Synaptic integration and intrinsic firing properties of basal ganglia neurons

基底节神经元的突触整合和内在放电特性

• 批准号: 10915986
• 负责人: ZAYD M KHALIQ
• 金额: $ 243.5万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10915986
• 关键词: Acetylcholine; Acute; Animal Model; Automobile Driving; Axon; Basal Ganglia; Behavior; Behavioral; Biochemical Markers; Calcium; Calcium Signaling; Categories; Cells; Computer Models; Corpus striatum structure; Dendrites; Diazepam; Dopamine; Dopaminergic Cell; Frequencies; Future; GABA-A Receptor; Glutamates; Goals; Heterogeneity; Interneurons; Journals; Laboratories; Laser Scanning Microscopy; Lateral; Ligands; Measures; Medial; Midbrain structure; Motivation; Neurons; Neurosciences; Nicotinic Receptors; Nucleus Accumbens; Pacemakers; Parkinson Disease; Pattern; Physiology; Picrotoxin; Play; Presynaptic Terminals; Property; Publications; Receptor Inhibition; Rewards; Role; Shapes; Signal Transduction; Slice; Sodium; Speed; Stimulus; Study Section; Substantia nigra structure; Synapses; Techniques; Tissues; Transgenic Animals; Ventral Tegmental Area; Vertebral column; Work; antagonist; cholinergic; dopamine system; dopaminergic neuron; experimental study; motor disorder; motor learning; neuronal cell body; neurophysiology; neuropsychiatric disorder; neurotransmission; optogenetics; patch clamp; pharmacologic; positive allosteric modulator; receptor; transmission process; two-photon

The Cellular Neurophysiology Section studies the physiology of neurons located in the midbrain dopamine system and as well as their circuit integration in the basal ganglia. Our laboratory has focused on understanding how dopamine signaling in the striatum is shaped by ligand-gated receptors on dopaminergic axon terminals. In particular, the axons of dopaminergic cells receive input from acetylcholine-releasing neurons within the striatum that may influence dopamine release. In addition, we have demonstrated that the dopaminergic axons express GABA-A receptors that many locally inhibit striatal dopamine release. Recently, we have been examining how axonal GABA-A receptors influence the integration of input arriving from local cholinergic interneurons to shape axonal excitability and dopamine release. In our analysis of axonal calcium influx using GCaMP in ex vivo tissue slices, we isolated the two main components of the axonal calcium signals one component resulting from direct axonal stimulation and a later component due to transmission onto axonal nicotinic receptors. We find that axonal GABA-A receptors inhibits directly-evoked axonal signal but has a stronger effect on the amplitude and speed of the nicotinic component. Using direct axonal recordings, we show that the GABA-A receptor positive allosteric modulator, diazepam, decreases the magnitude of subthreshold nicotinic input onto dopamine axons. In our studies examining the GABA-A receptor interaction with nicotinic receptors, we found show that picrotoxin potently blocks striatal nicotinic receptors at concentrations that have typically been used for physiology experiments suggesting that caution must be used when selecting GABA-A receptor antagonists. Together, our results highlight that striatal dopamine axons integrate information from cholinergic interneurons in a manner that is regulated by axonal GABAA receptors. In a separate project, we investigated the contribution of the sodium leak conductance, NALCN, to pacemaking in different dopamine neuron subpopulations. We found that NALCN contributes to firing in dopaminergic neurons located in the ventral tegmental area (VTA DANs), particularly those that project to medial and lateral nucleus accumbens. Specifically, we found acute pharmacological blockade of NALCN substantially slowed pacemaking in medial VTA DANs. Thus, NALCN is a primary driver of pacemaking in VTA DANs. In substantia nigra (SNc) DANs, however, we found that NALCN is functionally present but pacemaking in SNc DANs was unaffected by inhibition of NALCN. Instead, we show that NALCN reduces the gain of frequency-current plots of firing frequencies measured at rates slower than spontaneous firing. In separate experiments, we explored to role of the hyperpolarization-activated current (Ih) and found that simultaneous inhibition of NALCN and Ih resulted in significant reduction in pacemaker rate in SNc neurons. Thus, we found NALCN makes substantial contributions to driving pacemaking in VTA DAN subpopulations while in SNc DANs, NALCN is not critical for pacemaking but inhibition of this current makes cells more sensitive to hyperpolarizing stimuli. This study has been submitted for publication and was accepted at the Journal of Neuroscience (Cobb-Lewis et al. 2023). These findings will inform future efforts to obtain dopaminergic neuron subpopulation specific treatments in neuropsychiatric and motor disorders such as Parkinsons Disease. In a separate study, we have been investigating the role of the sodium leak conductance, NALCN, to slow spontaneous firing called pacemaking in different dopamine neuron subpopulations. We have found that while NALCN contributes to firing in substantia nigra neurons, the contribution of NALCN is much stronger in medial dopaminergic neurons, particularly those that project to medial nucleus accumbens. This study has been submitted for publication and is currently in revisions.

