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1.
2.
Nat Neurosci ; 23(6): 707-717, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32451484

RESUMEN

Neuronal activation induces rapid transcription of immediate early genes (IEGs) and longer-term chromatin remodeling around secondary response genes (SRGs). Here, we use high-resolution chromosome-conformation-capture carbon-copy sequencing (5C-seq) to elucidate the extent to which long-range chromatin loops are altered during short- and long-term changes in neural activity. We find that more than 10% of loops surrounding select IEGs, SRGs, and synaptic genes are induced de novo during cortical neuron activation. IEGs Fos and Arc connect to activity-dependent enhancers via singular short-range loops that form within 20 min after stimulation, prior to peak messenger RNA levels. By contrast, the SRG Bdnf engages in both pre-existing and activity-inducible loops that form within 1-6 h. We also show that common single-nucleotide variants that are associated with autism and schizophrenia are colocalized with distinct classes of activity-dependent, looped enhancers. Our data link architectural complexity to transcriptional kinetics and reveal the rapid timescale by which higher-order chromatin architecture reconfigures during neuronal stimulation.


Asunto(s)
Ensamble y Desensamble de Cromatina/fisiología , Expresión Génica/fisiología , Genoma/genética , Neuronas/fisiología , Animales , Bicuculina/farmacología , Factor Neurotrófico Derivado del Encéfalo/fisiología , Ensamble y Desensamble de Cromatina/genética , Proteínas del Citoesqueleto/fisiología , Genoma/efectos de los fármacos , Humanos , Ratones , Proteínas del Tejido Nervioso/fisiología , Neuronas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/fisiología , Tetrodotoxina/farmacología , Factores de Tiempo
3.
Elife ; 82019 07 16.
Artículo en Inglés | MEDLINE | ID: mdl-31309928

RESUMEN

Symbiotic microbes impact the function and development of the central nervous system (CNS); however, little is known about the contribution of the microbiota during viral-induced neurologic damage. We identify that commensals aid in host defense following infection with a neurotropic virus through enhancing microglia function. Germfree mice or animals that receive antibiotics are unable to control viral replication within the brain leading to increased paralysis. Microglia derived from germfree or antibiotic-treated animals cannot stimulate viral-specific immunity and microglia depletion leads to worsened demyelination. Oral administration of toll-like receptor (TLR) ligands to virally infected germfree mice limits neurologic damage. Homeostatic activation of microglia is dependent on intrinsic signaling through TLR4, as disruption of TLR4 within microglia, but not the entire CNS (excluding microglia), leads to increased viral-induced clinical disease. This work demonstrates that gut immune-stimulatory products can influence microglia function to prevent CNS damage following viral infection.


Asunto(s)
Encefalitis Viral/patología , Encefalitis Viral/prevención & control , Microbioma Gastrointestinal/inmunología , Microglía/inmunología , Transducción de Señal , Simbiosis , Receptores Toll-Like/metabolismo , Animales , Modelos Animales de Enfermedad , Vida Libre de Gérmenes , Ratones
4.
Neuron ; 98(6): 1124-1132.e7, 2018 06 27.
Artículo en Inglés | MEDLINE | ID: mdl-29861284

RESUMEN

Neuronal activity regulates the transcription and translation of the immediate-early gene Arc/Arg3.1, a key mediator of synaptic plasticity. Proteasome-dependent degradation of Arc tightly limits its temporal expression, yet the significance of this regulation remains unknown. We disrupted the temporal control of Arc degradation by creating an Arc knockin mouse (ArcKR) where the predominant Arc ubiquitination sites were mutated. ArcKR mice had intact spatial learning but showed specific deficits in selecting an optimal strategy during reversal learning. This cognitive inflexibility was coupled to changes in Arc mRNA and protein expression resulting in a reduced threshold to induce mGluR-LTD and enhanced mGluR-LTD amplitude. These findings show that the abnormal persistence of Arc protein limits the dynamic range of Arc signaling pathways specifically during reversal learning. Our work illuminates how the precise temporal control of activity-dependent molecules, such as Arc, regulates synaptic plasticity and is crucial for cognition.


