Distinct projections from the infralimbic cortex exert opposing effects in modulating anxiety and fear
Yi-Hua Chen, … , Jian-Ming Yang, Tian-Ming Gao
Yi-Hua Chen, … , Jian-Ming Yang, Tian-Ming Gao
Published July 15, 2021
Citation Information: J Clin Invest. 2021;131(14):e145692. https://doi.org/10.1172/JCI145692.
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Research Article Neuroscience

Distinct projections from the infralimbic cortex exert opposing effects in modulating anxiety and fear

Abstract

Anxiety-related disorders can be treated by cognitive therapies and transcranial magnetic stimulation, which involve the medial prefrontal cortex (mPFC). Subregions of the mPFC have been implicated in mediating different and even opposite roles in anxiety-related behaviors. However, precise causal targets of these top-down connections among diverse possibilities have not been established. Here, we show that the lateral septum (LS) and the central nucleus of the amygdala (CeA) represent 2 direct targets of the infralimbic cortex (IL), a subregion of the mPFC that modulates anxiety and fear. Two projections were unexpectedly found to exert opposite effects on the anxious state and learned freezing: the IL-LS projection promoted anxiety-related behaviors and fear-related freezing, whereas the IL-CeA projection exerted anxiolytic and fear-releasing effects for the same features. Furthermore, selective inhibition of corresponding circuit elements showed opposing behavioral effects compared with excitation. Notably, the IL-CeA projection implemented top-down control of the stress-induced high-anxiety state. These results suggest that distinct IL outputs exert opposite effects in modulating anxiety and fear and that modulating the excitability of these projections with distinct strategies may be beneficial for the treatment of anxiety disorders.

Authors

Yi-Hua Chen, Jian-Lin Wu, Neng-Yuan Hu, Jia-Pai Zhuang, Wei-Peng Li, Sheng-Rong Zhang, Xiao-Wen Li, Jian-Ming Yang, Tian-Ming Gao

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Figure 5

IL-LS and IL-CeA inhibition shows opposite effects on anxiety-related behaviors.

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IL-LS and IL-CeA inhibition shows opposite effects on anxiety-related be...
(A) Experimental paradigm for optogenetic inhibition. Neurons in the IL were transduced with either NpHR-eYFP or eYFP. Yellow light was delivered via bilateral optical fibers implanted into the LS or CeA after 6–7 weeks of viral incubation. (B–D) eNpHR IL-LS mice, compared with eYFP mice, showed increased open-arm exploration [B, Finteraction (4,38) = 15.69, P < 0.0001] and a higher probability of open-arm entry [C, Finteraction (4,38) = 17.89, P < 0.0001] in the EPM test and increased center exploration time [D, Finteraction (4,38) = 18.38, P < 0.0001] in the OFT during the illumination epoch, whereas yellow light induced opposite effects on the NpHR-IL-CeA mice. n = 8 eYFP mice; n = 7 eNpHR-LS mice; n = 7 eNpHR-CeA mice. (E) total distance traveled. (F) Experimental paradigm for pharmacogenetic inhibition. Neurons in the IL were transduced with either hM4DGi-mCherry or mCherry. CNO was delivered via bilateral guide cannula implanted into the LS or CeA 30 minutes before the behavioral assays, after 6 to 7 weeks of viral incubation. (G–I) hM4DGi IL-LS mice, compared with mCherry mice, showed an increase in both open-arm exploration in the EPM test [G, F(2,25) = 36.92, P < 0.0001; H, F(2,25) = 32.10, P < 0.0001] and center exploration in the OFT [I, F(2,25) = 80.83, P < 0.0001] after CNO infusion, whereas CNO induced opposite effects on the hM4DGi IL-CeA mice. n = 9 eYFP mice; n = 10 eNpHR-LS mice; n = 9 eNpHR-CeA mice. (J) Total distance traveled. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-way, repeated-measures ANOVA with Dunnett’s multiple-comparison test (B–E) and 1-way ANOVA with Dunnett’s multiple-comparison test (G–J). Data are presented as the mean ± SEM. See Supplemental Table 1 for statistical details.