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BioRxiv : the Preprint Server For... Jun 2024Motor skill learning induces long-lasting synaptic plasticity at not only the inputs, such as dendritic spines, but also at the outputs to the striatum of motor cortical...
Motor skill learning induces long-lasting synaptic plasticity at not only the inputs, such as dendritic spines, but also at the outputs to the striatum of motor cortical neurons. However, very little is known about the activity and structural plasticity of corticostriatal axons during learning in the adult brain. Here, we used longitudinal in vivo two-photon imaging to monitor the activity and structure of thousands of corticostriatal axonal boutons in the dorsolateral striatum in awake mice. We found that learning a new motor skill induces dynamic regulation of axonal boutons. The activities of motor corticostriatal axonal boutons exhibited selectivity for rewarded movements (RM) and un-rewarded movements (UM). Strikingly, boutons on the same axonal branches showed diverse responses during behavior. Motor learning significantly increased the fraction of RM boutons and reduced the heterogeneity of bouton activities. Moreover, motor learning-induced profound structural dynamism in boutons. By combining structural and functional imaging, we identified that newly formed axonal boutons are more likely to exhibit selectivity for RM and are stabilized during motor learning, while UM boutons are selectively eliminated. Our results highlight a novel form of plasticity at corticostriatal axons induced by motor learning, indicating that motor corticostriatal axonal boutons undergo dynamic reorganization that facilitates the acquisition and execution of motor skills.
PubMed: 38915677
DOI: 10.1101/2024.06.10.598366 -
BioRxiv : the Preprint Server For... Jun 2024In schizophrenia, layer 3 pyramidal neurons (L3PNs) in the dorsolateral prefrontal cortex (DLPFC) are thought to receive fewer excitatory synaptic inputs and to have...
UNLABELLED
In schizophrenia, layer 3 pyramidal neurons (L3PNs) in the dorsolateral prefrontal cortex (DLPFC) are thought to receive fewer excitatory synaptic inputs and to have lower expression levels of activity-dependent genes and of genes involved in mitochondrial energy production. In concert, these findings from previous studies suggest that DLPFC L3PNs are hypoactive in schizophrenia, disrupting the patterns of activity that are crucial for working memory, which is impaired in the illness. However, whether lower PN activity produces alterations in inhibitory and/or excitatory synaptic strength has not been tested in the primate DLPFC. Here, we decreased PN excitability in rhesus monkey DLPFC using adeno-associated viral vectors (AAVs) to produce Cre recombinase-mediated overexpression of Kir2.1 channels, a genetic silencing tool that efficiently decreases neuronal excitability. In acute slices prepared from DLPFC 7-12 weeks post-AAV microinjections, Kir2.1-overexpressing PNs had a significantly reduced excitability largely attributable to highly specific effects of the AAV-encoded Kir2.1 channels. Moreover, recordings of synaptic currents showed that Kir2.1-overexpressing DLPFC PNs had reduced strength of excitatory synapses whereas inhibitory synaptic inputs were not affected. The decrease in excitatory synaptic strength was not associated with changes in dendritic spine number, suggesting that excitatory synapse quantity was unaltered in Kir2.1-overexpressing DLPFC PNs. These findings suggest that, in schizophrenia, the excitatory synapses on hypoactive L3PNs are weaker and thus might represent a substrate for novel therapeutic interventions.
SIGNIFICANCE STATEMENT
In schizophrenia, dorsolateral prefrontal cortex (DLPFC) pyramidal neurons (PNs) have both transcriptional and structural alterations that suggest they are hypoactive. PN hypoactivity is thought to produce synaptic alterations in schizophrenia, however the effects of lower neuronal activity on synaptic function in primate DLPFC have not been examined. Here, we used, for the first time in primate neocortex, adeno-associated viral vectors (AAVs) to reduce PN excitability with Kir2.1 channel overexpression and tested if this manipulation altered the strength of synaptic inputs onto the Kir2.1-overexpressing PNs. Recordings in DLPFC slices showed that Kir2.1 overexpression depressed excitatory (but not inhibitory), synaptic currents, suggesting that, in schizophrenia, the hypoactivity of PNs might be exacerbated by reduced strength of the excitatory synapses they receive.
PubMed: 38915638
DOI: 10.1101/2024.06.12.598658 -
BioRxiv : the Preprint Server For... Jun 2024During development, microglia prune excess synapses to refine neuronal circuits. In neurodegeneration, the role of microglia-mediated synaptic pruning in circuit...
During development, microglia prune excess synapses to refine neuronal circuits. In neurodegeneration, the role of microglia-mediated synaptic pruning in circuit remodeling and dysfunction is important for developing therapies aimed at modulating microglial function. Here we analyzed the role of microglia in the synapse disassembly of degenerating postsynaptic neurons in the inner retina. After inducing transient intraocular pressure elevation to injure retinal ganglion cells, microglia increase in number, shift to ameboid morphology, and exhibit greater process movement. Furthermore, due to the greater number of microglia, there is increased colocalization of microglia with synaptic components throughout the inner plexiform layer and with excitatory synaptic sites along individual ganglion cell dendrites. Microglia depletion partially restores ganglion cell function, suggesting that microglia activation may be neurotoxic in early neurodegeneration. Our results demonstrate the important role of microglia in synapse disassembly in degenerating circuits, highlighting their recruitment to synaptic sites early after neuronal injury.
