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JOURNAL/nrgr/04.03/01300535-202503000-00027/figure1/v/2024-06-17T092413Z/r/image-tiff Repetitive traumatic brain injury impacts adult neurogenesis in the hippocampal dentate gyrus, leading to long-term cognitive impairment. However, the mechanism underlying this neurogenesis impairment remains unknown. In this study, we established a male mouse model of repetitive traumatic brain injury and performed long-term evaluation of neurogenesis of the hippocampal dentate gyrus after repetitive traumatic brain injury. Our results showed that repetitive traumatic brain injury inhibited neural stem cell proliferation and development, delayed neuronal maturation, and reduced the complexity of neuronal dendrites and spines. Mice with repetitive traumatic brain injuryalso showed deficits in spatial memory retrieval. Moreover, following repetitive traumatic brain injury, neuroinflammation was enhanced in the neurogenesis microenvironment where C1q levels were increased, C1q binding protein levels were decreased, and canonical Wnt/ß-catenin signaling was downregulated. An inhibitor of C1 reversed the long-term impairment of neurogenesis induced by repetitive traumatic brain injury and improved neurological function. These findings suggest that repetitive traumatic brain injury-induced C1-related inflammation impairs long-term neurogenesis in the dentate gyrus and contributes to spatial memory retrieval dysfunction.
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At the synapse, presynaptic neurotransmitter release is tightly controlled by release machinery, involving the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins and Munc13. The Ca2+ sensor Doc2 cooperates with Munc13 to regulate neurotransmitter release, but the underlying mechanisms remain unclear. In our study, we have characterized the binding mode between Doc2 and Munc13 and found that Doc2 originally occludes Munc13 to inhibit SNARE complex assembly. Moreover, our investigation unveiled that EphB2, a presynaptic adhesion molecule (SAM) with inherent tyrosine kinase functionality, exhibits the capacity to phosphorylate Doc2. This phosphorylation attenuates Doc2 block on Munc13 to promote SNARE complex assembly, which functionally induces spontaneous release and synaptic augmentation. Consistently, application of a Doc2 peptide that interrupts Doc2-Munc13 interplay impairs excitatory synaptic transmission and leads to dysfunction in spatial learning and memory. These data provide evidence that SAMs modulate neurotransmitter release by controlling SNARE complex assembly.
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Proteínas de Ligação ao Cálcio , Proteínas do Tecido Nervoso , Neurotransmissores , Receptor EphB2 , Proteínas SNARE , Transmissão Sináptica , Proteínas SNARE/metabolismo , Animais , Neurotransmissores/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Fosforilação , Receptor EphB2/metabolismo , Receptor EphB2/genética , Proteínas de Ligação ao Cálcio/metabolismo , Ligação Proteica , Humanos , Camundongos , RatosRESUMO
INTRODUCTION: Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer with an extremely dismal prognosis and few treatment options. As a desmoplastic tumor, TNBC tumor cells are girdled by stroma composed of cancer-associated fibroblasts (CAFs) and their secreted stromal components. The rapidly proliferating tumor cells, together with the tumor stroma, exert additional solid tissue pressure on tumor vasculature and surrounding tissues, severely obstructing therapeutic agent from deep intratumoral penetration, and resulting in tumor metastasis and treatment resistance. OBJECTIVES: Fucoxanthin (FX), a xanthophyll carotenoid abundant in marine algae, has attracted widespread attention as a promising alternative candidate for tumor prevention and treatment. Twist is a pivotal regulator of epithelial to mesenchymal transition, and its depletion has proven to sensitize antitumor drugs, inhibit metastasis, reduce CAFs activation and the following interstitial deposition, and increase tumor perfusion. The nanodrug delivery system co-encapsulating FX and nucleic acid drug Twist siRNA (siTwist) was expected to form a potent anti-TNBC therapeutic cyclical feedback loop. METHODS AND RESULTS: Herein, our studies constituted a novel self-assembled polymer nanomedicine (siTwist/FX@HES-CH) based on the amino-modified hydroxyethyl starch (HES-NH2) grafted with hydrophobic segment cholesterol (CH). The MTT assay, flow cytometry apoptosis analysis, transwell assay, western blot, and 3D multicellular tumor spheroids growth inhibition assay all showed that siTwist/FX@HES-CH could kill tumor cells and inhibit their metastasis in a synergistic manner. The in vivo anti-TNBC efficacy was demonstrated that siTwist/FX@HES-CH remodeled tumor microenvironment, facilitated interstitial barrier crossing, killed tumor cells synergistically, drastically reduced TNBC orthotopic tumor burden and inhibited lung metastasis. CONCLUSION: Systematic studies revealed that this dual-functional nanomedicine that targets both tumor cells and tumor microenvironment significantly alleviates TNBC orthotopic tumor burden and inhibits lung metastasis, establishing a new paradigm for TNBC therapy.