Asunto(s)
Cognición/fisiología , Proteínas del Citoesqueleto/genética , Depresión Sináptica a Largo Plazo/genética , Proteínas del Tejido Nervioso/genética , Plasticidad Neuronal/genética , ARN Mensajero/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Aprendizaje Inverso/fisiología , Aprendizaje Espacial/fisiología , Animales , Proteínas del Citoesqueleto/metabolismo , Técnicas de Sustitución del Gen , Depresión Sináptica a Largo Plazo/fisiología , Ratones , Mutación , Proteínas del Tejido Nervioso/metabolismo , Transporte de Proteínas , Proteolisis , Receptores AMPA/metabolismo , Factores de Tiempo , Ubiquitinación
6.
Cell ; 172(1-2): 275-288.e18, 2018 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-29328916

RESUMEN

The neuronal gene Arc is essential for long-lasting information storage in the mammalian brain, mediates various forms of synaptic plasticity, and has been implicated in neurodevelopmental disorders. However, little is known about Arc's molecular function and evolutionary origins. Here, we show that Arc self-assembles into virus-like capsids that encapsulate RNA. Endogenous Arc protein is released from neurons in extracellular vesicles that mediate the transfer of Arc mRNA into new target cells, where it can undergo activity-dependent translation. Purified Arc capsids are endocytosed and are able to transfer Arc mRNA into the cytoplasm of neurons. These results show that Arc exhibits similar molecular properties to retroviral Gag proteins. Evolutionary analysis indicates that Arc is derived from a vertebrate lineage of Ty3/gypsy retrotransposons, which are also ancestors to retroviruses. These findings suggest that Gag retroelements have been repurposed during evolution to mediate intercellular communication in the nervous system.


Asunto(s)
Proteínas del Citoesqueleto/metabolismo , Exosomas/metabolismo , Productos del Gen gag/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , ARN Mensajero/metabolismo , Animales , Células Cultivadas , Proteínas del Citoesqueleto/química , Proteínas del Citoesqueleto/genética , Endocitosis , Femenino , Productos del Gen gag/química , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Neuronas/fisiología
7.
Proc Natl Acad Sci U S A ; 114(34): 9182-9187, 2017 08 22.
Artículo en Inglés | MEDLINE | ID: mdl-28790183

RESUMEN

The molecular basis for the decline in experience-dependent neural plasticity over age remains poorly understood. In visual cortex, the robust plasticity induced in juvenile mice by brief monocular deprivation during the critical period is abrogated by genetic deletion of Arc, an activity-dependent regulator of excitatory synaptic modification. Here, we report that augmenting Arc expression in adult mice prolongs juvenile-like plasticity in visual cortex, as assessed by recordings of ocular dominance (OD) plasticity in vivo. A distinguishing characteristic of juvenile OD plasticity is the weakening of deprived-eye responses, believed to be accounted for by the mechanisms of homosynaptic long-term depression (LTD). Accordingly, we also found increased LTD in visual cortex of adult mice with augmented Arc expression and impaired LTD in visual cortex of juvenile mice that lack Arc or have been treated in vivo with a protein synthesis inhibitor. Further, we found that although activity-dependent expression of Arc mRNA does not change with age, expression of Arc protein is maximal during the critical period and declines in adulthood. Finally, we show that acute augmentation of Arc expression in wild-type adult mouse visual cortex is sufficient to restore juvenile-like plasticity. Together, our findings suggest a unifying molecular explanation for the age- and activity-dependent modulation of synaptic sensitivity to deprivation.


