bioRxiv Subject Collection: Neuroscience's Journal
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Monday, July 28th, 2025
| Time |
Event |
| 12:32a |
The Alzheimer's therapeutic Lecanemab induces an amyloid-clearing program in microglia
Controversies over anti-amyloid immunotherapies underscore the need to elucidate their mechanisms of action. Here we demonstrate that Lecanemab, a leading anti-A{beta} antibody, mediates amyloid clearance by triggering effector functions in the microglia. Using a human microglia xenograft model, we show that Lecanemab significantly reduces A{beta} pathology and associated neuritic damage, while neither Fc-inactivated Lecanemab nor microglia deficiency elicit this effect despite intact plaque binding. Single-cell RNA sequencing and spatial transcriptomic analyses reveal that Lecanemab induces a focused transcriptional program that enhances phagocytosis, lysosomal degradation, metabolic reprogramming, interferon gamma genes, and antigen presentation. Finally, we identify SPP1/osteopontin as a major factor induced by Lecanemab treatment and demonstrate its role in promoting A{beta} clearance. These findings highlight that effective amyloid removal depends on the engagement of microglia through Fc fragment, providing critical insights for optimizing anti-amyloid therapies in AD. | | 6:45a |
Sex-specific hypothalamic axis disruption in the rNLS8 mouse model of amyotrophic lateral sclerosis (ALS)
Sex-related differences have gained increasing attention in recent years due to evidence of varying prevalence, pathophysiology, survival rates, and disease progression between males and females in amyotrophic lateral sclerosis (ALS). Differences in brain metabolism between sexes in ALS patients have also been reported; however, the specific molecular mechanisms remain poorly understood. As growing evidence supports a strong metabolic component in ALS, this study investigates alterations in leptin, one of the key regulators of metabolism, that is known to be altered during ALS progression in rNLS8 mice, a transgenic mouse model of ALS which closely recapitulates the TAR DNA-binding protein (TDP-43) pathology observed in most patients with ALS. We also examined changes in hypothalamic neuronal genes involved in metabolic regulation through food intake in rNLS8 mice. Additionally, pathological alterations in the spinal cord, a primary site of ALS pathology, were also assessed. Using molecular biology techniques we analysed the expression levels of leptin, its long receptor (Ob-Rb), and its downstream signaling pathways (Akt and STAT3) in rNLS8 mice compared to age- and sex-matched wild-type littermates. Our results revealed significant sex- and disease stage-dependent differences in leptin and Ob-Rb expression in white adipose tissue and the hypothalamus, along with increased activation of the Akt signaling pathway in the spinal cord of rNLS8 mice. These findings suggest that ALS progression differs by sex in rNLS8 mice, which may impact overall disease progression and the effectiveness of potential therapeutic interventions targeting metabolism, such as nutritional strategies that influence leptin levels. | | 7:16a |
NG2-Glia Heterogeneity Across Cortical Layers
NG2-glia are a unique and heterogeneous glial cell population with diverse roles in the central nervous system. However, their morphological diversity across brain regions and cortical layers remains poorly understood. Here, we use StarTrack labeling and in utero electroporation at embryonic day 14 (E14) to reconstruct individual NG2-glial cells in the adult mouse cortex and corpus callosum. Through detailed two- and three-dimensional morphometric analyses, including Sholl analysis, principal component analysis, and hierarchical clustering, we uncover striking layer-specific patterns. NG2-glia in deep cortical layers (L5-6) exhibit significantly larger somatic areas, more elaborate arborizations, and higher process complexity compared to those in superficial layers (L1-4) and the corpus callosum. In contrast, NG2-glia in layer 1 and the corpus callosum share a compact morphology characterized by smaller somata and simplified processes, suggesting common microenvironmental constraints. Moreover, Sholl analysis, principal component analysis, and hierarchical clustering reveal distinct morphological subpopulations within the NG2-glial population and highlight heterogeneity in upper cortical layers. Comparative analyses with astrocytes reveal fundamental structural differences: NG2-glia have thinner, longer processes and larger enclosing radii but occupy smaller volumes, whereas astrocytes form denser, more compact arbors with higher branch numbers. Together, our finding establish the first comprehensive morphological atlas of cortical adult NG2-glia, highlighting region- and layer-specific adaptations that likely underlie their diverse roles in CNS physiology and repair. | | 5:34p |
Inception: Simulating Personalized Long-Term Recovery in Disorders of Consciousness using Whole-Brain Computational Perturbations