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The mechanisms behind a lack of efficient fear extinction in some individuals are unclear. Here, by employing a principal components analysis-based approach, we differentiated the mice into extinction-resistant and susceptible groups. We determined that elevated synapsin 2a (Syn2a) in the infralimbic cortex (IL) to basolateral amygdala (BLA) circuit disrupted presynaptic orchestration, leading to an excitatory/inhibitory imbalance in the BLA region and causing extinction resistance. Overexpression or silencing of Syn2a levels in IL neurons replicated or alleviated behavioral, electrophysiological, and biochemical phenotypes in resistant mice. We further identified that the proline-rich domain H in the C-terminus of Syn2a was indispensable for the interaction with synaptogyrin-3 (Syngr3) and demonstrated that disrupting this interaction restored extinction impairments. Molecular docking revealed that ritonavir, an FDA-approved HIV drug, could disrupt Syn2a-Syngr3 binding and rescue fear extinction behavior in Syn2a-elevated mice. In summary, the aberrant elevation of Syn2a expression and its interaction with Syngr3 at the presynaptic site were crucial in fear extinction resistance, suggesting a potential therapeutic avenue for related disorders.
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Medo , Córtex Pré-Frontal , Animais , Camundongos , Extinção Psicológica/fisiologia , Medo/fisiologia , Simulação de Acoplamento Molecular , Córtex Pré-Frontal/metabolismo , Sinapsinas/genética , Sinapsinas/metabolismo , Sinaptogirinas/metabolismoRESUMO
OBJECTIVE: To evaluate the impact of endoscopic surgery (ES) versus robot CAS-R-2 assisted with stereotactic drainage on prognosis of basal ganglia hypertensive intracerebral hemorrhage (HICH). METHODS: This retrospective observational study included patients who underwent ES or robot CAS-R-2 assisted with stereotactic drainage for basal ganglia HICH in Shanghai Sixth People's Hospital between June 2017 and May 2022. The outcomes were 6-month mortality and modified Rankin Scale (mRS) score. RESULTS: A total of 94 patients were included; 68 (age 51.26 ± 9.18 years, 17 women) of them underwent ES, while the other 26 (age 56.50 ± 12.91, 11 women) underwent robot CAS-R-2. The 6-month mortality rates were similar (P > 0.05) between the patients who underwent ES (6 of 68, 8.82%) and robot CAS-R-2 (2 of 26,7.69%), while the rate of good prognosis in the ES group was significantly higher compared with that in the robot CAS-R-2 group (P = 0.024). Univariate logistic analysis found that endoscopic surgery, age, and hematoma volume were associated with poor prognosis at 6 months. Multivariate logistic regression analysis showed that, after adjusted for the preoperative hematoma volume and age, endoscopy surgery (relative risk 0.21, 95% CI 0.06-0.68, P = 0.009) was associated with good prognosis at 6 months follow-up. CONCLUSIONS: Compared with robot CAS-R-2 assisted with stereotactic drainage, ES might have higher rate of good prognosis at 6-month follow-up for basal ganglia HICH.
