The medial prefrontal cortex (mPFC) controls behavior via connections with limbic excitatory afferents that engage various inhibitory motifs to shape mPFC circuit function. The dynorphin (Dyn) / kappa-opioid receptor (KOR) system is highly enriched in the mPFC, and its dysregulation is implicated in neuropsychiatric disorders. However, it is unclear how the Dyn / KOR system modulates excitatory and inhibitory circuits that are integral for mPFC information processing and behavioral control. Here, we provide a circuit-based framework wherein mPFC Dyn / KOR signaling regulates excitation-inhibition balance by toggling which afferents drive mPFC neurons. Dyn / KOR regulation of afferent inputs is pathway-specific. Dyn acting on presynaptic KORs inhibits glutamate release from afferent inputs to the mPFC, including the basolateral amygdala (BLA), paraventricular nucleus of the thalamus, and contralateral cortex. The majority of excitatory synapses to mPFC neurons, including those from the ventral hippocampus (VH), do not express presynaptic KOR, rendering them insensitive to Dyn / KOR modulation. Dyn / KOR signaling also suppresses afferent-driven recruitment of specific inhibitory sub-networks, providing a basis for Dyn to disinhibit mPFC circuits. Specifically, Dyn / KOR signaling preferentially suppresses SST interneuron- relative to PV interneuron-mediated inhibition. Selective KOR action on afferents or within mPFC microcircuits gates how distinct limbic inputs drive spiking in mPFC neurons. Presynaptic Dyn / KOR signaling decreases KOR-positive input-driven (e.g. BLA) spiking of mPFC neurons. In contrast, KOR-negative input recruitment of mPFC neurons is enhanced by Dyn / KOR signaling via suppression of mPFC inhibitory microcircuits. Thus, by acting on distinct circuit elements, Dyn / KOR signaling shifts KOR-positive and negative afferent control of mPFC circuits, providing mechanistic insights into the role of neuropeptides in shaping mPFC function. Together, these findings highlight the utility of targeting the mPFC Dyn / KOR system as a means to treat neuropsychiatric disorders characterized by dysregulation in mPFC integration of long-range afferents with local inhibitory microcircuits.

内侧前额叶皮层 (mPFC) 通过与边缘兴奋性传入神经的连接来控制行为，边缘兴奋性传入神经参与各种抑制性基序来塑造 mPFC 回路功能。强啡肽 (Dyn)/κ-阿片受体 (KOR) 系统在 mPFC 中高度丰富，其失调与神经精神疾病有关。然而，目前尚不清楚 Dyn / KOR 系统如何调节 mPFC 信息处理和行为控制不可或缺的兴奋性和抑制性电路。在这里，我们提供了一个基于电路的框架，其中 mPFC Dyn / KOR 信号通过切换驱动 mPFC 神经元的传入神经来调节兴奋-抑制平衡。 Dyn / KOR 传入输入的调节是通路特异性的。 Dyn 作用于突触前 KOR，抑制 mPFC 传入输入的谷氨酸释放，包括基底外侧杏仁核 (BLA)、丘脑室旁核和对侧皮质。 mPFC 神经元的大多数兴奋性突触，包括来自腹侧海马 (VH) 的神经元，不表达突触前 KOR，从而使它们对 Dyn / KOR 调制不敏感。 Dyn / KOR 信号传导还抑制传入驱动的特定抑制子网络的募集，为 Dyn 去抑制 mPFC 回路提供了基础。具体而言，相对于 PV 中间神经元介导的抑制，Dyn/KOR 信号传导优先抑制 SST 中间神经元。对传入神经或 mPFC 微电路内的选择性 KOR 作用可控制不同的边缘输入如何驱动 mPFC 神经元的尖峰。突触前 Dyn / KOR 信号传导可减少 mPFC 神经元的 KOR 正输入驱动（例如 BLA）尖峰。相比之下，Dyn/KOR 信号传导通过抑制 mPFC 抑制微电路增强了 mPFC 神经元的 KOR 阴性输入募集。 因此，通过作用于不同的电路元件，Dyn / KOR 信号传导改变了 mPFC 电路的 KOR 正向和负向传入控制，为神经肽在塑造 mPFC 功能中的作用提供了机制见解。总之，这些发现强调了以 mPFC Dyn / KOR 系统作为治疗神经精神疾病的手段的实用性，其特征是远程传入与局部抑制微电路的 mPFC 整合失调。