Most mental disorders involve dysfunction of the dorsolateral prefrontal cortex (dlPFC), a recently evolved brain region that subserves working memory, abstraction, and the thoughtful regulation of attention, action, and emotion. For example, schizophrenia, depression, long COVID, and Alzheimer’s disease are all associated with dlPFC dysfunction, with neuropathology often being focused in layer III. The dlPFC has extensive top-down projections, e.g., to the posterior association cortices to regulate attention and to the subgenual cingulate cortex via the rostral and medial PFC to regulate emotional responses. However, the dlPFC is particularly dependent on arousal state and is very vulnerable to stress and inflammation, which are etiological and/or exacerbating factors for most mental disorders. The cellular mechanisms by which stress and inflammation impact the dlPFC are a topic of current research and are summarized in this review. For example, the layer III dlPFC circuits that generate working memory–related neuronal firing have unusual neurotransmission, depending on NMDA receptor and nicotinic α7 receptor actions that are blocked under inflammatory conditions by kynurenic acid. These circuits also have unusual neuromodulation, with the molecular machinery to magnify calcium signaling in spines needed to support persistent firing, which must be tightly regulated to prevent toxic calcium actions. Stress rapidly weakens layer III connectivity by driving feedforward calcium-cAMP (cyclic adenosine monophosphate) opening of potassium channels on spines. This is regulated by postsynaptic noradrenergic α adrenergic receptor and mGluR3 (metabotropic glutamate receptor 3) signaling but dysregulated by inflammation and/or chronic stress exposure, which contribute to spine loss. Treatments that strengthen the dlPFC via pharmacological (the α adrenergic receptor agonist, guanfacine) or repetitive transcranial magnetic stimulation manipulation provide a rational basis for therapy.

中文翻译：

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压力和炎症目标背外侧前额皮质功能：认知控制减弱的神经机制


大多数精神障碍都涉及背外侧前额叶皮层（dlPFC）的功能障碍，这是一个最近进化的大脑区域，有助于工作记忆、抽象以及对注意力、行动和情绪的深思熟虑的调节。例如，精神分裂症、抑郁症、长期新冠肺炎和阿尔茨海默病都与 dlPFC 功能障碍有关，神经病理学通常集中在第三层。 dlPFC 具有广泛的自上而下的投射，例如，投射到后联皮层以调节注意力，并通过头侧和内侧 PFC 投射到膝下扣带皮层以调节情绪反应。然而，dlPFC 特别依赖于唤醒状态，并且非常容易受到压力和炎症的影响，而压力和炎症是大多数精神障碍的病因和/或加剧因素。压力和炎症影响 dlPFC 的细胞机制是当前研究的一个主题，本综述对此进行了总结。例如，产生工作记忆相关神经元放电的第 III 层 dlPFC 回路具有不寻常的神经传递，这取决于 NMDA 受体和烟碱 α7 受体的作用，这些受体在炎症条件下会被犬尿酸阻断。这些回路还具有不寻常的神经调节功能，其分子机制可以放大脊柱中支持持续放电所需的钙信号传导，必须严格调节以防止有毒的钙作用。压力通过驱动棘上钾通道的前馈钙-cAMP（环磷酸腺苷）打开，迅速削弱第三层连接。 这是由突触后去甲肾上腺素能 α 肾上腺素能受体和 mGluR3（代谢型谷氨酸受体 3）信号调节的，但会因炎症和/或慢性压力暴露而失调，从而导致脊柱损失。通过药物（α 肾上腺素能受体激动剂、胍法辛）或重复经颅磁刺激操作来增强 dlPFC 的治疗为治疗提供了合理的基础。