms to maintain flexible brain function, while modulation reconfigures circuits to prioritize resource seeking. In Drosophila, hunger inhibits aversively reinforcing dopaminergic neurons (DANs) to permit the expression of food-seeking memories. Multitasking the reinforcement system for motivation potentially undermines aversive learning. We find that chronic hunger mildly enhances aversive learning and that satiated-baseline and hunger-enhanced learning require endocrine adipokinetic hormone (AKH) signaling. Circulating AKH influences aversive learning via its receptor in four neurons in the ventral brain, two of which are octopaminergic. Connectomics revealed AKH receptor-expressing neurons to be upstream of several classes of ascending neurons, many of which are presynaptic to aversively reinforcing DANs. Octopaminergic modulation of and output from at least one of these ascending pathways is required for shock- and bitter-taste-reinforced aversive learning. We propose that coordinated enhancement of input compensates for hunger-directed inhibition of aversive DANs to preserve reinforcement when required.
New insights into axonal regulators of dopamine transmission in health and disease.
Dopamine release in the striatum is credited with being critical to the selection and learning of motivated actions and outcomes. Dysregulation of striatal dopamine release underlies multiple disorders of action selection and reward-processing, such as Parkinson's disease, schizophrenia and addiction disorders, and is a major target for therapeutic interventions. The axonal molecular and circuit mechanisms governing dopamine exocytosis are incompletely resolved, but accumulating evidence suggests some key points of divergence from canonical neurotransmitter synapses. In this review, we bring together recent insights into mechanisms shaping dopamine transmission in the striatum, spanning the molecular machinery regulating exocytosis, striatal modulators locally governing release probability, and the mechanisms regulating dopamine vesicle endocytosis. Together, these findings continue to support points of divergence from canonical presynaptic mechanisms, they inform principles of axonal neuromodulation, and point to potential contributions to the susceptibility to neurodegeneration in Parkinson's disease.
Auditory Salience Detection Across Wake and Sleep States: Mismatch Negativity and Event-Related Spectral Perturbation in the Rat Superior Colliculus.
Understanding the detection of salient auditory stimuli by the deep layer of the superior colliculus (dSC) during REM and NREM sleep offers valuable insights into the neurophysiological mechanisms of state-dependent auditory information processing. We recorded local field potentials (LFP) from dSC, electrocorticogram (ECoG) from frontal/parietal cortical regions, and neck electromyogram (EMG) in freely moving rats during sleep and awake states under oddball paradigm auditory stimulations. Our analysis focused on mismatch negativity (MMN) responses and event-related spectral perturbation (ERSP) in slow gamma (30-60 Hz) activity (SGA) and medium gamma (60-95 Hz) activity (MGA) frequency bands in wakefulness, REM and NREM sleep using three different intensities (35-, 55-, 80-dB) of stimulation. Data were analysed using repeated-measure two-way ANOVA and Linear Mixed Model. We found that the dSC exhibited significantly increased MMN responses to salient auditory stimuli across nearly all conditions (p
Axonal regulation of dopamine transmission by striatal neuromodulators
Striatal dopamine release can be modulated by diverse neuromodulators acting throughout the full anatomical extent of dopamine neurons, from dendrites and soma in the midbrain to axons in the striatum. Besides influencing somatodendritic integration and generation of action potentials by dopamine neurons, neuromodulators act on axons to shape axonal excitability and neurotransmitter release probability. Mesostriatal dopamine axons are immensely arborized, forming thousands of branches per neuron and 105 potential release sites per axonal tree, comprising more than 99% of the surface of the neuron. Dopamine axons therefore offer strategic sites for the regulation of dopamine output by striatal neuromodulators that will then shape dopamine function and dysfunction, and potentially offer therapeutic opportunities for treating dopaminergic disorders. Here, we summarize current knowledge of the striatal neuromodulators and corresponding receptors that influence dopamine release and their underlying circuits where known.
Dopamine transmission in the tail striatum: Regional variation and contribution of dopamine clearance mechanisms.
