Plasticity of spinal L3 propriospinal neurons in urination recovery after thoracic SCI
胸部 SCI 后排尿恢复中脊髓 L3 本体脊髓神经元的可塑性
基本信息
- 批准号:10575973
- 负责人:
- 金额:$ 43.59万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-22 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdultAffectAxonBladderBladder ControlBrain StemCellsChronicCommissureCytomegalovirusDataDorsalElectric StimulationElectromyographyElectrophysiology (science)FemaleFrequenciesFunctional disorderFutureInjuryInterneuronsKidney FailureLabelLeadMediatingMethodsMicturition ReflexModelingMorbidity - disease rateMotor NeuronsNamesNeuronal PlasticityNeuronsNeurostimulation procedures of spinal cord tissueNeurotransmittersParalysedPathway interactionsPatternPhenotypePhysiologicalPilot ProjectsPopulationRattusRecombinant adeno-associated virus (rAAV)RecoveryRecovery of FunctionRecurrenceReflex actionRelaxationRoleSpinalSpinal CordSpinal Cord transection injurySpinal cord injurySpinal cord injury patientsSynapsesSynaptic TransmissionTechniquesTherapeuticThoracic spinal cord structureUrethral sphincterUrinationUrineViralViral VectorVirusdeprivationeffective therapyimprovedmad itch virusmalemortalitynerve supplyneural circuitoptogeneticspartial recoverypatient populationpostsynapticpostsynaptic neuronsrecombinant virusrelating to nervous systemspinal reflextetanospasminurinary
项目摘要
Abstract
Bladder function recovery is a top priority among the SCI patient population, yet so far there are few effective
therapies. One major reason is the limited understanding of intraspinal mechanisms for both spontaneous
plasticity and for therapeutic functional recovery after SCI. A transection SCI deprives supraspinal control of the
external urethral sphincter (EUS) which paralyzes its relaxation function and leads to urine retention. Partial
recovery of EUS relaxation and voiding occurs spontaneously only if the neural circuits between lumbar 3 (L3)
and lumbar 6 (L6) spinal cord level remain intact. Voiding function can be further improved by electrical
stimulation of the L3 spinal cord in a chronic SCI model. However, the cellular mechanism underneath is unclear.
In our preliminary study, we applied an anterograde trans-monosynaptic AAV1-GFP-Cre virus and found that a
population of L3 propriospinal neurons (PSNs) projected to the L6 dorsal commissure (DCM) and synapsed with
EUS-related interneurons (INs). We named these PSNs as PSNsL3-L6 DCM. Optogenetic stimulation of these
PSNsL3-L6 DCM induced field potential of EUS Motoneurons (MNEUS) as well as EUS electromyography (EMGEUS)
potential. These results indicate a functional connection between PSNsL3-L6 DCM and the EUS. We hypothesize
that PSNsL3-L6 DCM participate in a spinal circuit to modulate EUS relaxation and mediate the spontaneous
recovery of the EUS relaxation function after complete thoracic SCI. To evaluate the physiological function
of PSNsL3-L6 DCM, we will inject recombinant viruses to transduce those neurons and express channelrhodopsin
for optogenetic stimulation or hM4di for chemogenetic inhibition of neuronal function. We will evaluate whether
manipulation of these neurons affects EUS relaxation and voiding function by bladder cystometry, EMGEUS, and
field potential recording of DCM and MNEUS at L6. We will also combine anterograde and retrograde transsynaptic
viral tracing and immunostaining to characterize the neurotransmitter phenotype of these PSNsL3-L6 DCM and their
postsynaptic neurons. We will then further explore whether a T8 transection SCI will enhance synaptic
connections between PSNsL3-L6 DCM and their target cells to mediate the spontaneous functional recovery of the
EUS. We will use similar methods as above to verify whether more synaptic connections are established in this
circuit at 4 weeks after SCI when the spinal reflex for EUS relaxation spontaneously recovers. Furthermore,
chronic inhibition of PSNsL3-L6 DCM will be made immediately after SCI for 4 weeks to determine the causal
contribution of neural plasticity to the functional recovery of EUS relaxation and voiding function. This study will
be the first to explore the role of PSNs in EUS control in both intact and injured spinal cords, thus extending our
understanding of cellular mechanisms of EUS control. This will provide a fundamental basis for some promising
future therapies such as electrical stimulation of the spinal cord as a means of recovering bladder function.
摘要
项目成果
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