bioRxiv Subject Collection: Neuroscience's Journal
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Monday, May 20th, 2024
| Time |
Event |
| 3:30a |
Brain Extracellular Matrix implications in multiple neurological disorders are revealed through a meta-analysis of transcriptional changes
Neurological disorders comprise a wide range of illnesses that may affect the central and peripheral nervous systems. Despite diverse etiologies, patients with these disorders may share symptoms. In this study, we aimed to explore potential common mechanisms between seven neurological disorders spanning three categories: neurodegenerative diseases, neuropsychiatric disorders, and neurodevelopmental disorders, by comparing gene expression profiles and focusing on the most prominent dysregulated genes consistently reported within and across disorders. Our results demonstrate 31 genes that are commonly differentially expressed in brain cells and tissues derived from human disease models when compared to healthy controls. These genes were enriched in brain Extracellular Matrix (ECM) pathways, Growth factor binding, Response to acid chemical, and External encapsulating structure. Remarkedly, dysregulation of ECM genes was evident separately in each of the three categories of disorders. This suggests a notable distinction in the brain ECM in disease states. Furthermore, we identified that the most frequently reported genes among all disorders were GFAP, and IFITM3. | | 3:30a |
Hidden state inference requires abstract contextual representations in ventral hippocampus
The ability to form and utilize subjective, latent contextual representations to influence decision making is a crucial determinant of everyday life. The hippocampus is widely hypothesized to bind together otherwise abstract combinations of stimuli to represent such latent contexts, and to allow their use to support the process of hidden state inference. Yet, direct evidence for this remains limited. Here we show that the CA1 area of the ventral hippocampus is necessary for mice to perform hidden state inference during a 2-armed bandit task. vCA1 neurons robustly differentiate between the two abstract contexts required for this strategy in a manner similar to the differentiation of spatial locations, despite the contexts being formed only from past probabilistic outcomes. These findings offer insight into how latent contextual information is used to optimize decision-making processes, and emphasize a key role of the hippocampus in hidden state inference. | | 3:30a |
Astrocytes adopt a progenitor-like migratory strategy for regeneration in adult brain
Mature astrocytes become activated upon non-specific tissue damage and contribute to glial scar formation. Proliferation and migration of adult reactive astrocytes after injury is considered very limited. However, the regenerative behavior of individual astrocytes following selective astroglial loss, as seen in astrocytopathies, such as neuromyelitis optica spectrum disorder, remains unexplored. Here, we performed longitudinal in vivo imaging of cortical astrocytes after focal astrocyte ablation in mice. We discovered that perilesional astrocytes develop a remarkable plasticity for efficient lesion repopulation. A subset of mature astrocytes transforms into reactive progenitor-like (REPL) astrocytes that not only undergo multiple asymmetric divisions but also remain in a multinucleated interstage. This regenerative response facilitates efficient migration of newly formed daughter cell nuclei towards unoccupied astrocyte territories. Our findings define the cellular principles of astrocyte plasticity upon focal lesion, unravelling the REPL phenotype as a fundamental regenerative strategy of mature astrocytes to restore astrocytic networks in the adult mammalian brain. Promoting this regenerative phenotype bears therapeutic potential for neurological conditions involving glial dysfunction. | | 3:30a |
Digital Twin Brain Simulator: Harnessing Primate ECoG Data for Real-Time Consciousness Monitoring and Virtual Intervention
At the forefront of bridging computational brain modeling with personalized medicine, this study introduces a novel, real-time, electrocorticogram (ECoG) simulator based on the digital twin brain concept. Utilizing advanced data assimilation techniques, specifically a Variational Bayesian Recurrent Neural Network model with hierarchical latent units, the simulator dynamically predicts ECoG signals reflecting real-time brain latent states. By assimilating broad ECoG signals from Macaque monkeys across awake and anesthetized conditions, the model successfully updated its latent states in real-time, enhancing the precision of ECoG signal simulations. Behind the successful data assimilation, a self-organization of latent states in the model was observed, reflecting brain states and individuality. This self-organization facilitated simulation of virtual drug administration and uncovered functional networks underlying changes in brain function during anesthesia. These results show that the proposed model is not only capable of simulating brain signals in real-time with high accuracy, but is also useful for revealing underlying information processing dynamics. | | 3:30a |
Phagocytosis-driven neurodegeneration through opposing roles of an ABC transporter in neurons and phagocytes