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Hemorragia dos Gânglios da Base , Hemorragia Intracraniana Hipertensiva , Robótica , Humanos , Feminino , Recém-Nascido , Adulto , Pessoa de Meia-Idade , Resultado do Tratamento , Hemorragia Intracraniana Hipertensiva/cirurgia , China , Prognóstico , Drenagem , Endoscopia , Gânglios da Base , Estudos Retrospectivos , Hematoma/cirurgia , Hemorragia dos Gânglios da Base/cirurgia , Hemorragia Cerebral/cirurgiaRESUMO
Sorting nexin17 (SNX17) is a member of the sorting nexin family, which plays a crucial role in endosomal trafficking. Previous research has shown that SNX17 is involved in the recycling or degradation of various proteins associated with neurodevelopmental and neurological diseases in cell models. However, the significance of SNX17 in neurological function in the mouse brain has not been thoroughly investigated. In this study, we generated Snx17 knockout mice and observed that the homozygous deletion of Snx17 (Snx17-/-) resulted in lethality. On the other hand, heterozygous mutant mice (Snx17+/-) exhibited anxiety-like behavior with a reduced preference for social novelty. Furthermore, Snx17 haploinsufficiency led to impaired synaptic transmission and reduced maturation of dendritic spines. Through GST pulldown and interactome analysis, we identified the SRC kinase inhibitor, p140Cap, as a potential downstream target of SNX17. We also demonstrated that the interaction between p140Cap and SNX17 is crucial for dendritic spine maturation. Together, this study provides the first in vivo evidence highlighting the important role of SNX17 in maintaining neuronal function, as well as regulating social novelty and anxiety-like behaviors.
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Espinhas Dendríticas , Nexinas de Classificação , Animais , Camundongos , Espinhas Dendríticas/metabolismo , Homozigoto , Transporte Proteico , Deleção de Sequência , Nexinas de Classificação/genética , Nexinas de Classificação/metabolismoRESUMO
Sporadic or late-onset Alzheimer's disease (LOAD) accounts for more than 95% of Alzheimer's disease (AD) cases without any family history. Although genome-wide association studies have identified associated risk genes and loci for LOAD, numerous studies suggest that many adverse environmental factors, such as social isolation, are associated with an increased risk of dementia. However, the underlying mechanisms of social isolation in AD progression remain elusive. In the current study, we found that 7 days of social isolation could trigger pattern separation impairments and presynaptic abnormalities of the mossy fibre-CA3 circuit in AD mice. We also revealed that social isolation disrupted histone acetylation and resulted in the downregulation of 2 dentate gyrus (DG)-enriched miRNAs, which simultaneously target reticulon 3 (RTN3), an endoplasmic reticulum protein that aggregates in presynaptic regions to disturb the formation of functional mossy fibre boutons (MFBs) by recruiting multiple mitochondrial and vesicle-related proteins. Interestingly, the aggregation of RTN3 also recruits the PP2A B subunits to suppress PP2A activity and induce tau hyperphosphorylation, which, in turn, further elevates RTN3 and forms a vicious cycle. Finally, using an artificial intelligence-assisted molecular docking approach, we determined that senktide, a selective agonist of neurokinin3 receptors (NK3R), could reduce the binding of RTN3 with its partners. Moreover, application of senktide in vivo effectively restored DG circuit disorders in socially isolated AD mice. Taken together, our findings not only demonstrate the epigenetic regulatory mechanism underlying mossy fibre synaptic disorders orchestrated by social isolation and tau pathology but also reveal a novel potential therapeutic strategy for AD.
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Doença de Alzheimer , Fragmentos de Peptídeos , Substância P/análogos & derivados , Camundongos , Animais , Doença de Alzheimer/metabolismo , Inteligência Artificial , Estudo de Associação Genômica Ampla , Simulação de Acoplamento Molecular , Transtornos da Memória/metabolismoRESUMO
Membraneless organelles formed by phase separation of proteins and nucleic acids play diverse cellular functions. Whether and, if yes, how membraneless organelles in ways analogous to membrane-based organelles also undergo regulated fusion and fission is unknown. Here, using a partially reconstituted mammalian postsynaptic density (PSD) condensate as a paradigm, we show that membraneless organelles can undergo phosphorylation-dependent fusion and fission. Without phosphorylation of the SAPAP guanylate kinase domain-binding repeats, the upper and lower layers of PSD protein mixtures form two immiscible sub-compartments in a phase-in-phase organization. Phosphorylation of SAPAP leads to fusion of the two sub-compartments into one condensate accompanied with an increased Stargazin density in the condensate. Dephosphorylation of SAPAP can reverse this event. Preventing SAPAP phosphorylation in vivo leads to increased separation of proteins from the lower and upper layers of PSD sub-compartments. Thus, analogous to membrane-based organelles, membraneless organelles can also undergo regulated fusion and fission.
