Coordinated modulation of cortical circuits by serotonin and acetylcholine
血清素和乙酰胆碱对皮质回路的协调调节
基本信息
- 批准号:10665047
- 负责人:
- 金额:$ 41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-13 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AcetylcholineAction PotentialsAdvanced DevelopmentAreaAutomobile DrivingAxonBehaviorBrain StemCellsCerebral cortexCholineCognitionCommunicationContralateralCorpus striatum structureDataDistantEtiologyExcitatory SynapseExhibitsG-Protein-Coupled ReceptorsGenerationsGlutamatesHippocampusImpaired cognitionMapsMeasuresMedialMedial Dorsal NucleusMental disordersMissionMusNational Institute of Mental HealthNeocortexNeuronsNeurotransmittersOpticsOutputPatientsPatternPerformancePhysiologicalPilot ProjectsPrefrontal CortexPublic HealthPyramidal TractsRegulationReportingResearchResearch ProposalsReuniens Thalamic NucleusSerotoninSignal TransductionSourceSynapsesSystemTestingThalamic structureViralWhole-Cell Recordingscholinergicclinically relevantcognitive functioncognitive taskexcitatory neuronhippocampal pyramidal neuroninnovationinsightneocorticalneural circuitneuronal circuitryneuronal excitabilityneuropsychiatric disorderneuroregulationnovel therapeutic interventionoptogeneticspostsynapticpostsynaptic neuronspresynapticsegregationserotonergic regulation
项目摘要
Abstract
Cortical circuits, comprising specialized neuron subpopulations and their selective synaptic connections,
send output to long-distance cortical and subcortical targets via two distinct classes of projection neurons:
intratelencephalic (IT) neurons that project primary within and across cortical hemispheres, and pyramidal tract
(PT) neurons that project to deep subcortical targets (e.g., the thalamus and brainstem). Cortical circuits are
regulated by a variety of modulatory neurotransmitters, such as serotonin (5-HT) and acetylcholine (ACh), that
optimize circuit performance for different cognitive tasks. Indeed, disruption of serotonergic or cholinergic
signaling in the cortex impairs cognition and normal behavior, and both transmitter systems are implicated in a
range of psychiatric diseases. Therefore, revealing the physiological mechanisms by which 5-HT and ACh
influence cortical processing will enhance our understanding of normal cognition, and will advance the
development of novel therapeutic strategies for psychiatric patients.
In the mouse prefrontal cortex (PFC), 5-HT and ACh act via G-protein-coupled receptors to reciprocally
regulate the postsynaptic excitability of IT and PT neurons. 5-HT promotes IT neuron output, but suppresses
PT neurons. Conversely, ACh preferentially excites PT neurons, but has limited impact on IT neurons.
Regardless of neuromodulatory state, action potential generation in IT and PT neurons requires excitatory
synaptic drive that may also be regulated, at the presynaptic level, by 5-HT and/or ACh. Our pilot studies
suggest that 5-HT and ACh act differentially to regulate key excitatory afferents to IT and PT neurons. This
current project will test the overarching hypothesis that 5-HT and ACh bias the “throughput” of cortical circuits
via coordinated pre- and postsynaptic regulation of specific combinations of excitatory afferent and cortical
projection target neuron subtype. Our first aim is to map the relative targeting, and functional excitatory drive,
of IT and PT neurons by key extrinsic excitatory afferents to the mouse medial PFC. Our second aim is to test
for afferent-specific presynaptic regulation by 5-HT and ACh, thereby determining whether pre- and
postsynaptic neuromodulation is coordinated to facilitate specific combinations of afferent input and cortical
projection output. Our third aim is to test whether 5-HT and/or ACh regulate local circuit communication
between IT and PT neurons in a manner consistent with the opposing postsynaptic impacts of these
modulators on excitability.
Completion of these aims will establish a rigorous, circuit-based framework for understanding cholinergic
and serotonergic regulation of cognitive function, and will provide insight into how disruptions of
neuromodulatory circuits contribute to psychiatric disease.
