Top-Down Control of Serotonin Systems by the Prefrontal Cortex: A Path toward Restored Socioemotional Function in Depression.
Top-Down Control of Serotonin Systems by the Prefrontal Cortex: A Path toward Restored Socioemotional Function in Depression.
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DOI：
10.1021/acschemneuro.5b00007
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发表时间：
2015-07-15
影响因子：
5
通讯作者：
Berton O
中科院分区：
文献类型：
--
作者：
Challis C;Berton O
社交退缩、威胁感知增加和夸大的寻求安慰行为是重性抑郁障碍（MDD）的突出人际症状。长期以来，人们一直怀疑5-羟色胺（5-HT）系统和皮质边缘连接障碍与这些症状有关，然而，在社会情绪互动过程中控制5-HT输出的潜在回路和内在细胞机制仍然知之甚少。我们回顾文献，暗示腹内侧前额叶皮层（vmPFC）和中缝背核（DRN）之间的适应性和病理控制的社会接近-回避行为的直接通路。在人类接近-回避任务中的成像和神经调节指出，脑干回路的皮质控制是社会情绪决策和行动的重要调节器。使用基于病毒的连接组学和光遗传学的平行啮齿动物研究开始提供底层电路的细胞蓝图。在这些研究中，操纵VMPFC突触输入DRN揭示了双向影响社会情感行为通过直接的单突触兴奋和间接的双突触抑制5-HT神经元。此外，导致永久性回避偏见的不良社会经历，如社交失败，在这个微回路中驱动持久的可塑性，增强对5-HT输出的间接抑制。相反，通过脑深部电刺激（DBS）对vmPFC进行神经调节，通过恢复5-HT神经元的直接兴奋性驱动和加强前脑5-HT投射的关键子集来减弱回避偏差。更好地理解vmPFC-DRN通路的细胞组织并确定其神经可塑性的分子决定因素可以为情感障碍的治疗开辟新的途径。
Social withdrawal, increased threat perception and exaggerated reassurance seeking behaviors are prominent interpersonal symptoms in major depressive disorder (MDD). Altered serotonin (5-HT) systems and corticolimbic dysconnectivity have long been suspected to contribute to these symptomatic facets, however, the underlying circuits and intrinsic cellular mechanisms that control 5-HT output during socioemotional interactions remain poorly understood. We review literature that implicates a direct pathway between the ventromedial prefrontal cortex (vmPFC) and dorsal raphe nucleus (DRN) in the adaptive and pathological control of social approach-avoidance behaviors. Imaging and neuromodulation during approach-avoidance tasks in humans point to the cortical control of brainstem circuits as an essential regulator of socioemotional decisions and actions. Parallel rodent studies using viral-based connectomics and optogenetics are beginning to provide a cellular blueprint of the underlying circuitry. In these studies, manipulations of vmPFC synaptic inputs to the DRN have revealed bidirectional influences on socioaffective behaviors via direct monosynaptic excitation and indirect disynaptic inhibition of 5-HT neurons. Additionally, adverse social experiences that result in permanent avoidance biases, such as social defeat, drive long-lasting plasticity in this microcircuit, potentiating the indirect inhibition of 5-HT output. Conversely, neuromodulation of the vmPFC via deep brain stimulation (DBS) attenuates avoidance biases by restoring the direct excitatory drive of 5-HT neurons and strengthening a key subset of forebrain 5-HT projections. Better understanding the cellular organization of the vmPFC-DRN pathway and identifying molecular determinants of its neuroplasticity can open fundamentally novel avenues for the treatment of affective disorders.