Rapid inhibitory circuit plasticity as a homeostatic mechanism in cerebral cortex
快速抑制回路可塑性作为大脑皮层的稳态机制
基本信息
- 批准号:10318639
- 负责人:
- 金额:$ 34.41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-12-15 至 2023-11-30
- 项目状态:已结题
- 来源:
- 关键词:AgeAreaBiological ModelsBrainCalciumCerebral cortexChronicDataDevelopmentDiseaseFunctional disorderHomeostasisHourImageImpairmentIn VitroInterneuronsMapsMeasuresMediatingMethodsModelingMusNeuronsParvalbuminsPhysiologyProcessPyramidal CellsRecording of previous eventsRecurrenceRegulationRodentRoleSchizophreniaSensorySensory DeprivationSliceSomatosensory CortexSomatostatinSynapsesTestingTimeTransgenic MiceVibrissaeVisual CortexWhole-Cell Recordingsautism spectrum disordercritical perioddeprivationexperienceextracellularin vivoin vivo Modelmouse modelnervous system disorderneural circuitnoveloptogeneticsrapid testresponsesensory cortexsomatosensorytwo-photon
项目摘要
Experience robustly regulates the development and function of GABAergic inhibitory circuits in cerebral
cortex, but the purpose of this inhibitory circuit plasticity is unclear. Recent findings in rodent somatosensory
(S1) and visual cortex suggest that inhibitory plasticity may contribute to homeostatic stabilization of firing
rate in cortical networks. We recently discovered that during competitive map plasticity in S1, sensory
deprivation weakens parvalbumin (PV) inhibitory circuits very rapidly (< 1 day). This is faster than classical
homeostatic mechanisms like synaptic scaling, and promotes firing rate stability in the S1 network. We
propose that PV circuit plasticity functions as a rapid, bidirectional homeostat, operating on the time scale of
hours, and that its role is to stabilize cortical firing rate. We propose that it accomplishes this by adaptively
altering PV circuit gain and excitation-inhibition (E-I) ratio in local pyramidal cells as a function of the recent
history of network activity. This rapid inhibitory plasticity may be a major contributor to controlling firing rate in
cerebral cortex.
Here, we test this hypothesis, using L2/3 of mouse whisker S1 cortex as a model system. In Aim 1,
we use slice physiology and layer-specific optogenetics to measure how whisker deprivation alters the gain of
L4-L2/3 feedforward and L2/3-L2/3 recurrent inhibitory circuits, and quantify the dynamics of this plasticity.
We test whether direct chemogenetic modulation of pyramidal cell firing rate induces inhibitory circuit
plasticity, whether this is bidirectional, and whether it is general across cortical areas. In Aim 2, we use dual
whole-cell recording to identify the specific synaptic and cellular changes that mediate rapid inhibitory
plasticity in PV and Somatostatin (SOM) circuits. In Aim 3, we use 2-photon calcium imaging and chronic
extracellular unit recording to characterize firing rate homeostasis in L2/3, determine its magnitude and
dynamics across age, and measure its relationship to inhibitory circuit plasticity.
Breakdown of inhibitory homeostasis could contribute to circuit dysfunction in autism, schizophrenia,
and other disorders. In Aim 4, we test this hypothesis by asking whether inhibition or inhibitory homeostasis
is disrupted in cortex in several transgenic mouse models of autism. Preliminary data show that excitation-inhibition ratio is disrupted in common across four genetically unrelated mouse models. This provides key
support for the long-held E-I ratio model of autism. Overall, this project will reveal whether inhibitory circuit
plasticity is an important mechanism for rapid homeostasis of cortical firing rate, and whether its disruption
may contribute to neurological disease.