抽象的
皮质回路,包括专门的神经元亚群及其选择性突触连接,
通过两类不同的投射神经元将输出发送到长距离皮质和皮质下目标:
端脑内(IT)神经元在皮质半球和锥体束内和跨过皮质半球和锥体束投射初级神经元
投射到皮层下深层目标(例如丘脑和脑干)的(PT)神经元是。
受多种调节性神经递质的调节,例如血清素 (5-HT) 和乙酰胆碱 (ACh),
优化不同认知任务的电路性能。事实上,破坏血清素能或胆碱能。
皮层中的信号传导会损害认知和正常行为,并且两个发射系统都与
因此,揭示 5-HT 和 ACh 的生理机制。
影响皮层处理将增强我们对正常认知的理解,并将促进
为精神病患者开发新的治疗策略。
在小鼠前额皮质 (PFC) 中,5-HT 和 ACh 通过 G 蛋白偶联受体相互作用
调节 IT 和 PT 神经元的突触后兴奋性,5-HT 促进 IT 神经元输出,但抑制。
离线时,ACh 优先兴奋 PT 神经元,但对 IT 神经元影响有限。
无论神经调节状态如何,IT 和 PT 神经元的动作电位生成都需要兴奋性
突触驱动也可能在突触前水平受到 5-HT 和/或 ACh 我们的试点研究的调节。
表明 5-HT 和 ACh 的作用不同,以调节 IT 和 PT 神经元的关键兴奋性传入。
当前的项目将测试 5-HT 和 ACh 偏向皮质回路“吞吐量”的总体假设
通过兴奋性传入和皮质特定组合的协调突触前和突触后调节
我们的首要目标是映射相对目标和功能性兴奋驱动,
我们的第二个目标是测试小鼠内侧 PFC 的关键外在兴奋性传入神经元的 IT 和 PT 神经元。
5-HT 和 ACh 的传入特异性突触前调节,从而确定前和
协调突触后神经调节以促进传入输入和皮质的特定组合
我们的第三个目标是测试 5-HT 和/或 ACh 是否调节局部电路通信。
IT 和 PT 神经元之间的相互作用与这些神经元的相反突触后影响一致
兴奋性调节剂。
完成这些目标将为理解胆碱能建立一个严格的、基于电路的框架
和认知功能的血清素调节,并将提供关于如何破坏认知功能的见解
神经调节回路导致精神疾病。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Cholinergic activation of corticofugal circuits in the adult mouse prefrontal cortex.
成年小鼠前额皮质中皮质回路的胆碱能激活。
- DOI:
- 发表时间:2023-07-22
- 期刊:
- 影响因子:0
- 作者:Gulledge; Allan T
- 通讯作者:Allan T
Cholinergic Activation of Corticofugal Circuits in the Adult Mouse Prefrontal Cortex.
成年小鼠前额皮质皮质回路的胆碱能激活。
- DOI:
- 发表时间:2024-01-17
- 期刊:
- 影响因子:0
- 作者:Gulledge; Allan T
- 通讯作者:Allan T
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Allan T Gulledge其他文献
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{{ truncateString('Allan T Gulledge', 18)}}的其他基金
Cortical circuitry and mechanisms underlying remote cue-specific fear memory and extinction
远程线索特异性恐惧记忆和消退背后的皮层电路和机制
- 批准号:
10417350 - 财政年份:2019
- 资助金额:
$ 41万 - 项目类别:
Cortical circuitry and mechanisms underlying remote cue-specific fear memory and extinction
远程线索特异性恐惧记忆和消退背后的皮层电路和机制
- 批准号:
10612415 - 财政年份:2019
- 资助金额:
$ 41万 - 项目类别:
Cortical circuitry and mechanisms underlying remote cue-specific fear memory and extinction
远程线索特异性恐惧记忆和消退背后的皮层电路和机制
- 批准号:
9815038 - 财政年份:2019
- 资助金额:
$ 41万 - 项目类别:
Cortical circuitry and mechanisms underlying remote cue-specific fear memory and extinction
远程线索特异性恐惧记忆和消退背后的皮层电路和机制
- 批准号:
10401949 - 财政年份:2019
- 资助金额:
$ 41万 - 项目类别:
Neuromodulation of cortical circuits in health and disease
健康和疾病中皮质回路的神经调节
- 批准号:
8722034 - 财政年份:2013
- 资助金额:
$ 41万 - 项目类别:
Neuromodulation of cortical circuits in health and disease
健康和疾病中皮质回路的神经调节
- 批准号:
8576665 - 财政年份:2013
- 资助金额:
$ 41万 - 项目类别:
Cholinergic signaling in cortical neurons: a unifying hypothesis
皮质神经元中的胆碱能信号传导:一个统一的假设
- 批准号:
7888378 - 财政年份:2008
- 资助金额:
$ 41万 - 项目类别:
Cholinergic signaling in cortical neurons: a unifying hypothesis
皮质神经元中的胆碱能信号传导:一个统一的假设
- 批准号:
7655524 - 财政年份:2008
- 资助金额:
$ 41万 - 项目类别:
Cholinergic signaling in cortical neurons: a unifying hypothesis
皮质神经元中的胆碱能信号传导:一个统一的假设
- 批准号:
8089261 - 财政年份:2008
- 资助金额:
$ 41万 - 项目类别:
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