Molecular Mechanisms Regulating Inhibitory Circuitry in the Spinal Cord
Molecular Mechanisms Regulating Inhibitory Circuitry in the Spinal Cord
批准号:
10624944
负责人:
Julia Anna Kaltschmidt
金额:
$36.16万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2013
资助国家:
美国
项目状态:
已结题
起止时间:
2013-07-01 至 2024-04-30
关键词:
AdhesionsAdhesivesAfferent NeuronsAnimal BehaviorBindingBiological AssayCNTNAP1 geneCell AdhesionCell Adhesion MoleculesCentral Nervous SystemCholera Toxin Protomer BCoupledDedicationsDevelopmentDiseaseDistalDyesElectrophysiology (science)ExtensorFlexorFunctional disorderGenerationsGoalsHealthIn VitroIndividualInjectionsInjuryInterneuronsKnowledgeLabelLimb structureMeasuresMediatingMedicalMethodologyMicroanatomyMissionMolecularMotorMotor NeuronsMusMuscleMuscle functionNeurodegenerative DisordersNeurologicNeuronsNeurotrophin 3PhenotypePhysiologicalProcessProprioceptorProteinsPublic HealthReporterResearchRoleSchizophreniaScienceSensorySignal TransductionSpecificitySpinalSpinal CordSpinal cord injurySynapsesTamoxifenTestingTracerUnited States National Institutes of HealthVertebral columnWorkcontactindensitydifferential expressioneffective therapyexperimental studyfluorophoreimprovedin vivoinhibitory neuroninnovationknowledge basemouse geneticsnervous system disorderneuralneural circuitneuronal circuitryneuropsychiatryneurotransmitter releasepresynapticprotein complexreceptorsensory inputsynaptic inhibitionsynaptogenesistargeted treatmenttime use
中文摘要
Establishing specific neuronal circuits is fundamental for the generation of coordinated muscle function.
However, the signals underlying the specificity of connection between interneurons and their targets in the
mammalian central nervous system (CNS) remain largely unknown to date. Our long-term research goal is to
understand the rules of interneuron circuit wiring and the molecular mechanisms that control it. The objective of
the proposed research is to describe how a combination of adhesive and neurotrophic signals determine
GABAergic interneuron circuit connectivity. A class of GABAergic interneurons, termed GABApre, forms synaptic
contacts with the terminals of proprioceptive sensory afferents, and thus directly controls proprioceptive sensory
input through an inhibitory strategy known as presynaptic inhibition. We will test the hypothesis that the
connectivity of a class of spinal GABAergic neurons varies between functionally-distinct sensory neurons and
that this connectivity is mediated via (ii) differential expression of muscle-derived neurotrophin (NT)-3 and (ii) a
matrix of IgSF adhesion proteins. The rationale underlying this proposal is that through understanding the
mechanisms underlying GABAergic interneuron circuit formation, we will enhance our understanding of - and
ultimately control over - inhibitory neuronal circuit development and function in vivo. We will test our hypothesis
with the following three aims: #1) Determine the functional specificity of GABAergic interneuron circuitry; #2)
Investigate the influence of muscle-derived NT-3 on GABApre synapse formation; and #3) Assess the role of
Contactin-5 in GABApre-sensory synapse formation. In the first aim, we combine timed tamoxifen injections,
mouse genetics and CTb labeling to analyze whether the specific connectivity of individual GABApre
interneurons may be functionally relevant. In the second aim, we examine the expression of Gabrg1 in
functionally distinct proprioceptive sensory neurons and assess consequences of changing NT-3 levels on both
Gabrg1 expression and GABApre terminal number. In the third aim, we perturb cell adhesion signaling using
mouse genetics and perform phenotypic analysis using molecular, micro-anatomic and functional assays,
including an electrophysiological measure of presynaptic inhibition. We also use an in vitro binding assay to
screen for new adhesion molecule candidates relevant for GABApre synaptic specificity in vivo. The research
proposed in this application is innovative because it combines a molecularly-defined interneuronal circuit with a
unique constellation of methodologies to integrate functional specificity with target-derived signals. The research
will provide an understanding of functional diverse GABApre circuitry and also advance our understanding of
how basic circuit paradigms may be adapted for diverse motor functions. The proposed work is significant
because it will contribute to fundamental knowledge of the formation of circuit-level mechanisms and neural
strategies used in the CNS; this in turn will advance our efforts to develop effective therapies to rebuild circuitry
and muscle function after spinal cord injury or other neurological diseases.
英文摘要
Establishing specific neuronal circuits is fundamental for the generation of coordinated muscle function.