细胞神经生理学部分研究位于中脑多巴胺系统的神经元的生理学，以及它们在基底神经节中的回路整合。我们的实验室一直致力于了解纹状体中的多巴胺信号是如何通过多巴胺能轴突末梢上的配体门控受体形成的。特别是，多巴胺能细胞的轴突接收来自纹状体内的乙酰胆碱释放神经元的输入，这可能影响多巴胺的释放。此外，我们已经证明，多巴胺能轴突表达GABA-A受体，许多局部抑制纹状体多巴胺的释放。最近，我们一直在研究轴突GABA-A受体如何影响来自局部胆碱能中间神经元的输入的整合，以塑造轴突兴奋性和多巴胺释放。在我们使用GCaMP在离体组织切片中对轴突钙内流的分析中，我们分离了轴突钙信号的两个主要成分，一个成分来自直接轴突刺激，另一个成分由于传递到轴突烟碱受体上。我们发现，轴突GABA-A受体抑制直接诱发的轴突信号，但对烟碱成分的幅度和速度有更强的影响。使用直接轴突记录，我们表明，GABA-A受体阳性变构调节剂，安定，降低多巴胺轴突的阈下烟碱输入的幅度。在我们检查GABA-A受体与烟碱受体相互作用的研究中，我们发现印防己毒素在通常用于生理学实验的浓度下有效地阻断纹状体烟碱受体，这表明在选择GABA-A受体拮抗剂时必须谨慎。总之，我们的研究结果强调，纹状体多巴胺轴突整合胆碱能中间神经元的方式，是由轴突GABAA受体调节的信息。 在一个单独的项目中，我们研究了钠漏电导（NALCN）对不同多巴胺神经元亚群起搏的贡献。我们发现NALCN有助于位于腹侧被盖区（VTA DAN）的多巴胺能神经元的放电，特别是那些投射到内侧和外侧核的多巴胺能神经元。具体来说，我们发现NALCN的急性药物阻断显著减缓了内侧VTA DAN的起搏。因此，NALCN是VTA DAN中起搏的主要驱动因素。然而，在黑质（SNc）DAN中，我们发现NALCN在功能上存在，但SNc DAN中的起搏不受NALCN抑制的影响。 相反，我们表明，NALCN降低了增益的频率电流图的发射频率测量速率慢于自发放电。在单独的实验中，我们探索了超极化激活电流（Ih）的作用，发现同时抑制NALCN和Ih导致SNc神经元起搏频率显著降低。因此，我们发现NALCN在VTA DAN亚群中对驱动起搏做出了实质性贡献，而在SNc DAN中，NALCN对于起搏并不关键，但抑制该电流使细胞对超极化刺激更敏感。本研究已提交发表，并已被《神经科学杂志》接受（Cobb-Lewis et al. 2023）。这些发现将为未来的努力提供信息，以获得多巴胺能神经元亚群特异性治疗神经精神和运动障碍，如帕金森病。 在另一项研究中，我们一直在研究钠漏电导（NALCN）在不同多巴胺神经元亚群中减缓自发放电（称为起搏）的作用。我们已经发现，虽然NALCN有助于黑质神经元的放电，但NALCN的贡献在内侧多巴胺能神经元中要强得多，特别是投射到内侧核的那些。这项研究已提交出版，目前正在修订中。

项目成果

Diversity, Equity, Inclusion, and Health Inequities Training in Neurologic Disorders and Stroke: Analysis and Recommendations From the NINDS Advisory Council Working Group.

神经系统疾病和中风的多样性、公平性、包容性和健康不平等培训：NINDS 咨询委员会工作组的分析和建议。

• DOI: 10.1212/wnl.0000000000207567
• 发表时间: 2023
• 期刊: Neurology
• 影响因子: 9.9
• 作者: Brody,DavidL;Gottesman,RebeccaF;Griffin,Gerald;Khaliq,ZaydM;Lackland,DanielT;Ling,Geoff;Mohile,Nimish
• 通讯作者: Mohile,Nimish

Electrical and Ca(2+) signaling in dendritic spines of substantia nigra dopaminergic neurons.

黑质多巴胺能神经元树突棘中的电信号和 Ca(2) 信号传导。

• DOI: 10.7554/elife.13905
• 发表时间: 2016
• 期刊: eLife
• 影响因子: 7.7
• 作者: Hage,TravisA;Sun,Yujie;Khaliq,ZaydM
• 通讯作者: Khaliq,ZaydM

Enhanced Sensitivity to Hyperpolarizing Inhibition in Mesoaccumbal Relative to Nigrostriatal Dopamine Neuron Subpopulations.

相对于黑质纹状体多巴胺神经元亚群，中累积体对超极化抑制的敏感性增强。

• DOI: 10.1523/jneurosci.2969-16.2017
• 发表时间: 2017
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Tarfa,RahillaA;Evans,RebekahC;Khaliq,ZaydM
• 通讯作者: Khaliq,ZaydM