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1.
EMBO J ; 41(15): e110721, 2022 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-35730718

RESUMEN

ΔfosB is an alternatively spliced product of the FosB gene that is essential for dopamine-induced reward pathways and that acts as a master switch for addiction. However, the molecular mechanisms of its generation and regulation by dopamine signaling are unknown. Here, we report that dopamine D1 receptor signaling synergizes with the activin/ALK4/Smad3 pathway to potentiate the generation of ΔFosB mRNA in medium spiny neurons (MSNs) of the nucleus accumbens (NAc) via activation of the RNA-binding protein PCBP1, a regulator of mRNA splicing. Concurrent activation of PCBP1 and Smad3 by D1 and ALK4 signaling induced their interaction, nuclear translocation, and binding to sequences in exon-4 and intron-4 of FosB mRNA. Ablation of either ALK4 or PCBP1 in MSNs impaired ΔFosB mRNA induction and nuclear translocation of ΔFosB protein in response to repeated co-stimulation of D1 and ALK4 receptors. Finally, ALK4 is required in NAc MSNs of adult mice for behavioral sensitization to cocaine. These findings uncover an unexpected mechanism for ΔFosB generation and drug-induced sensitization through convergent dopamine and ALK4 signaling.


Asunto(s)
Cocaína , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ARN/metabolismo , Receptores de Activinas Tipo I/metabolismo , Empalme Alternativo , Animales , Cocaína/metabolismo , Cocaína/farmacología , Dopamina/metabolismo , Ratones , Ratones Endogámicos C57BL , Núcleo Accumbens , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , ARN Mensajero/metabolismo , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo
2.
PLoS Biol ; 19(11): e3001350, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34748545

RESUMEN

The medial habenula (mHb) is an understudied small brain nucleus linking forebrain and midbrain structures controlling anxiety and fear behaviors. The mechanisms that maintain the structural and functional integrity of mHb neurons and their synapses remain unknown. Using spatiotemporally controlled Cre-mediated recombination in adult mice, we found that the glial cell-derived neurotrophic factor receptor alpha 1 (GFRα1) is required in adult mHb neurons for synaptic stability and function. mHb neurons express some of the highest levels of GFRα1 in the mouse brain, and acute ablation of GFRα1 results in loss of septohabenular and habenulointerpeduncular glutamatergic synapses, with the remaining synapses displaying reduced numbers of presynaptic vesicles. Chemo- and optogenetic studies in mice lacking GFRα1 revealed impaired circuit connectivity, reduced AMPA receptor postsynaptic currents, and abnormally low rectification index (R.I.) of AMPARs, suggesting reduced Ca2+ permeability. Further biochemical and proximity ligation assay (PLA) studies defined the presence of GluA1/GluA2 (Ca2+ impermeable) as well as GluA1/GluA4 (Ca2+ permeable) AMPAR complexes in mHb neurons, as well as clear differences in the levels and association of AMPAR subunits with mHb neurons lacking GFRα1. Finally, acute loss of GFRα1 in adult mHb neurons reduced anxiety-like behavior and potentiated context-based fear responses, phenocopying the effects of lesions to septal projections to the mHb. These results uncover an unexpected function for GFRα1 in the maintenance and function of adult glutamatergic synapses and reveal a potential new mechanism for regulating synaptic plasticity in the septohabenulointerpeduncular pathway and attuning of anxiety and fear behaviors.


Asunto(s)
Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Habénula/metabolismo , Neuronas/metabolismo , Envejecimiento , Animales , Ansiedad/fisiopatología , Conducta Animal , Miedo/fisiología , Glutamatos/metabolismo , Ratones Endogámicos C57BL , Red Nerviosa/fisiología , Terminales Presinápticos , Receptores AMPA/metabolismo , Sinapsis
3.
BMC Microbiol ; 14: 211, 2014 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-25085553

RESUMEN

BACKGROUND: The ability of S. pneumoniae to generate infections depends on the restrictions imposed by the host's immunity, in order to prevent the bacterium from spreading from the nasopharynx to other tissues, such as the brain. Some authors claim that strains of S. pneumoniae, which fail to survive in the bloodstream, can enter the brain directly from the nasal cavity by axonal transport through the olfactory and/or trigeminal nerves. However, from the immunological point of view, glial cells are far more responsive to bacterial infections than are neurons. This hypothesis is consistent with several recent reports showing that bacteria can infect glial cells from the olfactory bulb and trigeminal ganglia. Since our group previously demonstrated that Schwann cells (SCs) express a functional and appropriately regulated mannose receptor (MR), we decided to test whether SCs are involved in the internalization of S. pneumoniae via MR. RESULTS: Immediately after the interaction step, as well as 3 h later, the percentage of association was approximately 56.5%, decreasing to 47.2% and 40.8% after 12 and 24 h, respectively. Competition assays by adding a 100-fold excess of mannan prior to the S. pneumoniae infection reduced the number of infected cells at 3 and 24 h. A cytochemistry assay with Man/BSA-FITC binding was performed in order to verify a possible overlap between mannosylated ligands and internalized bacteria. Incubation of the SCs with Man/BSA-FITC resulted in a large number of intracellular S. pneumoniae, with nearly complete loss of the capsule. Moreover, the anti-pneumococcal antiserum staining colocalized with the internalized man/BSA-FITC, suggesting that both markers are present within the same endocytic compartment of the SC. CONCLUSIONS: Our data offer novel evidence that SCs could be essential for pneumococcal cells to escape phagocytosis and killing by innate immune cells. On the other hand, the results also support the idea that SCs are immunocompetent cells of the PNS that can mediate an efficient immune response against pathogens via MR.


