Russostaal5117

To study subtypes of ΔFosB-expressing neurons in the reward system, we performed in situ hybridization for glutamate decarboxylase 65 and tyrosine hydroxylase (TH) mRNA after ΔFosB immunohistochemistry. In the mPFC and Acb, the proportions of γ-aminobutyric acidergic (GABAergic) and non-GABAergic ΔFosB-expressing neurons were similar in BER and BEP rats. In the VTA, while the proportion of dopaminergic ΔFosB-expressing neurons was similar in both phenotypes, the proportion of GABAergic ΔFosB-expressing neurons was higher in BER than BEP rats. Our results suggest that reward processing brain regions, particularly the VTA, are important for the development of binge-like eating.During development, neurons generate excess processes which are then eliminated in concert with circuit maturation. C1q is the initiating protein in the complement cascade and has been implicated in this process, but whether C1q-mediated elimination is targeted to particular neural compartments is unclear. Using the murine retina, we identify C1q as a specific regulator of horizontal cell neurite confinement. Subsets of horizontal cell dendritic and axonal neurites extend into the outer retina suggesting that complement achieves both cellular and subcellular selectivity. These alterations emerge as outer retina synapses become mature. C1q expression is restricted to retina microglia, and the loss of C1q results in decreased microglia activation. This pathway appears independent of the C3a receptor (C3aR) and complement receptor 3 (CR3), as horizontal cells are normal when either protein is absent. Together, these data identify a new role for C1q in cell and neurite-specific confinement and implicate microglia-mediated phagocytosis in this process.The organization of proteins in the apposed nanodomains of pre- and postsynaptic compartments is thought to play a pivotal role in synaptic strength and plasticity. As such, the alignment between pre- and postsynaptic proteins may regulate, for example, the rate of presynaptic release or the strength of postsynaptic signaling. However, the analysis of these structures has mainly been restricted to subsets of synapses, providing a limited view of the diversity of synaptic protein cluster remodeling during synaptic plasticity. To characterize changes in the organization of synaptic nanodomains during synaptic plasticity over a large population of synapses, we combined STimulated Emission Depletion (STED) nanoscopy with a Python-based statistical object distance analysis (pySODA), in dissociated cultured hippocampal circuits exposed to treatments driving different forms of synaptic plasticity. The nanoscale organization, characterized in terms of coupling properties, of presynaptic (Bassoon, RIM1/2) and postsynaptic (PSD95, Homer1c) scaffold proteins was differently altered in response to plasticity-inducing stimuli. For the Bassoon - PSD95 pair, treatments driving synaptic potentiation caused an increase in their coupling probability, whereas a stimulus driving synaptic depression had an opposite effect. To enrich the characterization of the synaptic cluster remodeling at the population level, we applied unsupervised machine learning approaches to include selected morphological features into a multidimensional analysis. This combined analysis revealed a large diversity of synaptic protein cluster subtypes exhibiting differential activity-dependent remodeling, yet with common features depending on the expected direction of plasticity. The expanded palette of synaptic features revealed by our unbiased approach should provide a basis to further explore the widely diverse molecular mechanisms of synaptic plasticity.The ventromedial prefrontal cortex (vmPFC) plays a critical role in stress resilience through top-down inhibition of key stress-sensitive limbic and hindbrain structures, including the dorsal raphe nucleus (DRN). In a model of experience-dependent stress resistance, socially dominant Syrian hamsters display fewer signs of anxiety following acute social defeat when compared to subordinate or control counterparts. Further, dominants activate vmPFC neurons to a greater degree during stress than do subordinates and become stress-vulnerable following pharmacological inhibition of the vmPFC. Dominants also display fewer stress-activated DRN neurons than subordinates do, suggesting that dominance experience gates activation of vmPFC neurons that inhibit the DRN during social defeat stress. To test whether social dominance alters stress-induced activity of a vmPFC-DRN pathway, we injected a retrograde tracer, cholera toxin B (CTB), into the DRN of dominant, subordinate, and control hamsters and used a dual-label immunohistochemical approach to identify vmPFC neurons co-labeled with CTB and the defeat-induced expression of an immediate early gene, cFos. Results indicate that dominant hamsters display more cFos+ and dual-labeled cells in layers V/VI of infralimbic and prelimbic subregions of the vmPFC compared to other animals. Furthermore, vmPFC-DRN activation corresponded directly with proactive behavioral strategies during defeat, which is indicative of stress resilience. Together, results suggest that recruiting the vmPFC-DRN pathway during acute stress corresponds with resistance to the effects of social defeat in dominant hamsters. Overall, these findings indicate that a monosynaptic vmPFC-DRN pathway can be engaged in an experience-dependent manner, which has implications for behavioral interventions aimed at alleviating stress-related psychopathologies.Exercise plays a key role in preventing or treating mental or motor disorders caused by dysfunction of the serotonergic system. However, the electrophysiological and ionic channel mechanisms underlying these effects remain unclear. In this study, we investigated the effects of 3-week treadmill exercise on the electrophysiological and channel properties of dorsal raphe nucleus (DRN). Serotonin (5-HT) neurons in ePet-EYFP mice, using