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Condensados Biomoleculares , Densidade Pós-Sináptica , Animais , Fosforilação , Densidade Pós-Sináptica/metabolismo , Fenômenos Fisiológicos Celulares , Ligação Proteica , Organelas/metabolismo , MamíferosRESUMO
Alzheimer's disease (AD) is traditionally considered as a brain disorder featured by amyloid-ß (Aß) deposition. The current study on whether pathological changes of AD extend to the enteric nervous system (ENS) is still in its infancy. In this study, we found enteric Aß deposition, intestinal dysfunction, and colonic inflammation in the young APP/PS1 mice. Moreover, these mice exhibited cholinergic and nitrergic signaling pathways damages and enteric neuronal loss. Our data show that Aß42 treatment remarkably affected the gene expression of cultured myenteric neurons and the spontaneous contraction of intestinal smooth muscles. The intra-colon administration of Aß42 induced ENS dysfunction, brain gliosis, and ß-amyloidosis-like changes in the wild-type mice. Our results suggest that ENS mirrors the neuropathology observed in AD brains, and intestinal pathological changes may represent the prodromal events, which contribute to brain pathology in AD. In summary, our findings provide new opportunities for AD early diagnosis and prevention.
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Doença de Alzheimer , Gastroenteropatias , Camundongos , Animais , Doença de Alzheimer/genética , Camundongos Transgênicos , Peptídeos beta-Amiloides/genética , NeurôniosRESUMO
IQSEC2 (aka BRAG1) is a guanine nucleotide exchange factor (GEF) highly enriched in synapses. As a top neurodevelopmental disorder risk gene, numerous mutations are identified in Iqsec2 in patients with intellectual disabilities accompanied by other developmental, neurological, and psychiatric symptoms, though with poorly understood underlying molecular mechanisms. The atomic structures of IQSECs, together with biochemical analysis, presented in this study reveal an autoinhibition and Ca2+-dependent allosteric activation mechanism for all IQSECs and rationalize how each identified Iqsec2 mutation can alter the structure and function of the enzyme. Transgenic mice modeling two pathogenic variants of Iqsec2 (R359C and Q801P), with one activating and the other inhibiting the GEF activity of the enzyme, recapitulate distinct clinical phenotypes in patients. Our study demonstrates that different mutations on one gene such as Iqsec2 can have distinct neurological phenotypes and accordingly will require different therapeutic strategies.
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Cálcio , Fatores de Troca do Nucleotídeo Guanina , Transtornos do Neurodesenvolvimento , Animais , Humanos , Camundongos , Fatores de Troca do Nucleotídeo Guanina/genética , Camundongos Transgênicos , Mutação , Proteínas do Tecido Nervoso , FenótipoRESUMO
The inhibitory neurons in the brain play an essential role in neural network firing patterns by releasing γ-aminobutyric acid (GABA) as the neurotransmitter. In the mouse brain, based on the protein molecular markers, inhibitory neurons are usually to be divided into three non-overlapping groups: parvalbumin (PV), neuropeptide somatostatin (SST), and vasoactive intestinal peptide (VIP)-expressing neurons. Each neuronal group exhibited unique properties in molecule, electrophysiology, circuitry, and function. Calbindin 1 (Calb1), a ubiquitous calcium-binding protein, often acts as a "divider" in excitatory neuronal classification. Based on Calb1 expression, the excitatory neurons from the same brain region can be classified into two subgroups with distinct properties. Besides excitatory neurons, Calb1 also expresses in part of inhibitory neurons. But, to date, little research focused on the intersectional relationship between inhibitory neuronal subtypes and Calb1. In this study, we genetically targeted Calb1-expression (Calb1+) and Calb1-lacking (Calb1-) subgroups of PV and SST neurons throughout the mouse brain by flexibly crossing transgenic mice relying on multi-recombinant systems, and the distribution patterns and electrophysiological properties of each subgroup were further demonstrated. Thus, this study provided novel insights and strategies into inhibitory neuronal classification.