Asunto(s)
Proteínas del Citoesqueleto/fisiología , Proteínas del Tejido Nervioso/fisiología , Plasticidad Neuronal/fisiología , Corteza Visual/fisiología , Factores de Edad , Animales , Proteínas del Citoesqueleto/genética , Predominio Ocular/genética , Predominio Ocular/fisiología , Regulación del Desarrollo de la Expresión Génica , Depresión Sináptica a Largo Plazo/genética , Depresión Sináptica a Largo Plazo/fisiología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Plasticidad Neuronal/genética , Corteza Visual/crecimiento & desarrollo , Corteza Visual/metabolismo
8.
Front Mol Neurosci ; 10: 234, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28804447

RESUMEN

Angelman syndrome (AS) is a neurodevelopmental disorder that results from deletions or mutations in chromosome 15, which usually includes the UBE3A gene. Ube3A protein is an E3 ubiquitin ligase that ubiquitinates proteins and targets them for degradation. The immediate-early gene Arc, a master regulator of synaptic plasticity, was identified as a putative substrate of Ube3A, but there have been conflicting reports on whether Arc is a bona fide E3 ligase substrate. Using multiple approaches, we found no evidence for a physical interaction between Arc and Ube3A in vivo. Nonetheless, activity-induced subcellular distribution of Arc is altered in brains from Ube3am-/p+ mice, with abnormal concentration of Arc at synapses. Furthermore, although activation of Arc transcription is normal, the stability of Arc protein is enhanced in dendrites of hippocampal neurons cultured from Ube3am-/p+ mice. Finally, homeostatic synaptic scaling of surface AMPA receptors does not occur in Ube3am-/p+ hippocampal neurons, reminiscent of neurons that lack Arc protein. Although Ube3A does not seem to bind Arc in a canonical E3 ligase-substrate interaction, Arc-dependent synaptic plasticity is still altered in Ube3am-/p+ mice, which may underlie the cognitive deficits observed in AS.

9.
Neurotox Res ; 26(2): 152-67, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24562969

RESUMEN

Phasic dopamine (DA) signaling, during which burst firing by DA neurons generates short-lived elevations in extracellular DA in terminal fields called DA transients, is implicated in reinforcement learning. Disrupted phasic DA signaling is proposed to link DA depletions and cognitive-behavioral impairment in methamphetamine (METH)-induced neurotoxicity. Here, we further investigated this disruption by assessing effects of METH pretreatment on DA transients elicited by a drug cocktail of raclopride, a D2 DA receptor antagonist, and nomifensine, an inhibitor of the dopamine transporter (DAT). One advantage of this approach is that pharmacological activation provides a large, high-quality data set of transients elicited by endogenous burst firing of DA neurons for analysis of regional differences and neurotoxicity. These pharmacologically evoked DA transients were measured in the dorsomedial (DM) and dorsolateral (DL) striatum of urethane-anesthetized rats by fast-scan cyclic voltammetry. Electrically evoked DA levels were also recorded to quantify DA release and uptake, and DAT binding was determined by means of autoradiography to index DA denervation. Pharmacologically evoked DA transients in intact animals exhibited a greater amplitude and frequency and shorter duration in the DM compared to the DL striatum, despite similar pre- and post-drug assessments of DA release and uptake in both sub-regions as determined from the electrically evoked DA signals. METH pretreatment reduced transient activity. The most prominent effect of METH pretreatment on transients across striatal sub-region was decreased amplitude, which mirrored decreased DAT binding and was accompanied by decreased DA release. Overall, these results identify marked intrastriatal differences in the activity of DA transients that appear independent of presynaptic mechanisms for DA release and uptake and further support disrupted phasic DA signaling mediated by decreased DA release in rats with METH-induced neurotoxicity.