Lipid homeostasis is critical to the survival of neurons. Lipid transporters from the ATP-binding cassette A (ABCA) subfamily are important regulators of lipid trafficking and are associated with multiple neurodegenerative diseases. How ABCA transporters regulate specific aspects of lipid homeostasis to impact neurodegeneration is an outstanding question. Here we report that the Drosophila ABCA protein Engulfment ABC Transporter in the ovary (Eato) contributes to phagocytosis-dependent neurodegeneration by playing two opposing roles in neurons and nearby phagocytes: In neurons, Eato prevents dendrites and axons from being attacked and engulfed by neighboring phagocytes; in phagocytes, however, Eato enhances the ability of these cells to detect neurons as engulfment targets. Thus, Eato deficiency in neurons alone results in severe phagocytosis-dependent dendrite and axon degeneration, whereas removing Eato from both neurons and phagocytes completely rescues the neurite degeneration. Surprisingly, Eato exerts its functions in both neurons and phagocytes by suppressing the effects of the eat-me signal phosphatidylserine (PS) exposed on the cell surface. Interestingly, multiple human and C. elegans ABCA homologs can compensate for the loss of Eato in phagocytes but not in neurons, suggesting both conserved and cell type-specific activities of these ABCA proteins. These results reveal how ABCA proteins participate in neurodegeneration by regulating PS homeostasis and imply possible mechanisms of neuron-phagocyte interactions in neurodegenerative diseases. | | 3:30a |
The PVD neuron has male-specific structure and mating function in C. elegans
Neurons display unique shapes and establish intricate networks, which may differ between sexes. In complex organisms, studying sex differences in structure and function of individual neurons is difficult. The nematode Caenorhabditis elegans hermaphrodites and males present an exceptional model for studying neuronal morphogenesis in a simple, sexually-dimorphic system. We focus on the polymodal sensory bilateral neuron pair PVD, which forms a complex but stereotypic dendritic tree composed of multiple subunits that resemble candelabra. PVD was previously studied in hermaphrodites, but not in males. We find here that during larval development, male PVDs extend a similar architecture to the hermaphrodite utilizing a sexually-shared patterning mechanism. In early adulthood, however, male PVD develops a unique extension into the copulatory tail structure. This sexually-dimorphic arborization is absent in mutant backgrounds which perturb the sex-shared PVD guidance complex. SAX-7/L1CAM, a hypodermal component of this complex, shows a male-specific expression pattern which precedes PVD extension. Further, our results reveal that genetically altered arborization or ablation of the PVD result in male mating behavioral defects, particularly as males turn around the hermaphrodite. These results uncover an adult-stage sexual dimorphism of dendritic branching and uncover a new function for PVD in male sexual behavior. | | 3:30a |
Dynamic changes in mitochondria support phenotypic flexibility of microglia
The ability of microglia to sense the environment and alter their cellular phenotype according to local neuron and tissue needs is a hallmark feature of these cells. Numerous receptors that comprise the microglial "sensome" have been identified, but how microglia interpret combined signaling from diverse receptors and adjust multiple cellular attributes in a coordinated fashion is not well understood. Mitochondria are increasingly recognized as essential signaling hubs, and these organelles can regulate coordinated remodeling of cell attributes in immune cells, including macrophages. Given these findings, surprisingly little is known about microglial mitochondria in vivo and how the state of these organelles may impact microglial attributes and functions. Here, we generated novel transgenic crosses for high resolution analysis of microglial mitochondria in both fixed tissue and acute brain sections. Fixed tissue analysis indicated that mitochondrial abundance was tightly linked to microglial morphological complexity and that regional differences in microglial phenotype were accompanied by regional differences in mitochondrial mass and number. Surprisingly, multiphoton imaging revealed that mitochondrial abundance was not correlated with microglial cell process remodeling or rapid cell process extension toward focal sites of tissue injury. FACS- and qPCR-based analyses revealed remodeling of microglial mitochondrial state within hours of systemic LPS injections. Moreover, microglial expression of inflammation-, trophic-, and phagocytosis-relevant genes was strongly correlated with expression levels of numerous mitochondrial-relevant genes. Finally, FACS and fixed tissue imaging revealed that region-specific responses of microglia to aging were tightly linked to remodeling of these organelles. Overall, this study provides foundational information about microglial mitochondria and their relationship to differences in cell phenotype that occur across brain region, during pathological insults, and during aging. Moreover, these data demonstrate mitochondria support microglial phenotypic flexibility. | | 3:30a |
Mapping the Cerebrovascular Abnormality in Transgenic Alzheimer's Disease (AD) Mice with deep-learning-based super-resolution cerebral blood volume (CBV)-MRI
