Circuit structure and dynamics in prefrontal-limbic networks

前额叶边缘网络的电路结构和动力学

• 批准号: 10578724
• 负责人: Maria Medalla
• 金额: $ 41.25万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10578724
• 关键词: 3-Dimensional; Action Potentials; Address; Adult; Affect; Affective; Amygdaloid structure; Anatomy; Anesthesia procedures; Animals; Anterior; Area; Back; Behavior; Behavioral; Carbachol; Cells; Chemosensitization; Classification; Cognition; Cognitive; Communication; Complex; Confocal Microscopy; Electron Microscopy; Electrophysiology (science); Emotional; Emotions; Equilibrium; Exhibits; Frequencies; In Vitro; Inhibitory Synapse; Interneurons; Lateral; Limbic System; Macaca mulatta; Measures; Mediating; Membrane; Mental disorders; Monkeys; Mood Disorders; Motivation; Motor; Neuroanatomy; Neuromodulator; Neurons; Output; Pathway interactions; Pattern; Physiological; Prefrontal Cortex; Primates; Property; Regulation; Rodent; Sensory; Short-Term Memory; Signal Transduction; Stress; Structure; Synapses; System; Techniques; Testing; Time; Tracer; Update; Work; cingulate cortex; cognitive task; emotion regulation; executive function; flexibility; hippocampal pyramidal neuron; in vivo; inhibitory neuron; insight; nerve supply; neural; neurochemistry; neuropathology; neuroregulation; optogenetics; pharmacologic; postsynaptic; presynaptic; receptor; recruit; response; signal processing

PROJECT ABSTRACT The lateral prefrontal cortex (LPFC) and anterior cingulate cortex (ACC) in primates interact with each other, as key components of the executive control network. However, these areas participate in distinct extrinsic circuits and exhibit temporally-distinct activation patterns as they enhance task-relevant and suppresses task-irrelevant information to guide behavior. The LPFC rapidly encodes and transiently stores sensory-motor information for continuous updating of information in “working memory” for the task at hand. As temporal and cognitive- emotional demands increase (i.e., a higher number of temporally distinct motivational variables to consider), the ACC is additionally engaged. The ACC, as part of the limbic network, can integrate emotional and mnemonic information to modulate cognitive tasks that span both rapid and longer timescales. Cortical excitatory and inhibitory synaptic networks determine the spatial and temporal dynamics of signal enhancement or suppression in cognitive tasks. The scientific premise of this proposal is that the key differences in the temporal dynamics of processing in ACC vs LPFC in behavior are due to differences network excitatory-inhibitory (E:I) synaptic balance in these areas, which remain poorly understood. Our recent work suggests that higher inhibitory tone and longer membrane time constant in ACC neurons likely contribute to a longer temporal range for integration. The overall hypothesis of this proposal is that highly distinctive excitatory-inhibitory and neuromodulatory circuits in the ACC and LPFC underlie differential temporal dynamics of signal processing for cognitive-emotional integration by these two areas. Using multi-scale neuroanatomical, in vitro and in vivo electrophysiological, pharmacologic and optogenetic techniques in adult rhesus monkeys (Macaca mulatta), we aim to study the properties of inhibitory circuits that control the temporal dynamics of ACC vs LPFC pyramidal neuron activity, and how limbic input from the amygdala influences communication within the ACC-LPFC network. We will study GABAergic and neuromodulatory influences on these prefrontal networks that are highly implicated in the regulation of stress and emotions. In Aim 1 we will investigate the properties of temporally-distinct inhibitory circuits, using in vitro electrophysiological and pharmacological techniques to isolate fast versus slow inhibitory currents, as well as neuroanatomical techniques to classify inhibitory neurons based on their receptors and innervation patterns. In Aim 2 we will determine whether differential inhibitory signaling in ACC vs LPFC affects capacities for diverse network oscillations in vitro and in vivo. In Aim 3 we will study the properties of ACCamygdala vs ACCLPFC projections and how these neurons receive synaptic input from the amygdala, using optogenetics and 3D electron microscopy. Disruption of the E:I balance and oscillatory dynamics within this ACC-LPFC prefrontal-limbic network is the core neuropathology in cognitive-affective psychiatric disorders. The proposed study will shed light on the underlying circuit mechanisms of normal and disrupted cognitive-emotional integration in primates.

项目摘要 灵长类动物的外侧前额叶皮层 (LPFC) 和前扣带皮层 (ACC) 相互作用，如 执行控制网络的关键组成部分。然而，这些区域参与不同的外在回路 并表现出时间上不同的激活模式，因为它们增强了与任务相关的内容并抑制了与任务无关的内容 指导行为的信息。 LPFC 快速编码并瞬时存储感觉运动信息 不断更新“工作记忆”中当前任务的信息。作为时间和认知- 情感需求增加（即需要考虑更多数量的时间上不同的动机变量）， ACC 也参与其中。 ACC 作为边缘网络的一部分，可以整合情感和 用于调节跨越快速和较长时间尺度的认知任务的助记信息。皮质 兴奋性和抑制性突触网络决定信号的空间和时间动态 认知任务的增强或抑制。这一提议的科学前提是关键 ACC 与 LPFC 的行为处理时间动态差异是由于网络差异造成的 这些区域的兴奋性抑制（E:I）突触平衡目前仍知之甚少。我们最近的工作 表明 ACC 神经元中较高的抑制音调和较长的膜时间常数可能有助于 积分的时间范围更长。该提案的总体假设是高度独特的 ACC 和 LPFC 中的兴奋-抑制和神经调节回路是微分时间动态的基础 这两个区域进行认知情感整合的信号处理。利用多尺度神经解剖学， 成年恒河猴的体外和体内电生理学、药理学和光遗传学技术 （Macaca mulatta），我们的目标是研究控制时间动态的抑制电路的特性 ACC 与 LPFC 锥体神经元活动，以及杏仁核的边缘输入如何影响沟通 在 ACC-LPFC 网络内。我们将研究 GABA 能和神经调节对这些前额叶的影响 与压力和情绪调节高度相关的网络。在目标 1 中，我们将调查 利用体外电生理学和药理学研究时间上不同的抑制电路的特性 分离快速与慢速抑制电流的技术，以及分类的神经解剖学技术 基于其受体和神经支配模式的抑制性神经元。在目标 2 中，我们将确定是否 ACC 与 LPFC 中的差异抑制信号会影响体外和体内不同网络振荡的能力 体内。在目标 3 中，我们将研究 ACCamygdala 与 ACCLPFC 投影的特性以及这些投影如何 利用光遗传学和 3D 电子显微镜，神经元接收来自杏仁核的突触输入。破坏 ACC-LPFC 前额叶边缘网络内的 E:I 平衡和振荡动力学是核心 认知情感精神疾病的神经病理学。拟议的研究将揭示 灵长类动物正常和破坏的认知情绪整合的潜在回路机制。