Advancements in the treatment of Disorders of Consciousness have seen significant progress with perturbative techniques and pharmacological therapies. Despite their potential, the underlying mechanisms of their variable efficacy remain poorly understood. To address this challenge, recent studies have utilised whole-brain modelling to simulate in silico perturbations. However, existing models focus exclusively on system behaviour during active stimulations, leaving unexplored how the brain dynamics evolve in post-acute and long-term stages, crucial in the recovery of consciousness. Here, we introduce Inception, a novel personalized approach to in silico perturbation modelling. We use a whole-brain models to simulate the perturbations and to unravel information about the long term effects of the proposed intervention. Applied to fMRI data from patients in a minimally conscious state and an unresponsive wakefulness state, our approach effectively simulates the transition to a healthy state, generating perturbed data closely resembling healthy brain activity. Moreover, we show that Inception enhances patient classification through machine learning, outperforming functional connectivity-based approaches. Finally, we investigate the correlation between perturbation responses and brain neuroreceptors, proposing that Inception might capture the long-term effects of pharmacological interventions in Disorders of Consciousness treatment. | | 5:34p |
Locomotion Selectively Amplifies Sensitizing Neurons in Primary Visual Cortex
Sensory processing in the cortex is shaped both by adaptation to external stimuli and by changes in internal state but it is not known how these processes interact, in large part because neuromodulatory changes in synaptic strength are difficult to quantify in behaving animals. Here we combine two-photon calcium imaging, optogenetics and circuit modelling to investigate how locomotion adjusts adaptation in layer 2/3 of mouse primary visual cortex (V1). We show that this change in state preferentially increases gain in PCs that sensitize during a high-contrast visual stimulus, while having weaker effects on PCs that depress. A population model constrained by a number of optogenetic manipulations accounts for the differential modulation of PCs during locomotion on the basis of i) variations in the connections that individual PCs receive from PV and SST interneurons, ii) a broad weakening of PC and PV synapses to all local targets, and iii) enhanced inhibition from SST synapses targetting depressing PCs. These results provide a quantitative and integrated understanding of how state-dependent modulation of cortical circuits can selectively bias cortical computation toward different adaptive regimes. The apparently paradoxical combination of increased PC gain but decreased synaptic strength suggests a state-dependent gating mechanism that boosts signals leaving V1 for higher visual areas while simultaneously preventing disruption of the excitatory-inhibitory balance required for stable local computation. | | 5:34p |
Direction-selective retinal ganglion cells encode motion direction uniformly, despite having discretely distributed cardinal preferences
On-Off direction-selective retinal ganglion cells (DS RGCs) exhibit broad tuning curves, responding robustly to motion aligned with or near their preferred direction. These cells comprise four major subtypes, each tuned to motion along one of the four cardinal axes: nasal, superior, temporal, or inferior. However, natural stimuli can move in any direction, and it remains unclear whether intermediate directions are encoded less effectively, or whether this cardinal organization nevertheless supports uniform direction encoding. Here, we combined previous electrophysiological recordings with an information-theoretic measure, the Stimulus Specific Information, to estimate the directional sensitivity of small populations of recorded neurons. This analysis revealed that DS RGC populations are uniformly sensitive across all directions of motion. We then asked whether the observed homogeneous sensitivity was a consequence of DS RGCs maximizing the average stimulus information. Simulations with artificially modified tuning curve widths revealed that DS cells prioritize avoiding pronounced drops in sensitivity over maximizing the average transmitted Information. Maximizing this minimal sensitivity may therefore be a principle to understand the organization of sensory systems. | | 6:46p |
Distinct Roles of CaMKII in Synaptic Vesicle Dynamics at Zebrafish Retinal Rod Bipolar Ribbon Synapses
Calcium (Ca2+) not only serves as a fundamental trigger for neurotransmitter release but also participates in shaping neurotransmitter release (NTR) during prolonged presynaptic stimulation via multiple Ca2+-dependent processes. The Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) is enriched at various presynaptic terminals, including ribbon synapses, where it associates with synaptic ribbons and thus may contribute to the modulation of Ca2+-dependent NTR. This could arise via its ability to influence one or more steps that control either the Ca2+ signal, the release process, or synaptic vesicle dynamics affecting available pools. Yet, recent studies have yielded conflicting results regarding the ability of CaMKII to influence NTR at rod bipolar cell (RBC) ribbon synapses. To address this, we acutely manipulated CaMKII activity in synaptic terminals of zebrafish RBCs by infusion of either inhibitory peptides targeting CaMKII or CaM, or a constitutively active CaMKII, while using a combination of imaging and electrophysiological approaches. Neither inhibiting nor enhancing CaMKII activity affects presynaptic Ca2+ channel activity. However, capacitance measurements revealed that inhibition of either CaMKII or CaM reduces exocytosis. CaMKII inhibition also reduces synaptic vesicle replenishment. Surprisingly, elevation of CaMKII activity also diminished vesicle fusion, similar to the effect of CaMKII inhibition, suggesting that CaMKII activity naturally exists at optimal levels to support neurotransmitter release. In contrast to CaMKII inhibition, CaMKII activity elevation did not impair vesicle replenishment. Collectively, these data suggest that distinct synaptic vesicle populations are differentially reliant on the level of CaMKII activity. | | 6:46p |