经验对大脑皮层GABA能抑制回路的发育和功能具有强烈的调节作用
皮质,但这种抑制回路可塑性的目的尚不清楚。啮齿类动物躯体感觉的最新发现
(S1)和视觉皮层的研究表明,抑制性可塑性可能有助于稳态稳定的放电
皮层网络的速率。我们最近发现,在S1的竞争性地图可塑性过程中,
剥夺非常迅速地(< 1天)削弱小清蛋白(PV)抑制回路。这比古典音乐要快
稳态机制,如突触缩放,并促进放电率稳定的S1网络。我们
提出PV电路可塑性作为一个快速的,双向的稳态器,在时间尺度上运行,
小时,其作用是稳定皮质放电率。我们建议它通过自适应来实现这一点
改变PV电路增益和兴奋抑制(E-I)比在局部锥体细胞的功能,最近
网络活动的历史。这种快速的抑制可塑性可能是控制放电率的主要因素,
大脑皮层
在这里,我们测试这一假设,使用L2/3小鼠胡须S1皮层作为模型系统。在目标1中,
我们使用切片生理学和层特异性光遗传学来测量胡须剥夺如何改变
L4-L2/3前馈和L2/3-L2/3递归抑制回路,并量化这种可塑性的动力学。
我们测试是否直接化学发生调制锥体细胞放电率诱导抑制回路
可塑性,这是否是双向的,以及它是否在皮层区域普遍存在。在目标2中,我们使用dual
全细胞记录,以确定介导快速抑制的特定突触和细胞变化
PV和生长抑素(SOM)回路的可塑性。在目标3中,我们使用双光子钙成像和慢性
细胞外单位记录以表征L2/3中的放电率稳态,确定其幅度,
动力学,并测量其与抑制回路可塑性的关系。
抑制性稳态的破坏可能导致自闭症,精神分裂症,
和其他疾病。在目标4中,我们通过询问抑制或抑制性稳态是否
在几种自闭症转基因小鼠模型中,初步数据显示,兴奋抑制比在四种遗传上不相关的小鼠模型中共同被破坏。这提供了关键
支持长期持有的自闭症E-I比率模型。总的来说,本项目将揭示抑制回路是否
可塑性是皮层放电率快速稳态的重要机制,
可能导致神经系统疾病
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Circuit-level theories for sensory dysfunction in autism: convergence across mouse models.
- DOI:10.3389/fneur.2023.1254297
- 发表时间:2023
- 期刊:
- 影响因子:3.4
- 作者:
- 通讯作者:
Plasticity of population coding in primary sensory cortex.
- DOI:10.1016/j.conb.2018.04.029
- 发表时间:2018-12
- 期刊:
- 影响因子:5.7
- 作者:LeMessurier AM;Feldman DE
- 通讯作者:Feldman DE
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Daniel Feldman其他文献
Daniel Feldman的其他文献
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{{ truncateString('Daniel Feldman', 18)}}的其他基金
Organization of neural coding and plasticity in L2/3 of mouse S1 cortex
小鼠 S1 皮质 L2/3 的神经编码组织和可塑性
- 批准号:
10653516 - 财政年份:2023
- 资助金额:
$ 34.41万 - 项目类别:
Rapid inhibitory circuit plasticity as a homeostatic mechanism in cerebral cortex
快速抑制回路可塑性作为大脑皮层的稳态机制
- 批准号:
10063590 - 财政年份:2017
- 资助金额:
$ 34.41万 - 项目类别:
Neuroscience Training Program at UC Berkeley
加州大学伯克利分校神经科学培训项目
- 批准号:
9415647 - 财政年份:2017
- 资助金额:
$ 34.41万 - 项目类别:
Neuroscience Training Program at UC Berkeley
加州大学伯克利分校神经科学培训项目
- 批准号:
10614546 - 财政年份:2016
- 资助金额:
$ 34.41万 - 项目类别:
Neuroscience Training Program at UC Berkeley
加州大学伯克利分校神经科学培训项目
- 批准号:
10201129 - 财政年份:2016
- 资助金额:
$ 34.41万 - 项目类别:
Neuroscience Training Program at UC Berkeley
加州大学伯克利分校神经科学培训项目
- 批准号:
9086632 - 财政年份:2016
- 资助金额:
$ 34.41万 - 项目类别:
Neuroscience Training Program at UC Berkeley
加州大学伯克利分校神经科学培训项目
- 批准号:
10441619 - 财政年份:2016
- 资助金额:
$ 34.41万 - 项目类别:
Microscale organization and sensory coding in L2_3 of mouse somatosensory cortex
小鼠体感皮层 L2_3 的微观组织和感觉编码
- 批准号:
9906996 - 财政年份:2015
- 资助金额:
$ 34.41万 - 项目类别:
Microscale organization and sensory coding in L2_3 of mouse somatosensory cortex
小鼠体感皮层 L2_3 的微观组织和感觉编码
- 批准号:
9282640 - 财政年份:2015
- 资助金额:
$ 34.41万 - 项目类别:
Microscale organization and sensory coding in L2_3 of mouse somatosensory cortex
小鼠体感皮层 L2_3 的微观组织和感觉编码
- 批准号:
9428355 - 财政年份:2015
- 资助金额:
$ 34.41万 - 项目类别:
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