However, the signals underlying the specificity of connection between interneurons and their targets in the
mammalian central nervous system (CNS) remain largely unknown to date. Our long-term research goal is to
understand the rules of interneuron circuit wiring and the molecular mechanisms that control it. The objective of
the proposed research is to describe how a combination of adhesive and neurotrophic signals determine
GABAergic interneuron circuit connectivity. A class of GABAergic interneurons, termed GABApre, forms synaptic
contacts with the terminals of proprioceptive sensory afferents, and thus directly controls proprioceptive sensory
input through an inhibitory strategy known as presynaptic inhibition. We will test the hypothesis that the
connectivity of a class of spinal GABAergic neurons varies between functionally-distinct sensory neurons and
that this connectivity is mediated via (ii) differential expression of muscle-derived neurotrophin (NT)-3 and (ii) a
matrix of IgSF adhesion proteins. The rationale underlying this proposal is that through understanding the
mechanisms underlying GABAergic interneuron circuit formation, we will enhance our understanding of — and
ultimately control over — inhibitory neuronal circuit development and function in vivo. We will test our hypothesis
with the following three aims: #1) Determine the functional specificity of GABAergic interneuron circuitry; #2)
Investigate the influence of muscle-derived NT-3 on GABApre synapse formation; and #3) Assess the role of
Contactin-5 in GABApre-sensory synapse formation. In the first aim, we combine timed tamoxifen injections,
mouse genetics and CTb labeling to analyze whether the specific connectivity of individual GABApre
interneurons may be functionally relevant. In the second aim, we examine the expression of Gabrg1 in
functionally distinct proprioceptive sensory neurons and assess consequences of changing NT-3 levels on both
Gabrg1 expression and GABApre terminal number. In the third aim, we perturb cell adhesion signaling using
mouse genetics and perform phenotypic analysis using molecular, micro-anatomic and functional assays,
including an electrophysiological measure of presynaptic inhibition. We also use an in vitro binding assay to
screen for new adhesion molecule candidates relevant for GABApre synaptic specificity in vivo. The research
proposed in this application is innovative because it combines a molecularly-defined interneuronal circuit with a
unique constellation of methodologies to integrate functional specificity with target-derived signals. The research
will provide an understanding of functional diverse GABApre circuitry and also advance our understanding of
how basic circuit paradigms may be adapted for diverse motor functions. The proposed work is significant
because it will contribute to fundamental knowledge of the formation of circuit-level mechanisms and neural
strategies used in the CNS; this in turn will advance our efforts to develop effective therapies to rebuild circuitry
and muscle function after spinal cord injury or other neurological diseases.
期刊论文(5)
专著(0)
科研奖励(0)
会议论文
登录
查看更多内容
DOI:
10.1016/j.conb.2018.08.008
发表时间:
2018-12
期刊:
Current opinion in neurobiology
影响因子:
5.7
作者:
[Plant GW, Weinrich JA, Kaltschmidt JA]
通讯作者:
Kaltschmidt JA
DOI:
10.1098/rsob.140144
发表时间:
2014-10
期刊:
Open biology
影响因子:
5.8
作者:
[Russ JB, Kaltschmidt JA]
通讯作者:
Kaltschmidt JA
DOI:
10.1016/j.cophys.2021.02.003
发表时间:
2021-06
期刊:
Current opinion in physiology
影响因子:
2.5
作者:
[Shadrach JL, Gomez-Frittelli J, Kaltschmidt JA]
通讯作者:
Kaltschmidt JA
DOI:
10.1371/journal.pone.0276069
发表时间:
2022
期刊:
PloS one
影响因子:
3.7
作者:
[]
通讯作者:
Development and Patterning of the Enteric Nervous System
-
批准号:10741619
-
项目类别:
-
资助金额:$43.13万
-
财政年份:2023
-
负责人:Julia Anna Kaltschmidt
-
依托单位:
Molecular Mechanisms Regulating Inhibitory Circuitry in the Spinal Cord
-
批准号:9521466
-
项目类别:
-
资助金额:$37.08万
-
财政年份:2017
-
负责人:Julia Anna Kaltschmidt
-
依托单位:
Molecular Mechanisms Regulating Inhibitory Circuitry in the Spinal Cord
-
批准号:8692038
-
项目类别:
-
资助金额:$36.04万
-
财政年份:2013
-
负责人:Julia Anna Kaltschmidt
-
依托单位:
Molecular Mechanisms Regulating Inhibitory Circuitry in the Spinal Cord
-
批准号:8868192
-
项目类别:
-
资助金额:$36.63万
-
财政年份:2013
-
负责人:Julia Anna Kaltschmidt
-
依托单位:
Molecular Mechanisms Regulating Inhibitory Circuitry in the Spinal Cord
-
批准号:10413154
-
项目类别:
-
资助金额:$36.26万
-
财政年份:2013
-
负责人:Julia Anna Kaltschmidt
-
依托单位:
Molecular Mechanisms Regulating Inhibitory Circuitry in the Spinal Cord
-
批准号:8562065
-
项目类别:
-
资助金额:$36.19万
-
财政年份:2013
-
负责人:Julia Anna Kaltschmidt
-
依托单位:
Molecular Mechanisms Regulating Inhibitory Circuitry in the Spinal Cord
-
批准号:9093872
-
项目类别:
-
资助金额:$36.85万
-
财政年份:2013
-
负责人:Julia Anna Kaltschmidt
-
依托单位:
Molecular Mechanisms Regulating Inhibitory Circuitry in the Spinal Cord
-
批准号:10159975
-
项目类别:
-
资助金额:$36.36万
-
财政年份:2013
-
负责人:Julia Anna Kaltschmidt
-
依托单位:
海外基金