The striatum can be divided into four anatomically and functionally distinct domains: the dorsolateral, dorsomedial, ventral and the more recently identified caudolateral (tail) striatum. Dopamine transmission in these striatal domains underlies many important behaviours, yet little is known about this phenomenon in the tail striatum. Furthermore, the tail is divided anatomically into four divisions (dorsal, medial, intermediate and lateral) based on the profile of D1 and D2 dopamine receptor-expressing medium spiny neurons, something that is not seen elsewhere in the striatum. Considering this organisation, how dopamine transmission occurs in the tail striatum is of great interest. We recorded evoked dopamine release in the four tail divisions, with comparison to the dorsolateral striatum, using fast-scan cyclic voltammetry in rat brain slices. Contributions of clearance mechanisms were investigated using dopamine transporter knockout (DAT-KO) rats, pharmacological transporter inhibitors and dextran. Evoked dopamine release in all tail divisions was smaller in amplitude than in the dorsolateral striatum and, importantly, regional variation was observed: dorsolateral ≈ lateral > medial > dorsal ≈ intermediate. Release amplitudes in the lateral division were 300% of that in the intermediate division, which also exhibited uniquely slow peak dopamine clearance velocity. Dopamine clearance in the intermediate division was most dependent on DAT, and no alternative dopamine transporters investigated (organic cation transporter-3, norepinephrine transporter and serotonin transporter) contributed significantly to dopamine clearance in any tail division. Our findings confirm that the tail striatum is not only a distinct dopamine domain but also that each tail division has unique dopamine transmission characteristics. This supports that the divisions are not only anatomically but also functionally distinct. How this segregation relates to the overall function of the tail striatum, particularly the processing of multisensory information, is yet to be determined.
Altered network efficiency in isolated REM sleep behavior disorder: A multicentric study.
INTRODUCTION: Isolated rapid eye movement (REM) sleep behavior disorder (iRBD), characterized by abnormal movements during REM sleep, is a prodromal stage of dementia with Lewy bodies (DLB) and Parkinson's disease (PD). While iRBD shows emerging brain changes, their impact on structural connectivity and network efficiency, and their predictive value, remain poorly characterized. METHODS: In this international prospective study, 198 polysomnography-confirmed iRBD patients and 174 controls underwent diffusion magnetic resonance imaging and were analyzed. Cutting-edge diffusion tractography and network-based statistics were applied to reconstruct individual connectomes and assess network properties predicting DLB or PD. RESULTS: Structural architecture was already disrupted in iRBD, with both reduced and compensatory increased connections. Global efficiency was decreased. Local efficiency in motor regions was altered and associated with early clinical symptoms. Altered local efficiency in the supramarginal gyrus predicted DLB only. DISCUSSION: Early disruption of brain architecture in iRBD predicts progression to synucleinopathy-related dementia, offering a novel potential prognostic biomarker. HIGHLIGHTS: Isolated rapid eye movement sleep behavior disorder (iRBD) patients show significant alterations in inter-regional structural connectivity. Global efficiency is reduced in iRBD compared to controls. Areas with increased local efficiency contribute to decreased global efficiency. Altered network efficiency is associated with emerging Parkinsonian features. Higher supramarginal efficiency predicts dementia with Lewy bodies in iRBD.
Membrane curvature association of amphipathic helix 8 drives constitutive endocytosis of GPCRs
Cellular signaling relies on the activity of transmembrane receptors and their presentation on the cellular surface. Their continuous insertion in the plasma membrane is balanced by constitutive and activity-dependent internalization, which is orchestrated by adaptor proteins recognizing semispecific motifs within the receptors’ intracellular regions. Here, we describe a complementary trafficking mechanism for G protein–coupled receptors (GPCRs) that is evolutionary conserved and refined. This mechanism relies on the insertion of their amphipathic helix 8 into the inner leaflet of lipid membranes, orthogonal to the transmembrane helices. These amphipathic helices dictate subcellular localization of the receptors and autonomously drive their endocytosis by cooperative assembly and association with areas of high membrane curvature. The strength of helix 8 membrane insertion propensity quantitatively predicts the rate of constitutive internalization of GPCRs. This discovery advances our understanding of membrane protein trafficking and highlights a principle of receptor-lipid interactions that may have broad implications for cellular signaling and therapeutic targeting.
