Coordinated modulation of cortical circuits by serotonin and acetylcholine

摘要 皮质回路，由专门的神经元亚群及其选择性突触连接组成， 通过两种不同类别的投射神经元将输出信号发送到远距离皮质和皮质下目标： 在皮质半球和锥体束内和跨皮质投射初级神经元的脑内(IT)神经元 (Pt)投射到皮质下深层靶点(如丘脑和脑干)的神经元。大脑皮层回路 受多种调节性神经递质调节，如5-羟色胺(5-羟色胺)和乙酰胆碱(ACh)， 针对不同的认知任务优化电路性能。的确，5-羟色胺能或胆碱能的干扰 皮质中的信号会损害认知和正常行为，这两个递质系统都与 一系列精神疾病。因此，揭示了5-羟色胺和乙酰胆碱的生理机制 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。 在小鼠前额叶皮质，5-羟色胺和乙酰胆碱通过G蛋白偶联受体相互作用 调节IT和PT神经元突触后兴奋性。5-羟色胺促进IT神经元输出，但抑制 PT神经元。相反，ACh优先兴奋PT神经元，但对IT神经元的影响有限。 无论神经调节状态如何，IT和PT神经元的动作电位产生都需要兴奋性 突触驱动也可能在突触前水平上受到5-羟色胺和/或ACh的调节。我们的初步研究 提示5-羟色胺和乙酰胆碱对IT和PT神经元的兴奋性传入有不同的调节作用。这 目前的项目将测试最重要的假设，即5-羟色胺和乙酰胆碱偏向大脑皮层回路的“吞吐量” 通过对兴奋性传入和皮质的特定组合进行突触前和突触后的协调调节 投射靶神经元亚型。我们的第一个目标是绘制相对靶向和功能性兴奋驱动图， 小鼠内侧PFC的关键外源性兴奋性传入对IT和PT神经元的影响。我们的第二个目标是测试 5-羟色胺和ACh对传入特异性突触前的调节，从而决定是否前和 突触后神经调节是协调的，以促进传入输入和皮质的特定组合 投影输出。我们的第三个目标是测试5-羟色胺和/或ACh是否调节本地电路通信 在IT和PT神经元之间以与这些神经元突触后相反的影响相一致的方式 关于兴奋性的调节剂。 这些目标的完成将建立一个严格的、基于回路的框架来理解胆碱能 和5-羟色胺能调节认知功能，并将提供洞察如何扰乱 神经调节回路导致精神疾病。

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.