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1.
Sci Rep ; 10(1): 10953, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32616790

RESUMO

Anatomically incomplete spinal cord injuries can be followed by functional recovery mediated, in part, by the formation of intraspinal detour circuits. Here, we show that adult mice recover tactile and proprioceptive function following a unilateral dorsal column lesion. We therefore investigated the basis of this recovery and focused on the plasticity of the dorsal column-medial lemniscus pathway. We show that ascending dorsal root ganglion (DRG) axons branch in the spinal grey matter and substantially increase the number of these collaterals following injury. These sensory fibers exhibit synapsin-positive varicosities, indicating their integration into spinal networks. Using a monosynaptic circuit tracing with rabies viruses injected into the cuneate nucleus, we show the presence of spinal cord neurons that provide a detour pathway to the original target area of DRG axons. Notably the number of contacts between DRG collaterals and those spinal neurons increases by more than 300% after injury. We then characterized these interneurons and showed that the lesion triggers a remodeling of the connectivity pattern. Finally, using re-lesion experiments after initial remodeling of connections, we show that these detour circuits are responsible for the recovery of tactile and proprioceptive function. Taken together our study reveals that detour circuits represent a common blueprint for axonal rewiring after injury.


Assuntos
Gânglios Espinais/fisiologia , Regeneração Nervosa , Vias Neurais , Neurônios/fisiologia , Recuperação de Função Fisiológica , Células Receptoras Sensoriais/fisiologia , Traumatismos da Medula Espinal/prevenção & controle , Animais , Comportamento Animal , Gânglios Espinais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal , Neurônios/citologia , Traumatismos da Medula Espinal/etiologia , Traumatismos da Medula Espinal/patologia
2.
J Exp Med ; 216(11): 2503-2514, 2019 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-31391209

RESUMO

The remodeling of supraspinal axonal circuits mediates functional recovery after spinal cord injury. This process critically depends on the selection of appropriate synaptic connections between cortical projection and spinal relay neurons. To unravel the principles that guide this target selection, we used genetic and chemogenetic tools to modulate NMDA receptor (NMDAR) integrity and function, CREB-mediated transcription, and neuronal firing of relay neurons during injury-induced corticospinal remodeling. We show that NMDAR signaling and CREB-mediated transcription maintain nascent corticospinal tract (CST)-relay neuron contacts. These activity-dependent signals act during a defined period of circuit remodeling and do not affect mature or uninjured circuits. Furthermore, chemogenetic modulation of relay neuron activity reveals that the regrowing CST axons select their postsynaptic partners in a competitive manner and that preventing such activity-dependent shaping of corticospinal circuits limits motor recovery after spinal cord injury.


Assuntos
Neurônios/fisiologia , Tratos Piramidais/fisiopatologia , Recuperação de Função Fisiológica/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Animais , Axônios , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiopatologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Feminino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Modelos Neurológicos , Regeneração Nervosa/fisiologia , Neurônios/metabolismo , Tratos Piramidais/citologia , Tratos Piramidais/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Recuperação de Função Fisiológica/genética
3.
J Neurotrauma ; 35(24): 2904-2915, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29943672

RESUMO

Recent reports suggest that rehabilitation measures that increase physical activity of patients can improve functional outcome after incomplete spinal cord injuries (iSCI). To investigate the structural basis of exercise-induced recovery, we examined local and remote consequences of voluntary wheel training in spinal cord injured female mice. In particular, we explored how enhanced voluntary exercise influences the neuronal and glial response at the lesion site as well as the rewiring of supraspinal tracts after iSCI. We chose voluntary exercise initiated by providing mice with free access to running wheels over "forced overuse" paradigms because the latter, at least in some cases, can lead to worsening of functional outcomes after SCI. Our results show that mice extensively use their running wheels not only before but also after injury reaching their pre-lesion exercise levels within five days after injury. Enhanced voluntary exercise improved their overall and skilled motor function after injury. In addition, exercising mice started to recover earlier and reached better sustained performance levels. These improvements in motor performance are accompanied by early changes of axonal and glial response at the lesion site and persistent enhancements of the rewiring of supraspinal connections that resulted in a strengthening of both indirect and direct inputs to lumbar motoneurons.