Obesity and heart failure: exploring the cardiometabolic axis.
Obesity is one of the biggest risks to public health in both developed and developing countries, and yet incidence continues to skyrocket. Being the main risk factor for a large number of life-limiting conditions, obesity has the potential to cause enormous damage unless addressed urgently. Heart failure (HF) is the most common cardiovascular disease associated with obesity. The incidence of HF overall continues to rise and mortality rates remain high, despite the rapid and significant advances in pharmacotherapy which have recently transformed the landscape of HF treatment. Both obesity and heart failure are multisystem disorders which are closely interlinked. Obesity poses the body a number of challenges, ranging from haemodynamic, to neuroendocrine, to inflammatory, to intracellular physiology. This narrative review describes the pathophysiological 'vicious cycle' caused by the combination of obesity and HF. Management of obesity in established heart failure has for years been a controversial topic, and yet an increasing body of evidence suggests that there are numerous benefits to managing obesity and insulin resistance in heart failure. Here we review the existing evidence base, as well as exciting new developments, suggesting that we may finally be on the brink of a revolution in managing obesity in heart failure.
MicroRNA-210 Enhances Cell Survival and Paracrine Potential for Cardiac Cell Therapy While Targeting Mitophagy.
The therapeutic potential of presumed cardiac progenitor cells (CPCs) in heart regeneration has garnered significant interest, yet clinical trials have revealed limited efficacy due to challenges in cell survival, retention, and expansion. Priming CPCs to survive the hostile hypoxic environment may be key to enhancing their regenerative capacity. We demonstrate that microRNA-210 (miR-210), known for its role in hypoxic adaptation, significantly improves CPC survival by inhibiting apoptosis through the downregulation of Casp8ap2, a ~40% reduction in caspase activity, and a ~90% decrease in DNA fragmentation. Contrary to the expected induction of Bnip3-dependent mitophagy by hypoxia, miR-210 did not upregulate Bnip3, indicating a distinct anti-apoptotic mechanism. Instead, miR-210 reduced markers of mitophagy and increased mitochondrial biogenesis and oxidative metabolism, suggesting a role in metabolic reprogramming. Furthermore, miR-210 enhanced the secretion of paracrine growth factors from CPCs, with a ~1.6-fold increase in the release of stem cell factor and of insulin growth factor 1, which promoted in vitro endothelial cell proliferation and cardiomyocyte survival. These findings elucidate the multifaceted role of miR-210 in CPC biology and its potential to enhance cell-based therapies for myocardial repair by promoting cell survival, metabolic adaptation, and paracrine signalling.
Filamentation of hCTPS1 with CTP.
CTP synthase (CTPS) is a key enzyme in de novo CTP synthesis, playing a critical role in nucleotide metabolism and cellular proliferation. Human CTPS1 (hCTPS1), one of the two CTPS isoforms, is essential for immune responses and is highly expressed in proliferating cells, making it a promising therapeutic target for immune-related diseases and cancer. Despite its importance, the regulatory mechanisms governing hCTPS1 activity remain poorly understood. Here, we reveal that CTP, the product of CTPS, acts as a key regulator for hCTPS1 filamentation. Using cryo-electron microscopy (cryo-EM), we resolve the high-resolution structure of CTP-bound hCTPS1 filaments, uncovering the molecular details of CTP binding and its role in filament assembly. Importantly, we demonstrate that CTP generated from the enzymatic reaction does not trigger filament disassembly, suggesting a conserved regulatory pattern. Furthermore, by analyzing the binding modes of two distinct CTP-binding pockets, we provide evidence that this filamentation mechanism is evolutionarily conserved across species, particularly in eukaryotic CTPS. Our findings not only elucidate a novel regulatory mechanism of hCTPS1 activity but also deepen the understanding of how metabolic enzymes utilize filamentation as a conserved strategy for functional regulation. This study opens new avenues for targeting hCTPS1 in therapeutic interventions.