To measure the brain-wide vascular density (VD) alteration in degenerated brains with Alzheimer's Disease (AD), deep learning-based super-resolution approach was developed to assist the segmentation of micro-vessels from the Monocrystalline Iron Oxide Nanoparticle (MION)-based CBV MRI images of transgenic mouse brains. Iron-induced T2* amplification effect well separated micro-vessels with tens of microns from capillary-enriched parenchyma voxels, enabling vascular compartment-specific VD differential analysis between AD and wildtype control mice. The differential maps based on segmented micro-vessels identified decreased VD in the anterior cingulate cortex (ACC) and medial entorhinal cortex (mEC) and increased VD in several highlighted brain regions, including dentate gyrus (DG) of the hippocampus, central and geniculate thalamus, medial septal area (MS), ventral tegmental area (VTA), and lateral entorhinal cortex (lEC). In contrast, the T2*-weighted capillary density mapping from parenchyma voxels showed increased VD in several cortical regions, including somatosensory and visual cortex, retrosplenial cortex, as well as piriform area and lEC in AD brains. However, dramatic capillary VD decrease was observed in the subcortical areas including hippocampus, thalamus, hypothalamus, and pontine areas. These high-resolution MION-based CBV MRI elucidates altered vascular compartments in degenerated AD brains, reconciling the various region-specific vascular impairment and angiogenesis in functional areas critical for cognitive decline of AD. | | 3:30a |
Differential Control of Inhibitory and Excitatory Nerve Terminal Function by Mitochondria
Inhibitory neurons shape the brain's computational landscape and rely on different cellular architectures and intrinsic properties than excitatory neurons. Maintenance of the overall balance of excitatory (E) versus inhibitory (I) drive is essential, as disruptions can lead to neuropathological conditions, including autism and epilepsy. Metabolic perturbations are a common driver of E/I imbalance but differential sensitivity of these two neuron types to metabolic lesions is not well understood. Here, we characterized differences in presynaptic bioenergetic regulation between excitatory and inhibitory nerve terminals using genetically encoded indicators expressed in primary dissociated neuronal cultures. Our experiments showed that inhibitory nerve terminals sustain higher ATP levels than excitatory nerve terminals arising from increased mitochondrial metabolism. Additionally, mitochondria in inhibitory neurons play a greater role in buffering presynaptic Ca2+ and inhibitory mitochondrial Ca2+ handling is differentially regulated by TMEM65-meditaed acceleration of mitochondrial Ca2+ extrusion following bursts of activity. These experiments thus identify differential reliance on mitochondrial function across two major neuron types. | | 3:30a |
Intra-amygdala circuits of sleep disruption-induced anxiety in female mice
Combining mouse genetics, electrophysiology, and behavioral training and testing, we explored how sleep disruption may affect the function of anxiety-controlling circuits, focusing on projections from the basolateral nucleus of the amygdala (BLA) to CRF-positive cells in the lateral division of the central amygdala (CeL). We found in Crh-IRES-Cre::Ai14(tdTomato) reporter female mice that 6 hours of sleep disruption during their non-active (light) cycle may be anxiogenic. Notably, the AMPAR/NMDAR EPSC amplitude ratio at the BLA inputs to CRF-CeL cells (CRFCeL), assessed with whole-cell recordings in ex vivo experiments, was enhanced in slices from sleep-disrupted mice, whereas paired-pulse ratio (PPR) of the EPSCs induced by two closely spaced presynaptic stimuli remained unchanged. These findings indicate that sleep disruption-associated synaptic enhancements in glutamatergic projections from the BLA to CRF-CeL neurons may be postsynaptically expressed. We found also that the excitation/inhibition (E/I) ratio in the BLA to CRFCeL inputs was increased in sleep-disrupted mice, suggesting that the functional efficiency of excitation in BLA inputs to CRFCeL cells has increased following sleep disruption, thus resulting in their enhanced activation. The latter could be translated into enhanced anxiogenesis as activation of CRF cells in the CeL was shown to promote anxiety-like behaviors. | | 3:30a |
Bursts from the past: Intrinsic properties link a network model to zebra finch song
Neuronal intrinsic excitability is a mechanism implicated in learning and memory that is distinct from synaptic plasticity. Prior work in songbirds established that intrinsic properties (IPs) of premotor basal-ganglia-projecting neurons (HVCX) relate to learned song. Here we find that temporal song structure is related to specific HVCX IPs: HVCX from birds who sang longer songs including longer invariant vocalizations (harmonic stacks) had IPs that reflected increased post-inhibitory rebound. This suggests a rebound excitation mechanism underlying the ability of HVCX neurons to integrate over long periods of time and represent sequence information. To explore this, we constructed a network model of realistic neurons showing how in-vivo HVC bursting properties link rebound excitation to network structure and behavior. These results demonstrate an explicit link between neuronal IPs and learned behavior. We propose that sequential behaviors exhibiting temporal regularity require IPs to be included in realistic network-level descriptions. |
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