A Dynamic Diversity of Dopamine Neurons

多巴胺神经元的动态多样性

• 批准号: 9247593
• 负责人: Carmen Castro Canavier
• 金额: $ 34.21万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9247593
• 关键词: Adult; Affect; Automobile Driving; Behavior Control; Behavioral; Behavioral Mechanisms; Biophysical Process; Biophysics; Closure by clamp; Computer Simulation; Corpus striatum structure; Disease; Dissection; Dopamine; Electrophysiology (science); Exhibits; Exploratory Behavior; Frequencies; Head; In Vitro; Kinetics; Label; Lateral; Lead; Medial; Mediating; Midbrain structure; Modeling; Molecular; Morphology; Motor; Mus; Neurons; Nonlinear Dynamics; Nucleus Accumbens; Parkinson Disease; Pattern; Pharmacology; Phase; Phenotype; Population; Potassium Channel; Rewards; Schizophrenia; Signal Transduction; Slice; Substantia nigra structure; Synapses; Techniques; Testing; Therapeutic; Time; Tweens; Ventral Tegmental Area; addiction; awake; base; behavior test; calbindin; dopaminergic neuron; experimental study; extracellular; in vivo; novel; photo switch; signal processing; voltage; voltage clamp

Recently-identified, distinct subpopulations of midbrain dopamine (DA) neurons exhibit differences in their two primary in vivo activity patterns, tonic (single spike) firing and phasic bursting. These firing pat- terns, and transitions between them, are essential for driving axonal and dendritic dopamine release, and thus for controlling signal processing and behavioral functions of cortico-striatal circuits. We will show that the ionic mechanisms underlying these patterns, as well as the information content of these patterns, differ between DA subpopulations, with strong implications for behavioral control via distinct types of dopaminergic signaling. Aim 1 will uncover the biophysical mechanisms underlying the difference in tonic firing between the classic slow-firing and the more recently identified fast-firing DA neurons in the ventral tegmental area (VTA). These mechanisms likely also contribute to their distinct frequencies of burst firing in vivo. Aim 2 will elucidate the biophysical basis of bursts in the medial substantia nigra (SN), enabled by ATP-sensitive K+ (K-ATP) channels and necessary for novelty-induced exploration, versus bursts in the lateral SN that are controlled by Ca2+-activated SK K+ channels and may gate habitual motor sequences. Aim 3 will define the behavioral functions of two projection-specific DA subpopulations with the most distinctive in vivo firing patterns: the faster bursting VTA DA neurons projecting to the medial shell of the accumbens, which might be involved in salience or reward signaling, versus the medio-rostral SN DA neurons projecting to the lateral shell of the accumbens, which display continuous and slower bursting during novelty-mediated exploration. Differential biophysical control mechanisms of behaviorally-relevant firing patterns for distinct DA subpopulations may be selectively affected in the many known disorders of DA signaling, including addiction, schizophrenia and Parkinson's disease (PD). For example, a reduction in activity-dependent Ca2+ loading selective for SN DA neurons is a promising neuroprotective approach in PD. The further dissection of differences in the dynamics and molecular biophysics of both VTA and SN DA subpopulations proposed herein promises to lead to even more selectively tailored therapeutic strategies that tune the firing pattern in specific DA subpopulations. This project is based on recent, exciting advances in modeling the diversity of DA neurons in Dr. Canavier's lab that help explain the diversity of DA neurons pioneered by Dr. Roeper. The theoretical and computational approaches combine nonlinear dynamics and bifurcation analyses with morphologically realistic multi-compartmental modeling. Dr. Roeper's lab uses state of the art techniques, including retrograde tracing, adult mouse slice electrophysiology, channel-selective pharmacology, photoswitchable K-ATP blockers, and Dynamic Clamp, plus extracellular recordings and combined with juxtacellular labeling of single DA neurons with identified axonal projections in mice in vivo, to quantify the diversity of the DA populations in a comprehensive fashion, forming a synergistic loop for testing model predictions.

最近被识别的中脑多巴胺（DA）神经元的独特亚群在 他们的两个主要体内活性模式，补品（单峰）射击和阶段性爆发。这些射击 Terns和它们之间的过渡对于驱动轴突和树突状多巴胺释放至关重要，并且 因此，用于控制皮质 - 纹状体电路的信号处理和行为函数。我们将证明 这些模式以及这些模式的信息内容不同的离子机制不同 在DA亚群之间，通过不同类型的多巴胺能信号传导对行为控制具有很强的影响。 AIM 1将发现经典慢速射击和最近确定的腹侧刺激性DA神经元之间的强直性发射差异的生物物理机制 区域（VTA）。这些机制也可能有助于它们在体内爆发的独特频率。目的 2将阐明内侧黑质（SN）中突发的生物物理基础，通过ATP敏感 K+（K-ATP）通道，对于新颖性引起的探索所必需的，与外侧SN中的突发相比 由Ca2+激活的SK K+通道控制，可能习惯性运动序列。 AIM 3将定义 具有最独特的体内射击模式的两个投影特异性DA亚群的行为函数：爆发的vta da神经元爆发更快地投射到伏隔的内侧外壳上，这可能是 参与显着性或奖励信号，与投射到横向 伏伏壳的外壳，在新颖性介导的探索过程中显示出连续且较慢的破裂。 不同DA的差异性生物物理控制机制 在许多已知的DA信号传导中，包括成瘾，精神分裂症和帕金森氏病（PD）可能会有选择地影响亚群。例如，SN DA神经元的活性依赖性Ca2+负载选择性的减少是PD中有希望的神经保护方法。进一步的解剖 VTA和SN DA亚群的动力学和分子生物物理学的差异提出 这里有望导致更具选择性的量身定制的治疗策略，以调整发射方式 特定的DA亚群。该项目是基于最新，令人兴奋的进步来建模的多样性 Canavier博士实验室中的DA神经元有助于解释Roeper博士先驱DA神经元的多样性。 理论和计算方法将非线性动力学和分叉分析与 形态上现实的多室建模。 Roeper博士的实验室使用最先进的技术， 包括逆行跟踪，成年小鼠切片电生理学，通​​道选择性药理学，可拍摄的可开关K-ATP阻滞剂和动态夹具，以及细胞外记录，并与单个DA神经元的并置与鉴定的单个DA神经元的并置，并在小鼠中识别出轴突的轴突差异 DA人群以全面的方式形成了用于测试模型预测的协同循环。