Assuntos
Neuroglia/patologia , Condicionamento Físico Animal , Recuperação de Função Fisiológica/fisiologia , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Condicionamento Físico Animal/métodos , Condicionamento Físico Animal/fisiologia
4.
EMBO J ; 34(9): 1231-43, 2015 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-25766255

RESUMO

The remodeling of axonal circuits after injury requires the formation of new synaptic contacts to enable functional recovery. Which molecular signals initiate such axonal and synaptic reorganisation in the adult central nervous system is currently unknown. Here, we identify FGF22 as a key regulator of circuit remodeling in the injured spinal cord. We show that FGF22 is produced by spinal relay neurons, while its main receptors FGFR1 and FGFR2 are expressed by cortical projection neurons. FGF22 deficiency or the targeted deletion of FGFR1 and FGFR2 in the hindlimb motor cortex limits the formation of new synapses between corticospinal collaterals and relay neurons, delays their molecular maturation, and impedes functional recovery in a mouse model of spinal cord injury. These results establish FGF22 as a synaptogenic mediator in the adult nervous system and a crucial regulator of synapse formation and maturation during post-injury remodeling in the spinal cord.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Traumatismos da Medula Espinal/metabolismo , Sinapses/metabolismo , Animais , Axônios/fisiologia , Fatores de Crescimento de Fibroblastos/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Regeneração Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Traumatismos da Medula Espinal/fisiopatologia , Sinapses/fisiologia
5.
Immunity ; 42(2): 332-343, 2015 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-25692705

RESUMO

Dysfunction in Ataxia-telangiectasia mutated (ATM), a central component of the DNA repair machinery, results in Ataxia Telangiectasia (AT), a cancer-prone disease with a variety of inflammatory manifestations. By analyzing AT patient samples and Atm(-/-) mice, we found that unrepaired DNA lesions induce type I interferons (IFNs), resulting in enhanced anti-viral and anti-bacterial responses in Atm(-/-) mice. Priming of the type I interferon system by DNA damage involved release of DNA into the cytoplasm where it activated the cytosolic DNA sensing STING-mediated pathway, which in turn enhanced responses to innate stimuli by activating the expression of Toll-like receptors, RIG-I-like receptors, cytoplasmic DNA sensors, and their downstream signaling partners. This study provides a potential explanation for the inflammatory phenotype of AT patients and establishes damaged DNA as a cell intrinsic danger signal that primes the innate immune system for a rapid and amplified response to microbial and environmental threats.


Assuntos
Ataxia Telangiectasia/imunologia , Dano ao DNA , DNA/imunologia , Listeria monocytogenes/imunologia , Listeriose/imunologia , Proteínas de Membrana/metabolismo , Animais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Células da Medula Óssea/imunologia , Linhagem Celular , Citosol/imunologia , Citosol/microbiologia , Reparo do DNA/genética , Ativação Enzimática/imunologia , Células HEK293 , Humanos , Imunidade Inata , Interferon-alfa/biossíntese , Interferon beta/biossíntese , Interferon gama/biossíntese , Macrófagos/imunologia , Camundongos , Camundongos Knockout , Proteínas Serina-Treonina Quinases/metabolismo , RNA Interferente Pequeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
6.
Nat Med ; 20(5): 555-60, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24747747

RESUMO

Mitochondrial redox signals have a central role in neuronal physiology and disease. Here we describe a new optical approach to measure fast redox signals with single-organelle resolution in living mice that express genetically encoded redox biosensors in their neuronal mitochondria. Moreover, we demonstrate how parallel measurements with several biosensors can integrate these redox signals into a comprehensive characterization of mitochondrial function. This approach revealed that axonal mitochondria undergo spontaneous 'contractions' that are accompanied by reversible redox changes. These contractions are amplified by neuronal activity and acute or chronic neuronal insults. Multiparametric imaging reveals that contractions constitute respiratory chain-dependent episodes of depolarization coinciding with matrix alkalinization, followed by uncoupling. In contrast, permanent mitochondrial damage after spinal cord injury depends on calcium influx and mitochondrial permeability transition. Thus, our approach allows us to identify heterogeneity among physiological and pathological redox signals, correlate such signals to functional and structural organelle dynamics and dissect the underlying mechanisms.


