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Scientific Reports Aug 2023The capacity of a physical system to transport and localize energy or information is usually linked to its spatial configuration. This is relevant for integration and...
The capacity of a physical system to transport and localize energy or information is usually linked to its spatial configuration. This is relevant for integration and transmission of signals as performed, for example, by the dendrites of neuronal cells. Inspired by recent works on the organization of spines on the surface of dendrites and how they promote localization or propagation of electrical impulses in neurons, here we propose a linear photonic lattice configuration to study how the geometric features of a dendrite-inspired lattice allows for the localization or propagation of light on a completely linear structure. We show that by increasing the compression of the photonic analogue of spines and thus, by increasing the coupling strength of the spines with the main chain (the "photonic dendrite"), flat band modes become prevalent in the system, allowing spatial localization in the linear - low energy - regime. Furthermore, we study the inclusion of disorder in the distribution of spines and show that the main features of ordered systems persist due to the robustness of the flat band states. Finally, we discuss if the photonic analog, having evanescent interactions, may provide insight into linear morphological mechanisms at work occurring in some biological systems, where interactions are of electric and biochemical origin.
PubMed: 37567902
DOI: 10.1038/s41598-023-39985-8 -
Research Square Dec 2023Proteostasis is maintained through regulated protein synthesis and degradation and chaperone-assisted protein folding. However, this is challenging in neuronal...
Proteostasis is maintained through regulated protein synthesis and degradation and chaperone-assisted protein folding. However, this is challenging in neuronal projections because of their polarized morphology and constant synaptic proteome remodeling. Using high-resolution fluorescence microscopy, we discovered that neurons localize a subset of chaperone mRNAs to their dendrites and use microtubule-based transport to increase this asymmetric localization following proteotoxic stress. The most abundant dendritic chaperone mRNA encodes a constitutive heat shock protein 70 family member (HSPA8). Proteotoxic stress also enhanced mRNA translation efficiency in dendrites. Stress-mediated mRNA localization to the dendrites was impaired by depleting fused in sarcoma-an amyotrophic lateral sclerosis-related protein-in cultured mouse motor neurons and expressing a pathogenic variant of heterogenous nuclear ribonucleoprotein A2/B1 in neurons derived from human induced pluripotent stem cells. These results reveal a crucial and unexpected neuronal stress response in which RNA-binding proteins increase the dendritic localization of mRNA to maintain proteostasis and prevent neurodegeneration.
PubMed: 38168440
DOI: 10.21203/rs.3.rs-3673702/v1 -
Acta Neurobiologiae Experimentalis Nov 2023Dendritogenesis, a process of dendritic arbor development, is essential for the formation of functional neuronal networks, and in mammals, it begins in early life and...
Dendritogenesis, a process of dendritic arbor development, is essential for the formation of functional neuronal networks, and in mammals, it begins in early life and continues into adulthood. It is a highly dynamic process in which dendritic branches form and regress until mature connectivity is achieved. Thereafter, dendritic branches are considered stable and do not undergo substantial rearrangements, although several exceptions have been described in the literature. After this long period of relative stability, significant changes in dendritic branching occur when the brain begins to age. Several neurological diseases, occurring both during development and in adulthood, have severe effects on the morphology of dendritic arbors, often associated with intellectual dysfunction. The molecular mechanisms of dendritogenesis are fairly well described. In contrast, knowledge of the molecular mechanisms of dendritic arbor stabilization and pathology‑induced instability is still quite incomplete, and several important questions remain unanswered. We describe the dynamic changes during development and adulthood and in different pathologies. Whenever possible, we also provide details on the molecular mechanisms behind dendritic dynamics and stability.
Topics: Animals; Brain; Mammals
PubMed: 38224286
DOI: 10.55782/ane-2023-2456 -
Neurophotonics Jul 2024The function of the hippocampus in behavior and cognition has long been studied primarily through electrophysiological recordings from freely moving rodents. However,... (Review)
Review
SIGNIFICANCE
The function of the hippocampus in behavior and cognition has long been studied primarily through electrophysiological recordings from freely moving rodents. However, the application of optical recording methods, particularly multiphoton fluorescence microscopy, in the last decade or two has dramatically advanced our understanding of hippocampal function. This article provides a comprehensive overview of techniques and biological findings obtained from multiphoton imaging of hippocampal neural circuits.
