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前额皮质的不同投射介导自闭症和焦虑样行为。

Divergent projections of the prelimbic cortex mediate autism- and anxiety-like behaviors.

机构信息

International Joint Laboratory for Drug Target of Critical Illnesses, Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China.

Department of Physiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 211166, China.

出版信息

Mol Psychiatry. 2023 Jun;28(6):2343-2354. doi: 10.1038/s41380-023-01954-y. Epub 2023 Jan 23.

DOI:10.1038/s41380-023-01954-y
PMID:36690791
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10611563/
Abstract

The comorbidity of autism spectrum disorder and anxiety is common, but the underlying circuitry is poorly understood. Here, Tmem74 mice showed autism- and anxiety-like behaviors along with increased excitability of pyramidal neurons (PNs) in the prelimbic cortex (PL), which were reversed by Tmem74 re-expression and chemogenetic inhibition in PNs of the PL. To determine the underlying circuitry, we performed conditional deletion of Tmem74 in the PNs of PL of mice, and we found that alterations in the PL projections to fast-spiking interneurons (FSIs) in the dorsal striatum (dSTR) (PL-dSTR) mediated the hyperexcitability of FSIs and autism-like behaviors and that alterations in the PL projections to the PNs of the basolateral amygdaloid nucleus (BLA) (PL-BLA) mediated the hyperexcitability of PNs and anxiety-like behaviors. However, the two populations of PNs in the PL had different spatial locations, optogenetic manipulations revealed that alterations in the activity in the PL-dSTR or PL-BLA circuits led to autism- or anxiety-like behaviors, respectively. Collectively, these findings highlight that the hyperactivity of the two populations of PNs in the PL mediates autism and anxiety comorbidity through the PL-dSTR and PL-BLA circuits, which may lead to the development of new therapeutics for the autism and anxiety comorbidity.

摘要

自闭症谱系障碍和焦虑共病很常见，但潜在的发病机制仍不清楚。在这里，Tmem74 小鼠表现出自闭症和焦虑样行为，同时在前扣带皮层 (PL) 的锥体神经元 (PN) 兴奋性增加，这些行为可通过 PL 中的 Tmem74 重新表达和化学遗传抑制来逆转。为了确定潜在的发病机制，我们在小鼠 PL 的 PN 中进行了条件性 Tmem74 缺失，我们发现 PL 投射到背侧纹状体 (dSTR) 中的快速放电中间神经元 (FSI) 的改变 (PL-dSTR) 介导了 FSI 的过度兴奋和自闭症样行为，而 PL 投射到杏仁核基底外侧核 (BLA) 的 PN 的改变 (PL-BLA) 介导了 PN 的过度兴奋和焦虑样行为。然而，PL 中的这两种 PN 群体具有不同的空间位置，光遗传操作表明，PL-dSTR 或 PL-BLA 回路中活动的改变分别导致自闭症或焦虑样行为。总的来说，这些发现强调了 PL 中这两种 PN 群体的过度活跃通过 PL-dSTR 和 PL-BLA 回路介导自闭症和焦虑共病，这可能为自闭症和焦虑共病的治疗方法的发展提供新的途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d793/10611563/7ba08e71ae3f/41380_2023_1954_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d793/10611563/eb4cc6c2d1db/41380_2023_1954_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d793/10611563/8e9ebaccfca1/41380_2023_1954_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d793/10611563/7d4ce190fab0/41380_2023_1954_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d793/10611563/52fc4de4fcd1/41380_2023_1954_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d793/10611563/62c3846d8434/41380_2023_1954_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d793/10611563/7ba08e71ae3f/41380_2023_1954_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d793/10611563/eb4cc6c2d1db/41380_2023_1954_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d793/10611563/8e9ebaccfca1/41380_2023_1954_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d793/10611563/7d4ce190fab0/41380_2023_1954_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d793/10611563/52fc4de4fcd1/41380_2023_1954_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d793/10611563/62c3846d8434/41380_2023_1954_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d793/10611563/7ba08e71ae3f/41380_2023_1954_Fig6_HTML.jpg

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