Illusory tilt does not induce optostatic torsion
Viewing tilted images that contain spatial information about gravity and verticality, such as rotated landscapes, or leaning buildings, produces an eye movement response known as optostatic torsion (OST). OST consists of a small-amplitude rotation ~1deg of the eyes around the line of sight, in the same direction of image tilt. Here we aimed to determine whether illusory perceptions of visual tilt were sufficient to produce OST. The illusory stimulus was a variation of the Cafe Wall illusion, applied to four "walls" to approximate the appearance of a tilted room. In a first experiment we determined the perceived magnitude of tilt of the illusory stimulus using a two-alternative forced choice (2AFC) task, measuring the amount of tilt required to cancel the perceived illusory tilt for clockwise (CW) or counterclockwise (CCW) configurations. We found an illusory tilt of +3.67+-0.57deg and -3.80+-0.93deg, respectively. Then, in a second experiment, we recorded 3 dimensions of binocular eye movements in ten healthy subjects viewing one of four possible stimuli: 1) illusory, 2) non-illusory with small tilt, 3) landscape with small tilt, and 4) landscape with large tilt. Both the landscape (+-4deg tilt: 0.4+-0.1, p<0.05; +-30deg tilt: 0.5+-0.1, p<0.01;) and control stimulus (0.2deg+-0.1deg, p<0.05) produced a significant amount of OST when comparing left tilt and right tilt configurations while the illusory stimulus (0.11deg+-0.07deg, p=0.15) did not. This indicates a potential dissociation between our perception of tilt and the processing of tilt that drives the motor response of OST. | | 6:46p |
Two classes of amine/glutamate multi-transmitter neurons innervate Drosophila internal male reproductive organs
The essential outcome of a successful mating is the transfer of genetic material from males to females in sexually reproducing animals from insects to mammals. In males, this culminates in ejaculation, a precisely timed sequence of organ contractions driven by the concerted activity of interneurons, sensory neurons, and motor neurons. Although central command circuits that trigger copulation have been mapped, the motor architecture and the chemical logic that couple specific neuronal subclasses to organ specific contractility, seminal fluid secretion, and sperm emission remain largely uncharted. This gap in knowledge limits our ability to explain how neural circuits adapt to varying contexts and how their failure contributes to infertility. Here we present an in-depth anatomical and functional analysis of the motor neurons that innervate the internal male reproductive tract of Drosophila melanogaster. We identify two classes of multi-transmitter motor neurons based on neurotransmitter usage, namely octopamine and glutamate neurons (OGNs) and serotonin and glutamate neurons (SGNs), each with a biased pattern of innervation: SGNs predominate in the accessory glands, OGNs in the ejaculatory duct, with equal contributions of each to the seminal vesicles. Both classes co-express vesicular transporters for glutamate (vGlut) and amines (vMAT), confirming their dual chemical identity. Their target organs differentially express receptors for glutamate, octopamine, and serotonin, suggesting combinatorial neuromodulation of contractility. Functional manipulations show that SGNs are essential for male fertility but OGNs are dispensable. Glutamatergic transmission from both classes is also dispensable for fertility. These findings provide the first high-resolution map linking multi-transmitter motor neurons to specific reproductive organs, reveal an unexpected division of labor between serotonergic and octopaminergic signaling pathways, and establish a framework for dissecting conserved neural principles that govern ejaculation and male fertility. | | 6:46p |
Dynamics of Excitability in Axonal Trees
We report that axons of cortical neurons, structurally intricate excitable media, maintain somatic spike timing with high fidelity during spontaneous network activity, even at short (2--3 msec) inter-spike intervals. However, long series of external stimulation at physiological frequencies expose a vulnerability that varies depending on distance and branching. At 10 Hz, propagation delays increase within seconds, and failures accumulate over time, particularly in distal axonal branches. These effects are negligible at frequencies of 1--4 Hz. We attribute this phenomenon to the gradual and cumulative inactivation of sodium channels at vulnerable sites. Simulations incorporating this mechanism replicate the observed dynamics. Our findings underscore a limit on axonal reliability. To the extent that a sustained (seconds) drive at ca. 10 Hz or higher is physiologically feasible, axons should be regarded as active, heterogeneous structures with context-sensitive excitability. |
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