AIM
This review aims to summarize and discuss the recent technical advances in multiphoton imaging of hippocampal neural circuits and the accumulated biological knowledge gained through this technology.
APPROACH
First, we provide a brief overview of various techniques of multiphoton imaging of the hippocampus and discuss its advantages, drawbacks, and associated key innovations and practices. Then, we review a large body of findings obtained through multiphoton imaging by region (CA1 and dentate gyrus), cell type (pyramidal neurons, inhibitory interneurons, and glial cells), and cellular compartment (dendrite and axon).
RESULTS
Multiphoton imaging of the hippocampus is primarily performed under head-fixed conditions and can reveal detailed mechanisms of circuit operation owing to its high spatial resolution and specificity. As the hippocampus lies deep below the cortex, its imaging requires elaborate methods. These include imaging cannula implantation, microendoscopy, and the use of long-wavelength light sources. Although many studies have focused on the dorsal CA1 pyramidal cells, studies of other local and inter-areal circuitry elements have also helped provide a more comprehensive picture of the information processing performed by the hippocampal circuits. Imaging of circuit function in mouse models of Alzheimer's disease and other brain disorders such as autism spectrum disorder has also contributed greatly to our understanding of their pathophysiology.
CONCLUSIONS
Multiphoton imaging has revealed much regarding region-, cell-type-, and pathway-specific mechanisms in hippocampal function and dysfunction in health and disease. Future technological advances will allow further illustration of the operating principle of the hippocampal circuits via the large-scale, high-resolution, multimodal, and minimally invasive imaging.
PubMed: 38464393
DOI: 10.1117/1.NPh.11.3.033406 -
Autophagy Feb 2024The neuronal metastable proteome includes several aggregation-prone proteins related to neurodegeneration. The complex morphology of neurons with very thin processes and...
The neuronal metastable proteome includes several aggregation-prone proteins related to neurodegeneration. The complex morphology of neurons with very thin processes and enhanced protein turnover therefore necessitates efficient local machinery to remove excessive protein. In recent work we revealed that chaperone-mediated autophagy (CMA) provides cargo for dendritic exocytic lysosomes, a mechanism that serves in the rapid removal of disease-relevant, supersaturated proteins such as TARDBP/TDP-43 (TAR DNA binding protein) and HTT (huntingtin). We found that lysosomal exocytosis requires docking of the lysosomal protein LAMP2B to the glutamatergic receptor scaffold DLG3/SAP102 and that it is regulated by GRIN/NMDA (N-methyl-D-aspartate)-receptor activity. Thus, the small caliber of dendritic processes might impose a need for local disposal of aggregation-prone proteins like TARDBP and HTT. Moreover, we observed that lysosomal exocytosis might serve in both protein removal and modulation of synaptic processes, and the latter might be an inevitable consequence of the necessity for local disposal of CMA clients in dendrites.
Topics: Humans; Chaperone-Mediated Autophagy; Autophagy; Proteome; Neurons; Lysosomes
PubMed: 37876225
DOI: 10.1080/15548627.2023.2274256 -
Cell Death & Disease Apr 2024Cognitive dysfunction and dementia are critical symptoms of Lewy Body dementias (LBD). Specifically, alpha-synuclein (αSyn) accumulation in the hippocampus leading to...