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Encéfalo , Redes Neurais de Computação , Animais , Camundongos , Calbindina 1 , Camundongos Transgênicos , Neurônios , ParvalbuminasRESUMO
Retrograde tracing is an important method for dissecting neuronal connections and mapping neural circuits. Over the past decades, several virus-based retrograde tracers have been developed and have contributed to display multiple neural circuits in the brain. However, most of the previously widely used viral tools have focused on mono-transsynaptic neural tracing within the central nervous system, with very limited options for achieving polysynaptic tracing between the central and peripheral nervous systems. In this study, we generated a novel mouse line, GT mice, in which both glycoprotein (G) and ASLV-A receptor (TVA) were expressed throughout the body. Using this mouse model, in combination with the well-developed rabies virus tools (RABV-EnvA-ΔG) for monosynaptic retrograde tracing, polysynaptic retrograde tracing can be achieved. This allows functional forward mapping and long-term tracing. Furthermore, since the G-deleted rabies virus can travel upstream against the nervous system as the original strain, this mouse model can also be used for rabies pathological studies. Schematic illustrations about the application principles of GT mice in polysynaptic retrograde tracing and rabies pathological research.
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Vírus da Raiva , Raiva , Animais , Camundongos , Vírus da Raiva/fisiologia , Neurônios/fisiologia , Encéfalo , Rede NervosaRESUMO
The investigation of brain networks and neural circuits involves the crucial aspects of observing and modulating neurophysiological activity. Recently, opto-electrodes have emerged as an efficient tool for electrophysiological recording and optogenetic stimulation, which has greatly facilitated the analysis of neural coding. However, implantation and electrode weight control have posed significant challenges in achieving long-term and multi-regional brain recording and stimulation. To address this issue, we have developed a mold and custom-printed circuit board-based opto-electrode. We report successful opto-electrode placement and high-quality electrophysiological recordings from the default mode network (DMN) of the mouse brain. This novel opto-electrode facilitates synchronous recording and stimulation in multiple brain regions and holds promise for advancing future research on neural circuits and networks.
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H doping can enhance the performance of ZnO thin-film transistors (TFTs) to a certain extent, and the design of double active layers is an effective way to further improve a device's performance. However, there are few studies on the combination of these two strategies. We fabricated TFTs with ZnO:H (4 nm)/ZnO (20 nm) double active layers by magnetron sputtering at room temperature, and studied the effect of the hydrogen flow ratio on the devices' performance. ZnO:H/ZnO-TFT has the best overall performance when H2/(Ar + H2) = 0.13% with a mobility of 12.10 cm2/Vs, an on/off current ratio of 2.32 × 107, a subthreshold swing of 0.67 V/Dec, and a threshold voltage of 1.68 V, which is significantly better than the performance of single active layer ZnO:H-TFTs. This exhibits that the transport mechanism of carriers in double active layer devices is more complicated. On one hand, increasing the hydrogen flow ratio can more effectively suppress the oxygen-related defect states, thus reducing the carrier scattering and increasing the carrier concentration. On the other hand, the energy band analysis shows that electrons accumulate at the interface of the ZnO layer close to the ZnO:H layer, providing an additional path for carrier transport. Our research exhibits that the combination of a simple hydrogen doping process and double active layer construction can achieve the fabrication of high-performance ZnO-based TFTs, and that the whole room temperature process also provides important reference value for the subsequent development of flexible devices.
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The neuron-glia cross-talk is critical to brain homeostasis and is particularly affected by neurodegenerative diseases. How neurons manipulate the neuron-astrocyte interaction under pathological conditions, such as hyperphosphorylated tau, a pathological hallmark in Alzheimer's disease (AD), remains elusive. In this study, we identified excessively elevated neuronal expression of adenosine receptor 1 (Adora1 or A1R) in 3×Tg mice, MAPT P301L (rTg4510) mice, patients with AD, and patient-derived neurons. The up-regulation of A1R was found to be tau pathology dependent and posttranscriptionally regulated by Mef2c via miR-133a-3p. Rebuilding the miR-133a-3p/A1R signal effectively rescued synaptic and memory impairments in AD mice. Furthermore, neuronal A1R promoted the release of lipocalin 2 (Lcn2) and resulted in astrocyte activation. Last, silencing neuronal Lcn2 in AD mice ameliorated astrocyte activation and restored synaptic plasticity and learning/memory. Our findings reveal that the tau pathology remodels neuron-glial cross-talk and promotes neurodegenerative progression. Approaches targeting A1R and modulating this signaling pathway might be a potential therapeutic strategy for AD.