Assuntos
Técnicas Biossensoriais , Mitocôndrias/fisiologia , Neurônios/fisiologia , Oxirredução , Animais , Axotomia , Cálcio/metabolismo , Diagnóstico por Imagem , Expressão Gênica , Humanos , Camundongos , Mitocôndrias/patologia , Mitocôndrias/ultraestrutura , Neurônios/patologia , Espécies Reativas de Oxigênio/metabolismo
7.
PLoS One ; 9(2): e88449, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24523897

RESUMO

BACKGROUND: Spinal interneurons have emerged as crucial targets of supraspinal input during post-injury axonal remodelling. For example, lesioned corticospinal projections use propriospinal neurons as relay stations to form intraspinal detour circuits that circumvent the lesion site and contribute to functional recovery. While a number of the molecules that determine the formation of neuronal circuits in the developing nervous system have been identified, it is much less understood which of these cues are also expressed in the injured spinal cord and can thus guide growing collaterals and initiate synaptogenesis during circuit remodelling. METHODOLOGY/PRINCIPAL FINDINGS: To address this question we characterized the expression profile of a number of guidance and synaptogenic molecules in the cervical spinal cord of healthy and spinal cord-injured mice by in situ hybridization. To assign the expression of these molecules to distinct populations of interneurons we labeled short and long propriospinal neurons by retrograde tracing and glycinergic neurons using a transgenically expressed fluorescent protein. Interestingly, we found that most of the molecules studied including members of slit-, semaphorin-, synCAM-, neuroligin- and ephrin- families as well as their receptors are also present in the adult CNS. While many of these molecules were abundantly expressed in all interneurons examined, some molecules including slits, semaphorin 7a, synCAM4 and neuroligin 1 showed preferential expression in propriospinal interneurons. Overall the expression pattern of guidance and synaptogenic molecules in the cervical spinal cord appeared to be stable over time and was not substantially altered following a midthoracic spinal cord injury. CONCLUSIONS: Taken together, our study indicates that many of the guidance and synaptogenic cues that regulate neuronal circuit formation in development are also present in the adult CNS and therefore likely contribute to the remodelling of axonal connections in the injured spinal cord.


Assuntos
Regulação da Expressão Gênica , Interneurônios/patologia , Traumatismos da Medula Espinal/metabolismo , Animais , Axônios/metabolismo , Perfilação da Expressão Gênica , Hibridização In Situ , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Regeneração Nervosa/fisiologia , Plasticidade Neuronal , Neurônios/metabolismo , Neurônios/patologia , Tratos Piramidais/patologia , Medula Espinal/metabolismo , Medula Espinal/patologia , Traumatismos da Medula Espinal/patologia
8.
Cell Rep ; 4(2): 316-326, 2013 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-23871668

RESUMO

The specific roles of neuronal subcellular components in behavior and development remain largely unknown, even though advances in molecular biology and conventional whole-cell laser ablation have greatly accelerated the identification of contributors at the molecular and cellular levels. We systematically applied femtosecond laser ablation, which has submicrometer resolution in vivo, to dissect the cell bodies, dendrites, or axons of a sensory neuron (ASJ) in Caenorhabditis elegans to determine their roles in modulating locomotion and the developmental decisions for dauer, a facultative, stress-resistant life stage. Our results indicate that the cell body sends out axonally mediated and hormonal signals in order to mediate these functions. Furthermore, our results suggest that antagonistic sensory dendritic signals primarily drive and switch polarity between the decisions to enter and exit dauer. Thus, the improved resolution of femtosecond laser ablation reveals a rich complexity of neuronal signaling at the subcellular level, including multiple neurite and hormonally mediated pathways dependent on life stage.


Assuntos
Comportamento Animal/fisiologia , Caenorhabditis elegans/fisiologia , Sistema Endócrino/fisiologia , Terapia a Laser/métodos , Células Receptoras Sensoriais/fisiologia , Animais , Caenorhabditis elegans/crescimento & desenvolvimento , Transdução de Sinais , Fatores de Tempo
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