Cognitive dysfunction and dementia are critical symptoms of Lewy Body dementias (LBD). Specifically, alpha-synuclein (αSyn) accumulation in the hippocampus leading to synaptic dysfunction is linked to cognitive deficits in LBD. Here, we investigated the pathological impact of αSyn on hippocampal neurons. We report that either αSyn overexpression or αSyn pre-formed fibrils (PFFs) treatment triggers the formation of cofilin-actin rods, synapse disruptors, in cultured hippocampal neurons and in the hippocampus of synucleinopathy mouse models and of LBD patients. In vivo, cofilin pathology is present concomitantly with synaptic impairment and cognitive dysfunction. Rods generation prompted by αSyn involves the co-action of the cellular prion protein (PrP) and the chemokine receptor 5 (CCR5). Importantly, we show that CCR5 inhibition, with a clinically relevant peptide antagonist, reverts dendritic spine impairment promoted by αSyn. Collectively, we detail the cellular and molecular mechanism through which αSyn disrupts hippocampal synaptic structure and we identify CCR5 as a novel therapeutic target to prevent synaptic impairment and cognitive dysfunction in LBD.
Topics: Animals; Mice; Humans; alpha-Synuclein; Dendritic Spines; Lewy Body Disease; Cognition Disorders; Actin Depolymerizing Factors; Receptors, CCR5
PubMed: 38615035
DOI: 10.1038/s41419-024-06630-9 -
Molecular Biology of the Cell Mar 2024Synaptic plasticity is a process that shapes neuronal connections during neurodevelopment and learning and memory. Autophagy is a mechanism that allows the cell to...
Synaptic plasticity is a process that shapes neuronal connections during neurodevelopment and learning and memory. Autophagy is a mechanism that allows the cell to degrade its unnecessary or dysfunctional components. Autophagosomes appear at dendritic spines in response to plasticity-inducing stimuli. Autophagy defects contribute to altered dendritic spine development, autistic-like behavior in mice, and neurological disease. While several studies have explored the involvement of autophagy in synaptic plasticity, the initial steps of the emergence of autophagosomes at the postsynapse remain unknown. Here, we demonstrate a postsynaptic association of autophagy-related protein 9A (Atg9A), known to be involved in the early stages of autophagosome formation, with Rab11, a small GTPase that regulates endosomal trafficking. Rab11 activity was necessary to maintain Atg9A-positive structures at dendritic spines. Inhibition of mTOR increased Rab11 and Atg9A interaction and increased the emergence of LC3 positive vesicles, an autophagosome membrane-associated protein marker, in dendritic spines when coupled to NMDA receptor stimulation. Dendritic spines with newly formed LC3+ vesicles were more resistant to NMDA-induced morphologic change. Rab11 DN overexpression suppressed appearance of LC3+ vesicles. Collectively, these results suggest that initiation of autophagy in dendritic spines depends on neuronal activity and Rab11a-dependent Atg9A interaction that is regulated by mTOR activity.
Topics: Animals; Mice; Autophagosomes; Autophagy; Dendritic Spines; N-Methylaspartate; TOR Serine-Threonine Kinases
PubMed: 38294869
DOI: 10.1091/mbc.E23-02-0060 -
CNS Neuroscience & Therapeutics Feb 2024This study aimed to investigate whether minocycline could influence alterations of microglial subtypes, the morphology of dendrites and dendritic spines, the...
PURPOSE
This study aimed to investigate whether minocycline could influence alterations of microglial subtypes, the morphology of dendrites and dendritic spines, the microstructures of synapses and synaptic proteins, or even cognition outcomes in immature male mice following status epilepticus (SE) induced by kainic acid.
METHODS
Golgi staining was performed to visualize the dendrites and dendritic spines of neurons of the hippocampus. The microstructures of synapses and synaptic proteins were observed using transmission electron microscopy and western blotting analysis, respectively. Microglial reactivation and their markers were evaluated using flow cytometry. The Morris water maze (MWM) test was used to analyze spatial learning and memory ability.