Asunto(s)
Estimulantes del Sistema Nervioso Central/toxicidad , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/fisiopatología , Dopamina/metabolismo , Metanfetamina/toxicidad , Síndromes de Neurotoxicidad/fisiopatología , Animales , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/fisiología , Masculino , Terminales Presinápticos/efectos de los fármacos , Terminales Presinápticos/fisiología , Ratas Sprague-Dawley , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología
10.
Neuropsychopharmacology ; 39(4): 963-72, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24150570

RESUMEN

Methamphetamine (METH)-induced neurotoxicity results in long-lasting depletions of monoamines and changes in basal ganglia function. We previously reported that rats with METH-induced neurotoxicity no longer engage dorsomedial striatum during a response-reversal learning task, as their performance is insensitive to acute disruption of dorsomedial striatal function by local infusion of an N-methyl-D-aspartate receptor antagonist or an antisense oligonucleotide against the activity-regulated cytoskeleton-associated (Arc) gene. However, METH-pretreated rats perform the task as well as controls. Therefore, we hypothesized that the neural circuitry involved in the learning had changed in METH-pretreated rats. To test this hypothesis, rats were pretreated with a neurotoxic regimen of METH or with saline. After 3-5 weeks, rats were trained on the reversal-learning task and in situ hybridization for Arc was performed. A significant correlation between Arc expression and performance on the task was found in nucleus accumbens shell of METH-, but not saline-, pretreated rats. Consistent with the idea that the correlation between Arc expression in a brain region and behavioral performance implicates that brain region in the learning, infusion of an antisense oligonucleotide against Arc into the shell impaired consolidation of reversal learning in METH-, but not saline-, pretreated rats. These findings provide novel evidence suggesting that METH-induced neurotoxicity leads to a shift from dorsal to ventral striatal involvement in the reversal-learning task. Such reorganization of neural circuitry underlying learning and memory processes may contribute to impaired cognitive function in individuals with METH-induced neurotoxicity or others with striatal dopamine loss, such as patients with Parkinson's disease.


Asunto(s)
Encéfalo/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Proteínas del Citoesqueleto/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Metanfetamina/farmacología , Proteínas del Tejido Nervioso/metabolismo , Retención en Psicología/efectos de los fármacos , Aprendizaje Inverso/efectos de los fármacos , Animales , Monoaminas Biogénicas/metabolismo , Encéfalo/metabolismo , Proteínas del Citoesqueleto/genética , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Esquema de Medicación , Masculino , Red Nerviosa/efectos de los fármacos , Red Nerviosa/metabolismo , Proteínas del Tejido Nervioso/genética , Oligodesoxirribonucleótidos Antisentido/farmacología , Unión Proteica/efectos de los fármacos , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo
11.
J Neurochem ; 125(4): 555-65, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23480199

RESUMEN

Methamphetamine-induced partial dopamine depletions are associated with impaired basal ganglia function, including decreased preprotachykinin mRNA expression and impaired transcriptional activation of activity-regulated, cytoskeleton-associated (Arc) gene in striatum. Recent work implicates deficits in phasic dopamine signaling as a potential mechanism linking methamphetamine-induced dopamine loss to impaired basal ganglia function. This study thus sought to establish a causal link between phasic dopamine transmission and altered basal ganglia function by determining whether the deficits in striatal neuron gene expression could be restored by increasing phasic dopamine release. Three weeks after pretreatment with saline or a neurotoxic regimen of methamphetamine, rats underwent phasic- or tonic-like stimulation of ascending dopamine neurons. Striatal gene expression was examined using in situ hybridization histochemistry. Phasic-like, but not tonic-like, stimulation induced immediate-early genes Arc and zif268 in both groups, despite the partial striatal dopamine denervation in methamphetamine-pretreated rats, with the Arc expression occurring in presumed striatonigral efferent neurons. Phasic-like stimulation also restored preprotachykinin mRNA expression. These results suggest that disruption of phasic dopamine signaling likely underlies methamphetamine-induced impairments in basal ganglia function, and that restoring phasic dopamine signaling may be a viable approach to manage long-term consequences of methamphetamine-induced dopamine loss on basal ganglia functions.