PubMed: 38915631
DOI: 10.1101/2024.06.13.598914 -
BioRxiv : the Preprint Server For... Jun 2024Prosapip1 is a brain-specific protein localized to the postsynaptic density, where it promotes dendritic spine maturation in primary hippocampal neurons. However,...
Prosapip1 is a brain-specific protein localized to the postsynaptic density, where it promotes dendritic spine maturation in primary hippocampal neurons. However, nothing is known about the role of Prosapip1 . To examine this, we utilized the Cre-loxP system to develop a Prosapip1 neuronal knockout mouse. We found that Prosapip1 controls the synaptic localization of its binding partner SPAR, along with PSD-95 and the GluN2B subunit of the NMDA receptor (NMDAR) in the dorsal hippocampus (dHP). We next sought to identify the potential contribution of Prosapip1 to the activity and function of the NMDAR and found that Prosapip1 plays an important role in NMDAR-mediated transmission and long-term potentiation (LTP) in the CA1 region of the dHP. As LTP is the cellular hallmark of learning and memory, we examined the consequences of neuronal knockout of Prosapip1 on dHP-dependent memory. We found that global or dHP-specific neuronal knockout of Prosapip1 caused a deficit in learning and memory whereas developmental, locomotor, and anxiety phenotypes were normal. Taken together, Prosapip1 in the dHP promotes the proper localization of synaptic proteins which, in turn, facilitates LTP driving recognition, social, and spatial learning and memory.
PubMed: 38915579
DOI: 10.1101/2024.06.13.597459 -
BioRxiv : the Preprint Server For... Jun 2024The aging of mammalian ovary is accompanied by an increase in tissue fibrosis and heightened inflammation. Myeloid cells, including macrophages, monocytes, dendritic...
The aging of mammalian ovary is accompanied by an increase in tissue fibrosis and heightened inflammation. Myeloid cells, including macrophages, monocytes, dendritic cells, and neutrophils, play pivotal roles in shaping the ovarian tissue microenvironment and regulating inflammatory responses. However, a comprehensive understanding of the roles of these cells in the ovarian aging process is lacking. To bridge this knowledge gap, we utilized single-cell RNA sequencing (scRNAseq) and flow cytometry analysis to functionally characterize CD45 CD11b myeloid cell populations in young (3 months old) and aged (14-17 months old) murine ovaries. Our dataset unveiled the presence of five ovarian macrophage subsets, including a subset unique to the aged murine ovary. Most notably, our data revealed significant alterations in ANNEXIN and TGFβ signaling within aged ovarian myeloid cells, which suggest a novel mechanism contributing to the onset and progression of aging-associated inflammation and fibrosis in the ovarian tissue.
PubMed: 38915572
DOI: 10.1101/2024.06.13.598667 -
BioRxiv : the Preprint Server For... Jun 2024The basic excitatory neurons of the cerebral cortex, the pyramidal cells, are the most important signal integrators for the local circuit. They have quite characteristic...
The basic excitatory neurons of the cerebral cortex, the pyramidal cells, are the most important signal integrators for the local circuit. They have quite characteristic morphological and electrophysiological properties that are known to be largely constant with age in the young and adult cortex. However, the brain undergoes several dynamic changes throughout life, such as in the phases of early development and cognitive decline in the aging brain. We set out to search for intrinsic cellular changes in supragranular pyramidal cells across a broad age range: from birth to 85 years of age and we found differences in several biophysical properties between defined age groups. During the first year of life, subthreshold and suprathreshold electrophysiological properties changed in a way that shows that pyramidal cells become less excitable with maturation, but also become temporarily more precise. According to our findings, the morphological features of the three-dimensional reconstructions from different life stages showed consistent morphological properties and systematic dendritic spine analysis of an infantile and an old pyramidal cell showed clear significant differences in the distribution of spine shapes. Overall, the changes that occur during development and aging may have lasting effects on the properties of pyramidal cells in the cerebral cortex. Understanding these changes is important to unravel the complex mechanisms underlying brain development, cognition and age-related neurodegenerative diseases.
PubMed: 38915496
DOI: 10.1101/2024.06.13.598792 -
BioRxiv : the Preprint Server For... Jun 2024Producing dense 3D reconstructions from biological imaging data is a challenging instance segmentation task that requires significant ground-truth training data for...
Producing dense 3D reconstructions from biological imaging data is a challenging instance segmentation task that requires significant ground-truth training data for effective and accurate deep learning-based models. Generating training data requires intense human effort to annotate each instance of an object across serial section images. Our focus is on the especially complicated brain neuropil, comprising an extensive interdigitation of dendritic, axonal, and glial processes visualized through serial section electron microscopy. We developed a novel deep learning-based method to generate dense 3D segmentations rapidly from sparse 2D annotations of a few objects on single sections. Models trained on the rapidly generated segmentations achieved similar accuracy as those trained on expert dense ground-truth annotations. Human time to generate annotations was reduced by three orders of magnitude and could be produced by non-expert annotators. This capability will democratize generation of training data for large image volumes needed to achieve brain circuits and measures of circuit strengths.