RESULTS
Significant partial spines increase (predominate in thin spines) was observed in the dendrites of neurons after acute SE and partial loss (mainly in thin spines) was presented by days 14 and 28 post-SE. The postsynaptic ultrastructure was impaired on the 7th and 14th days after SE. The proportion of M1 microglia increased significantly only after acute SE Similarly, the proportion of M2 microglia increased in the acute stage with high expression levels of all surface markers. In contrast, a decrease in M2 microglia and their markers was noted by day 14 post-SE. Minocycline could reverse the changes in dendrites and synaptic proteins caused by SE, and increase the levels of synaptic proteins. Meanwhile, minocycline could inhibit the reactivation of M1 microglia and the expression of their markers, except for promoting CD200R. In addition, treatment with minocycline could regulate the expression of M2 microglia and their surface markers, as well as ameliorating the impaired spatial learning and memory on the 28th day after SE.
CONCLUSIONS
Dendritic spines and microglia are dynamically changed after SE. Minocycline could ameliorate the impaired cognition in the kainic acid-induced mouse model by decreasing the damage to dendrites and altering microglial reactivation.
Topics: Mice; Male; Animals; Kainic Acid; Microglia; Minocycline; Dendritic Spines; Hippocampus; Status Epilepticus
PubMed: 37438982
DOI: 10.1111/cns.14352 -
ENeuro Aug 2023Several neurodevelopmental disorders are associated with increased mTOR activity that results in pathogenic neuronal dysmorphogenesis (i.e., soma and dendrite...
Several neurodevelopmental disorders are associated with increased mTOR activity that results in pathogenic neuronal dysmorphogenesis (i.e., soma and dendrite overgrowth), leading to circuit alterations associated with epilepsy and neurologic disabilities. Although an mTOR analog is approved for the treatment of epilepsy in one of these disorders, it has limited efficacy and is associated with a wide range of side effects. There is a need to develop novel agents for the treatment of mTOR-pathway related disorders. Here, we developed a medium-throughput phenotypic assay to test drug efficacy on neurite morphogenesis of mouse neurons in a hyperactive mTOR condition. Our assay involved electroporation (IUE) of a selective population of cortical pyramidal neurons with a plasmid encoding the constitutively active mTOR activator, Rheb, and tdTomato. Labeled neurons from the somatosensory cortex (SSC) were cultured onto 96-well plates and fixed at various days or following Torin 1 treatment. Automated systems were used for image acquisition and neuron morphologic measurements. We validated our automated approach using traditional manual methods of neuron morphologic assessment. Both automated and manual analyses showed increased neurite length and complexity over time, and decreased neurite overgrowth and soma size with Torin 1. These data validate the accuracy of our automated approach that takes hours compared with weeks when using traditional manual methods. Taken together, this assay can be scaled to screen 32 compounds simultaneously in two weeks, highlighting its robustness and efficiency for medium-throughput screening of candidate therapeutics on a defined population of wild-type or diseased neurons.
Topics: Animals; Mice; Neurons; Neurites; Pyramidal Cells; Electroporation; TOR Serine-Threonine Kinases
PubMed: 37620147
DOI: 10.1523/ENEURO.0160-23.2023 -
Neuroscience and Biobehavioral Reviews Jun 2024Pyramidal neurons have a pivotal role in the cognitive capabilities of neocortex. Though they have been predominantly modeled as integrate-and-fire point processors,... (Review)
Review
Pyramidal neurons have a pivotal role in the cognitive capabilities of neocortex. Though they have been predominantly modeled as integrate-and-fire point processors, many of them have another point of input integration in their apical dendrites that is central to mechanisms endowing them with the sensitivity to context that underlies basic cognitive capabilities. Here we review evidence implicating impairments of those mechanisms in three major neurodevelopmental disabilities, fragile X, Down syndrome, and fetal alcohol spectrum disorders. Multiple dysfunctions of the mechanisms by which pyramidal cells are sensitive to context are found to be implicated in all three syndromes. Further deciphering of these cellular mechanisms would lead to the understanding of and therapies for learning disabilities beyond any that are currently available.
Topics: Humans; Animals; Learning Disabilities; Pyramidal Cells; Fetal Alcohol Spectrum Disorders; Neurodevelopmental Disorders; Down Syndrome; Fragile X Syndrome
PubMed: 38670298
DOI: 10.1016/j.neubiorev.2024.105688