Asunto(s)
Cuerpo Estriado/fisiología , Dopamina/fisiología , Neuronas Dopaminérgicas/fisiología , Haz Prosencefálico Medial/fisiología , Metanfetamina/toxicidad , Síndromes de Neurotoxicidad/fisiopatología , Trastornos Relacionados con Anfetaminas/genética , Trastornos Relacionados con Anfetaminas/fisiopatología , Animales , Estimulantes del Sistema Nervioso Central/toxicidad , Cuerpo Estriado/efectos de los fármacos , Proteínas del Citoesqueleto/genética , Desnervación/métodos , Neuronas Dopaminérgicas/efectos de los fármacos , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Estimulación Eléctrica/métodos , Expresión Génica/efectos de los fármacos , Expresión Génica/fisiología , Genes Inmediatos-Precoces/genética , Masculino , Haz Prosencefálico Medial/efectos de los fármacos , Proteínas del Tejido Nervioso/genética , Síndromes de Neurotoxicidad/genética , Precursores de Proteínas/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Taquicininas/genética
12.
Neuropsychopharmacology ; 37(4): 885-95, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22071872

RESUMEN

Methamphetamine (METH) causes partial depletion of central monoamine systems and cognitive dysfunction in rats and humans. We have previously shown and now further show that the positive correlation between expression of the immediate-early gene Arc (activity-regulated, cytoskeleton-associated) in the dorsomedial (DM) striatum and learning on a response reversal task is lost in rats with METH-induced striatal dopamine loss, despite normal behavioral performance and unaltered N-methyl-D-aspartate (NMDA) receptor-mediated excitatory post-synaptic currents, suggesting intact excitatory transmission. This discrepancy suggests that METH-pretreated rats may no longer be using the dorsal striatum to solve the reversal task. To test this hypothesis, male Sprague-Dawley rats were pretreated with a neurotoxic regimen of METH or saline. Guide cannulae were surgically implanted bilaterally into the DM striatum. Three weeks after METH treatment, rats were trained on a motor response version of a T-maze task, and then underwent reversal training. Before reversal training, the NMDA receptor antagonist DL-2-amino-5-phosphonopentanoic acid (AP5) or an Arc antisense oligonucleotide was infused into the DM striatum. Acute disruption of DM striatal function by infusion of AP5 impaired reversal learning in saline-, but not METH-, pretreated rats. Likewise, acute disruption of Arc, which is implicated in consolidation of long-term memory, disrupted retention of reversal learning 24 h later in saline-, but not METH-, pretreated rats. These results highlight the critical importance of Arc in the striatum in consolidation of basal ganglia-mediated learning and suggest that long-term toxicity induced by METH alters the cognitive strategies/neural circuits used to solve tasks normally mediated by dorsal striatal function.


Asunto(s)
Trastornos Relacionados con Anfetaminas/fisiopatología , Proteínas del Citoesqueleto/fisiología , Discapacidades para el Aprendizaje/inducido químicamente , Metanfetamina/administración & dosificación , Neostriado/efectos de los fármacos , Proteínas del Tejido Nervioso/fisiología , Inhibidores de Captación Adrenérgica/administración & dosificación , Trastornos Relacionados con Anfetaminas/genética , Trastornos Relacionados con Anfetaminas/metabolismo , Animales , Proteínas del Citoesqueleto/antagonistas & inhibidores , Proteínas del Citoesqueleto/genética , Modelos Animales de Enfermedad , Genes Inmediatos-Precoces/efectos de los fármacos , Genes Inmediatos-Precoces/genética , Discapacidades para el Aprendizaje/fisiopatología , Masculino , Neostriado/metabolismo , Neostriado/fisiopatología , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/genética , Neurotoxinas/administración & dosificación , Técnicas de Cultivo de Órganos , Ratas , Ratas Sprague-Dawley
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