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Doença de Alzheimer , MicroRNAs , Animais , Camundongos , Doença de Alzheimer/metabolismo , Astrócitos/metabolismo , Modelos Animais de Doenças , Camundongos Transgênicos , MicroRNAs/metabolismo , Neurônios/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismo , HumanosRESUMO
Post-stroke depression (PSD) is a serious and common complication of stroke, which seriously affects the rehabilitation of stroke patients. To date, the pathogenesis of PSD is unclear and effective treatments remain unavailable. Here, we established a mouse model of PSD through photothrombosis-induced focal ischemia. By using a combination of brain imaging, transcriptome sequencing, and bioinformatics analysis, we found that the hippocampus of PSD mice had a significantly lower metabolic level than other brain regions. RNA sequencing revealed a significant reduction of miR34b-3p, which was expressed in hippocampal neurons and inhibited the translation of eukaryotic translation initiation factor 4E (eIF4E). Furthermore, silencing eIF4E inactivated microglia, inhibited neuroinflammation, and abolished the depression-like behaviors in PSD mice. Together, our data demonstrated that insufficient miR34b-3p after stroke cannot inhibit eIF4E translation, which causes PSD by the activation of microglia in the hippocampus. Therefore, miR34b-3p and eIF4E may serve as potential therapeutic targets for the treatment of PSD.
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Depressão , MicroRNAs , Acidente Vascular Cerebral , Animais , Camundongos , Fator de Iniciação 4E em Eucariotos/genética , Fator de Iniciação 4E em Eucariotos/metabolismo , MicroRNAs/metabolismo , Neurônios/metabolismo , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/metabolismoRESUMO
Monosynaptic viral tracers are essential tools for dissecting neuronal connectomes and for targeted delivery of molecular sensors and effectors. Viral toxicity and complex multi-injection protocols are major limiting application barriers. To overcome these barriers, we developed an anterograde monosynaptic H129Amp tracer system based on HSV-1 strain H129. The H129Amp tracer system consists of two components: an H129-dTK-T2-pacFlox helper which assists H129Amp tracer's propagation and transneuronal monosynaptic transmission. The shared viral features of tracer/helper allow for simultaneous single-injection and subsequent high expression efficiency from multiple-copy of expression cassettes in H129Amp tracer. These improvements of H129Amp tracer system shorten experiment duration from 28-day to 5-day for fast-bright monosynaptic tracing. The lack of toxic viral genes in the H129Amp tracer minimizes toxicity in postsynaptic neurons, thus offering the potential for functional anterograde mapping and long-term tracer delivery of genetic payloads. The H129Amp tracer system is a powerful tracing tool for revealing neuronal connectomes.
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Conectoma , Rede Nervosa , Herpesvirus Humano 1/genética , NeurôniosRESUMO
Major depressive disorder (MDD) is a severe mental illness. Decreased brain plasticity and dendritic fields have been consistently found in MDD patients and animal models; however, the underlying molecular mechanisms remain to be clarified. Here, we demonstrate that the deletion of cancerous inhibitor of PP2A (CIP2A), an endogenous inhibitor of protein phosphatase 2A (PP2A), leads to depression-like behaviors in mice. Hippocampal RNA sequencing analysis of CIP2A knockout mice shows alterations in the PI3K-AKT pathway and central nervous system development. In primary neurons, CIP2A stimulates AKT activity and promotes dendritic development. Further analysis reveals that the effect of CIP2A in promoting dendritic development is dependent on PP2A-AKT signaling. In vivo, CIP2A deficiency-induced depression-like behaviors and impaired dendritic arborization are rescued by AKT activation. Decreased CIP2A expression and impaired dendrite branching are observed in a mouse model of chronic unpredictable mild stress (CUMS). Indicative of clinical relevance to humans, CIP2A expression is found decreased in transcriptomes from MDD patients. In conclusion, we discover a novel mechanism that CIP2A deficiency promotes depression through the regulation of PP2A-AKT signaling and dendritic arborization.