PubMed: 38915491
DOI: 10.1101/2024.06.14.599135 -
NPJ Climate and Atmospheric Science 2024Recent years have shown that secondary ice production (SIP) is ubiquitous, affecting all clouds from polar to tropical regions. SIP is not described well in models and...
Recent years have shown that secondary ice production (SIP) is ubiquitous, affecting all clouds from polar to tropical regions. SIP is not described well in models and may explain biases in warm mixed-phase cloud ice content and structure. Through modeling constrained by in-situ observations and its synergy with radar we show that SIP in orographic clouds exert a profound impact on the vertical distribution of hydrometeors and precipitation, especially in seeder-feeder cloud configurations. The mesoscale model simulations coupled with a radar simulator strongly support that enhanced aggregation and SIP through ice-ice collisions contribute to observed spectral bimodalities, skewing the Doppler spectra toward the slower-falling side at temperatures within the dendritic growth layer, ranging from -20 °C to -10 °C. This unique signature provides an opportunity to infer long-term SIP occurrences from the global cloud radar data archive, particularly for this underexplored temperature regime.
PubMed: 38915306
DOI: 10.1038/s41612-024-00671-9 -
PloS One 2024The intricate process of neuronal differentiation integrates multiple signals to induce transcriptional, morphological, and electrophysiological changes that reshape the...
The intricate process of neuronal differentiation integrates multiple signals to induce transcriptional, morphological, and electrophysiological changes that reshape the properties of neural precursor cells during their maturation and migration process. An increasing number of neurotransmitters and biomolecules have been identified as molecular signals that trigger and guide this process. In this sense, taurine, a sulfur-containing, non-essential amino acid widely expressed in the mammal brain, modulates the neuronal differentiation process. In this study, we describe the effect of taurine acting via the ionotropic GABAA receptor and the metabotropic GABAB receptor on the neuronal differentiation and electrophysiological properties of precursor cells derived from the subventricular zone of the mouse brain. Taurine stimulates the number of neurites and favors the dendritic complexity of the neural precursor cells, accompanied by changes in the somatic input resistance and the strength of inward and outward membranal currents. At the pharmacological level, the blockade of GABAA receptors inhibits these effects, whereas the stimulation of GABAB receptors has no positive effects on the taurine-mediated differentiation process. Strikingly, the blockade of the GABAB receptor with CGP533737 stimulates neurite outgrowth, dendritic complexity, and membranal current kinetics of neural precursor cells. The effects of taurine on the differentiation process involve Ca2+ mobilization and the activation of intracellular signaling cascades since chelation of intracellular calcium with BAPTA-AM, and inhibition of the CaMKII, ERK1/2, and Src kinase inhibits the neurite outgrowth of neural precursor cells of the subventricular zone.
Topics: Animals; Neural Stem Cells; Receptors, GABA-B; Mice; Cell Differentiation; Receptors, GABA-A; Lateral Ventricles; Taurine; Neurogenesis; Calcium
PubMed: 38913632
DOI: 10.1371/journal.pone.0305853 -
JCI Insight May 2024The regulated glycosylation of the proteome has widespread effects on biological processes that cancer cells can exploit. Expression of N-acetylglucosaminyltransferase V...
The regulated glycosylation of the proteome has widespread effects on biological processes that cancer cells can exploit. Expression of N-acetylglucosaminyltransferase V (encoded by Mgat5 or GnT-V), which catalyzes the addition of β1,6-linked N-acetylglucosamine to form complex N-glycans, has been linked to tumor growth and metastasis across tumor types. Using a panel of murine pancreatic ductal adenocarcinoma (PDAC) clonal cell lines that recapitulate the immune heterogeneity of PDAC, we found that Mgat5 is required for tumor growth in vivo but not in vitro. Loss of Mgat5 results in tumor clearance that is dependent on T cells and dendritic cells, with NK cells playing an early role. Analysis of extrinsic cell death pathways revealed Mgat5-deficient cells have increased sensitivity to cell death mediated by the TNF superfamily, a property that was shared with other non-PDAC Mgat5-deficient cell lines. Finally, Mgat5 knockout in an immunotherapy-resistant PDAC line significantly decreased tumor growth and increased survival upon immune checkpoint blockade. These findings demonstrate a role for N-glycosylation in regulating the sensitivity of cancer cells to T cell killing through classical cell death pathways.
Topics: Animals; Glycosylation; Mice; N-Acetylglucosaminyltransferases; Carcinoma, Pancreatic Ductal; Pancreatic Neoplasms; Cell Line, Tumor; Humans; T-Lymphocytes; Dendritic Cells; Killer Cells, Natural; Mice, Knockout
PubMed: 38912584
DOI: 10.1172/jci.insight.178804