Circuit structure and dynamics in prefrontal-limbic networks

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，因为它们增强了任务相关性，抑制了任务无关性 指导行为的信息。LPFC快速编码并瞬时存储感觉运动信息， 为手头的任务不断更新“工作记忆”中的信息。作为时间和认知- 情感需求增加（即，要考虑的更多数量的时间上不同的动机变量）， ACC被额外地占用。ACC作为边缘系统网络的一部分，可以整合情绪和 记忆信息来调节跨越快速和较长时间尺度的认知任务。皮质 兴奋性和抑制性突触网络决定了信号的空间和时间动态 增强或抑制认知任务。这一提议的科学前提是， 前扣带回与前额叶皮层在行为上的加工时间动态差异是由于网络差异造成的 兴奋抑制（E：I）突触平衡在这些领域，这仍然知之甚少。我们最近的工作 表明ACC神经元中较高的抑制性张力和较长的膜时间常数可能有助于 更长的整合时间范围。这一提议的总体假设是， ACC和LPFC中的兴奋-抑制和神经调节回路是差异时间动力学的基础 这两个区域对认知情绪整合的信号处理。使用多尺度神经解剖学， 成年恒河猴体外和体内电生理学、药理学和光遗传学技术 （Macaca mulatta），我们的目的是研究抑制回路的特性，这些回路控制着 ACC与LPFC锥体神经元活动，以及来自杏仁核的边缘系统输入如何影响交流 在ACC-LPFC网络中。我们将研究GABA能和神经调节对这些前额叶的影响， 这些网络与压力和情绪的调节密切相关。在目标1中，我们将研究 时间不同的抑制回路的特性，使用体外电生理学和药理学 技术，以隔离快与慢抑制电流，以及神经解剖技术，以分类 抑制性神经元基于它们的受体和神经支配模式。在目标2中，我们将确定 ACC与LPFC中的差异抑制信号影响体外和体内不同网络振荡的能力。 vivo.在目标3中，我们将研究ACC杏仁核和ACC杏仁核LPFC投射的特性，以及这些特性如何影响ACC杏仁核和LPFC的投射。 神经元接受来自杏仁核的突触输入，使用光遗传学和3D电子显微镜。中断 在这个ACC-LPFC前额叶-边缘系统网络中，E：I平衡和振荡动力学是核心 认知情感性精神障碍的神经病理学拟议的研究将阐明 灵长类动物正常和中断的认知情绪整合的潜在电路机制。

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.