whole-cell patch clamp recording. Treadmill exercise was induced in ePet-EYFP mice of P21-24 for 3 weeks, and whole-cell patch clamp recording was performed on EYFP-positive 5-HT neurons from DRN slices of P42-45 mice. Experiment data showed that 5-HT neurons in the DRN were a heterogeneous population with multiple firing patterns (single firing, phasic firing, and tonic firing). Persistent inward currents (PICs) with multiple patterns were expressed in 5-HT neurons and composed of Cav1.3 (Ca-PIC) and sodium (Na-PIC) components. Exercise hyperpolarized the voltage threshold for act1 μm (p less then 0.001) especially within the range of 50-200 μm from the soma. Functional analysis suggested that treadmill exercise enhanced Na-PIC for facilitation of spike initiation and Ca-PIC for regulation of repetitive firing. We concluded that PICs broadly existed in DRN 5-HT neurons and could influence serotonergic neurotransmission in juvenile mice and that 3-week treadmill exercise induced synaptic adaptations, enhanced PICs, and thus upregulated the excitability of the 5-HT neurons.Glioblastoma (GBM) is the most common and devastating primary brain tumor, leading to a uniform fatality after diagnosis. A major difficulty in eradicating GBM is the presence of microscopic residual infiltrating disease remaining after multimodality treatment. Glioma cancer stem cells (CSCs) have been pinpointed as the treatment-resistant tumor component that seeds ultimate tumor progression. Despite the key role of CSCs, the ideal preclinical model to study the genetic and epigenetic landmarks driving their malignant behavior while simulating an accurate interaction with the tumor microenvironment (TME) is still missing. The introduction of three-dimensional (3D) tumor platforms, such as organoids and 3D bioprinting, has allowed for a better representation of the pathophysiologic interactions between glioma CSCs and the TME. Thus, these technologies have enabled a more detailed study of glioma biology, tumor angiogenesis, treatment resistance, and even performing high-throughput screening assays of drug susceptibility. First, we will review the foundation of glioma biology and biomechanics of the TME, and then the most up-to-date insights about the applicability of these new tools in malignant glioma research.Ischemic stroke can induce rapid activation of the microglia. It has been reported that the microglia's survival is dependent on colony-stimulating factor 1 receptor (CSF1R) signaling and that pharmacological inhibition of CSF1R leads to morphological changes in the microglia in the healthy brain. However, the impact of CSF1R inhibition on neuronal structures and motor ability after ischemia-reperfusion remains unclear. In this study, we investigated microglial de-ramification, proliferation, and activation after inhibition of CSF1R by a tyrosine kinase inhibitor (ki20227) in a mouse model of global cerebral ischemia induced by bilateral common carotid artery ligation (BCAL). In addition to microglial morphology, we evaluated the mRNA expression of cytokines, chemokines, and inflammatory receptors. Our results show that pharmacological inhibition of CSF1R in ischemic mice resulted in the blockade of microglial proliferation and a shift in microglial morphology reflected by excessive de-ramification and a more activated phenotype accompanied by an enhanced innate immune response. Furthermore, we show that pharmacological inhibition of CSF1R in ischemic mice resulted in the aggravation of neuronal degeneration and behavioral impairment. Intravital two-photon imaging revealed that although pharmacological inhibition of CSF1R did not affect the recovery of dendritic structures, it caused a significant increase in spine elimination during reperfusion in ischemic mice. These findings suggest that pharmacological inhibition of CSF1R induces a blockade of microglial proliferation and causes acute activation of the microglia accompanied by a severe inflammatory response. It aggravates neuronal degeneration, loss of dendritic spines, and behavioral deficits after transient global cerebral ischemia.Tauopathies are a class of neurodegenerative diseases, including Alzheimer's disease (AD), Frontotemporal Dementia (FTD), Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), and many others where microtubule-associated protein tau (MAPT or tau) is hyperphosphorylated and aggregated to form insoluble paired helical filaments (PHFs) and ultimately neurofibrillary tangles (NFTs). Autophagic-endolysosomal networks (AELN) play important roles in tau clearance. Excessive soluble neurotoxic forms of tau and tau hyperphosphorylated at specific sites are cleared through the ubiquitin-proteasome system (UPS), Chaperon-mediated Autophagy (CMA), and endosomal microautophagy (e-MI). On the other hand, intra-neuronal insoluble tau aggregates are often degraded within lysosomes by macroautophagy. AELN defects have been observed in AD, FTD, CBD, and PSP, and lysosomal dysfunction was shown to promote the cleavage and neurotoxicity of tau. Moreover, several AD risk genes (e.g., PICALM, GRN, and BIN1) have been associated with dysregulation of AELN in the late-onset sporadic AD. Conversely, tau dissociation from microtubules interferes with retrograde transport of autophagosomes to lysosomes, and that tau fragments can also lead to lysosomal dysfunction. Recent studies suggest that tau is not merely an intra-neuronal protein, but it can be released to brain parenchyma via extracellular vesicles, like exosomes and ectosomes, and thus spread between neurons. Extracellular tau can also be taken up by microglial cells and astrocytes, either being degraded through AELN or propagated via exosomes. This article reviews the complex roles of AELN in the degradation and transmission of tau, potential diagnostic/therapeutic targets and strategies based on AELN-mediated tau clearance and propagation, and the current state of drug development targeting AELN and tau against tauopathies.