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 4

Monosynaptic and functional IL inputs into the LS or CeA.

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Monosynaptic and functional IL inputs into the LS or CeA. (A and D) Expe...
(A and D) Experimental scheme. Two methods were used: injection of retrobeads into the LS (A) or CeA (D) and injection of CAV-Cre virus into the LS (A) or CeA (D) and AAV-DIO-ChR2-Cherry virus into the IL (A and D). (B) Fluorescence images illustrating retrobead back-labeled LS-projecting IL neurons and graph indicating the total number of these neurons. LV, lateral ventricle. (C) Same as in B, but for mCherry expression. (E) Same as in B, but for CeA-projecting IL neurons. (F) Same as in E, but for mCherry expression. (G and K) Scheme for recording postsynaptic currents in the LS (G) or CeA (K) evoked by optogenetic activation of IL projections. (H and L) Overlay of light-triggered responses in the LS (H) and CeA (L). (I and M) Light-evoked postsynaptic currents were completely blocked by TTX and recovered by TTX plus 4AP, which were blocked by 6-cyano-7-nitroquinoxaline-2,3-dioneis (CNQX) [I, n = 7 neurons from 2 mice, F(3,24) = 27.01, P < 0.0001; M, n = 5 neurons from 2 mice, F(3,16) = 26.54, P < 0.0001; 1-way ANOVA with Tukey’s multiple-comparison test]. (J and N) Onset latencies for the LS (J) and CeA (N). (O) Experimental scheme showing that CTB was injected into 2 targets of IL neurons, the LS and the CeA. (P) Fluorescence images illustrating CTB targeted to the LS (CTB488, green) and the CeA (CTB555, red). (Q) Coronal section of the IL labeled with CTB in green (LS) and red (CeA). (R) Number of IL neurons labeled with CTB. LS-projecting IL neurons, n = 519 ± 13 cells (average from 3 mice; 459 [green circle] + 60 [yellow overlap] = 519); CeA-projecting IL neurons, n = 228 ± 11 cells (average from 3 mice; 168 [red circle] + 60 [yellow overlap] = 228). Scale bars: 100 μm (B, C, E, F, and Q) and 500 μm (P). ***P < 0.001, by 1-way ANOVA with Tukey’s multiple-comparison test (I and M). Data are presented as the mean ± SEM. See Supplemental Table 1 for statistical details.