Li Jiaxin, Zhou Yao, Yin Fangyuan, Du Yanfeng, Xu Jiancheng, Fan Shuyuan, Li Ziyi, Wang Xiaojie, Shen Qingfeng, Zhu Yongsheng, Ma Tengfei
Institute for Stem Cell and Neural Regeneration and Key Laboratory of Cardiovascular & Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, China.
Department of Substance Dependence, The Affiliated Xuzhou Eastern Hospital of Xuzhou Medical University, Xuzhou Eastern People's Hospital, Xuzhou, China.
Biol Psychiatry. 2025 Mar 15;97(6):614-626. doi: 10.1016/j.biopsych.2024.10.005. Epub 2024 Oct 11.
A top-down neuronal circuit from the orbitofrontal cortex (OFC) to the dorsomedial striatum (DMS) appears to be critical for cognitive flexibility. However, how OFC projections to different types of neurons in the DMS control cognitive flexibility and contribute to substance seeking and use, which are relatively inflexible behaviors, remains unclear.
Mice were trained on 2-bottle choice and operant alcohol self-administration procedures. The cognitive flexibility of the mice was tested through a place discrimination task. Electrophysiology and in vivo optogenetics were used to test the function of neural circuits in alcohol-seeking behavior.
We depicted a connection from the OFC to striatal neurons and found that OFC afferents could elicit functional flexibility in striatal cholinergic interneurons (CINs). A mouse model of chronic alcohol consumption showed impaired cognitive flexibility and reduced burst-pause firing. The impairment of the OFC-DMS circuit resulted in a reduction in glutamatergic transmission in OFC medium spiny neurons (MSNs) through a CIN-mediated preinhibition mechanism. Importantly, remodeling the OFC-DMS circuit by inducing long-term potentiation restored cognitive flexibility. Furthermore, CINs were responsible for the impact of remodeling of the OFC-DMS circuit on cognitive flexibility. This regulatory role of CINs preferentially facilitated the potentiation of glutamatergic transmission in D receptor-expressing MSNs, but not in D receptor-expressing MSNs. Finally, activation of the OFC-CIN-D receptor-expressing MSN circuit decreased alcohol-seeking behavior.
Improving OFC-CIN circuit-mediated cognitive flexibility may provide a novel strategy for treating uncontrolled alcohol-seeking behavior.
从眶额叶皮质（OFC）到背内侧纹状体（DMS）的自上而下的神经元回路似乎对认知灵活性至关重要。然而，OFC向DMS中不同类型神经元的投射如何控制认知灵活性并导致物质寻求和使用（相对不灵活的行为）仍不清楚。
对小鼠进行双瓶选择和操作性酒精自我给药程序训练。通过位置辨别任务测试小鼠的认知灵活性。采用电生理学和体内光遗传学方法测试神经回路在酒精寻求行为中的功能。
我们描绘了一条从OFC到纹状体神经元的连接，并发现OFC传入纤维可在纹状体胆碱能中间神经元（CINs）中引发功能灵活性。慢性酒精摄入的小鼠模型显示认知灵活性受损且爆发-暂停放电减少。OFC-DMS回路的损伤通过CIN介导的前抑制机制导致OFC中型多棘神经元（MSNs）中谷氨酸能传递减少。重要的是，通过诱导长时程增强重塑OFC-DMS回路可恢复认知灵活性。此外，CINs负责OFC-DMS回路重塑对认知灵活性的影响。CINs的这种调节作用优先促进了表达D受体的MSNs中谷氨酸能传递的增强，而不是表达D受体的MSNs。最后，激活OFC-CIN-表达D受体的MSN回路可减少酒精寻求行为。
改善OFC-CIN回路介导的认知灵活性可能为治疗不受控制的酒精寻求行为提供一种新策略。
