Distinct projections from the infralimbic cortex exert opposing effects in modulating anxiety and fear
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
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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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 2

Distinct IL outputs modulate opposite anxiety-related behaviors.

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Distinct IL outputs modulate opposite anxiety-related behaviors. (A and ...
(A and B) Confocal images of coronal sections showing IL terminals in the LS (A), BLA, and CeA (B). Scale bars: 200 μm. (C) Experimental design to investigate the behavioral impact of optogenetic activation of IL-LS or IL-CeA projections. (D) eYFP and ChR2 mice expressing eYFP or ChR2-eYFP, respectively, in the IL with optic fibers above the LS. n = 15 eYFP mic; n = 13 ChR2 mice. (E–H) Blue light decreased the exploration of open arms [E, Finteraction (2,52) = 8.447, P = 0.0007], as well as the probability of open-arm entry [F, Finteraction (2,52) = 11.35, P = 0.0002] and center exploration in the open field [G, Finteraction (2,52) = 11.90, P < 0.0001], without altering locomotion [H, Finteraction (2,52) = 0.1149, P = 0.8917]. (I–M) Same as in D–H, but for IL-CeA projections. n = 8 eYFP mice; n = 8 ChR2 mice. Yellow light increased the exploration of open arms [J, Finteraction (2,28) = 7.20, P = 0.0030], resulted in a higher probability of open-arm entry [K, Finteraction (2,28) = 7.264, P = 0.0029], increased center exploration in the open field [L, Finteraction (2,28) = 12.18, P = 0.0002], and did not alter locomotion [M, Finteraction (2,28) = 0.3525, P = 0.7060]. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-way, repeated-measures ANOVA with Bonferroni’s post hoc analysis (E–H and J–M). Data are presented as the mean ± SEM. See Supplemental Table 1 for statistical details.