Asunto(s)
Endocitosis , Interacciones Huésped-Patógeno , Lectinas Tipo C/metabolismo , Lectinas de Unión a Manosa/metabolismo , Receptores de Superficie Celular/metabolismo , Células de Schwann/inmunología , Células de Schwann/microbiología , Streptococcus pneumoniae/inmunología , Animales , Células Cultivadas , Receptor de Manosa , Ratas Wistar
4.
STAR Protoc ; 2(1): 100238, 2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33458703

RESUMEN

Adult-born neurons (ABNs) in the dentate gyrus bestow unique cellular plasticity to the mammalian brain. We recently found that the activity of ABNs during sleep is necessary for memory consolidation. Here, we describe our method for Ca2+ imaging of ABN activity using a miniaturized fluorescent microscope and sleep recordings. As preparatory surgery and post-recording data processing can be major obstacles, we provide detailed descriptions and problem-solving tips. For complete details on the use and execution of this protocol, please refer to Kumar et al. (2020).


Asunto(s)
Señalización del Calcio , Giro Dentado/metabolismo , Hipocampo/metabolismo , Microscopía Intravital , Neuronas/metabolismo , Animales , Ratones , Microscopía Fluorescente
5.
Neuron ; 107(3): 552-565.e10, 2020 08 05.
Artículo en Inglés | MEDLINE | ID: mdl-32502462

RESUMEN

The occurrence of dreaming during rapid eye movement (REM) sleep prompts interest in the role of REM sleep in hippocampal-dependent episodic memory. Within the mammalian hippocampus, the dentate gyrus (DG) has the unique characteristic of exhibiting neurogenesis persisting into adulthood. Despite their small numbers and sparse activity, adult-born neurons (ABNs) in the DG play critical roles in memory; however, their memory function during sleep is unknown. Here, we investigate whether young ABN activity contributes to memory consolidation during sleep using Ca2+ imaging in freely moving mice. We found that contextual fear learning recruits a population of young ABNs that are reactivated during subsequent REM sleep against a backdrop of overall reduced ABN activity. Optogenetic silencing of this sparse ABN activity during REM sleep alters the structural remodeling of spines on ABN dendrites and impairs memory consolidation. These findings provide a causal link between ABN activity during REM sleep and memory consolidation.


Asunto(s)
Condicionamiento Psicológico , Giro Dentado/fisiología , Consolidación de la Memoria/fisiología , Neuronas/fisiología , Sueño REM/fisiología , Animales , Calcio/metabolismo , Giro Dentado/citología , Electroencefalografía , Electromiografía , Miedo , Hipocampo , Aprendizaje , Ratones , Neurogénesis , Optogenética , Ritmo Teta
6.
Mol Neurodegener ; 7: 34, 2012 Jul 13.
Artículo en Inglés | MEDLINE | ID: mdl-22793996

RESUMEN

BACKGROUND: Among the essential biological roles of bone marrow-derived cells, secretion of many soluble factors is included and these small molecules can act upon specific receptors present in many tissues including the nervous system. Some of the released molecules can induce proliferation of Schwann cells (SC), satellite cells and lumbar spinal cord astrocytes during early steps of regeneration in a rat model of sciatic nerve transection. These are the major glial cell types that support neuronal survival and axonal growth following peripheral nerve injury. Fibroblast growth factor-2 (FGF-2) is the main mitogenic factor for SCs and is released in large amounts by bone marrow-derived cells, as well as by growing axons and endoneurial fibroblasts during development and regeneration of the peripheral nervous system (PNS). RESULTS: Here we show that bone marrow-derived cell treatment induce an increase in the expression of FGF-2 in the sciatic nerve, dorsal root ganglia and the dorsolateral (DL) region of the lumbar spinal cord (LSC) in a model of sciatic nerve transection and connection into a hollow tube. SCs in culture in the presence of bone marrow derived conditioned media (CM) resulted in increased proliferation and migration. This effect was reduced when FGF-2 was neutralized by pretreating BMMC or CM with a specific antibody. The increased expression of FGF-2 was validated by RT-PCR and immunocytochemistry in co-cultures of bone marrow derived cells with sciatic nerve explants and regenerating nerve tissue respectivelly. CONCLUSION: We conclude that FGF-2 secreted by BMMC strongly increases early glial proliferation, which can potentially improve PNS regeneration.


Asunto(s)
Células de la Médula Ósea/metabolismo , Proliferación Celular , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Regeneración Nerviosa/fisiología , Células de Schwann/metabolismo , Animales , Axotomía , Western Blotting , Línea Celular , Movimiento Celular , Técnica del Anticuerpo Fluorescente , Ganglios Espinales/metabolismo , Humanos , Masculino , Microscopía Confocal , Ratas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Nervio Ciático/lesiones , Nervio Ciático/metabolismo , Médula Espinal/metabolismo
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