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 3

Glutamatergic IL inputs into the LS or CeA modulate anxiety-related behaviors.

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Glutamatergic IL inputs into the LS or CeA modulate anxiety-related beha...
(A) Experimental paradigm. Experiments were performed 7 or 8 weeks after AAV2-CaMKIIα-ChR2-eYFP injection. Thirty minutes before the behavioral assays and laser stimulation, glutamate receptor antagonists (GluR antag: AP5 + NBQX) or saline were unilaterally infused locally into the LS or CeA using the same guide cannula that delivered light via an optical fiber. (B) Mice expressing ChR2 in the IL were treated with saline or AP5 plus NBQX via cannulas above the LS. (C–F) Relative to saline injections, AP5 plus NBQX injections into the LS blocked the light-induced decreases in open-arm exploration on the EPM test [C, Finteraction (2,44) = 12.57, P < 0.0001; D, Finteraction (2,44) = 17.71, P = 0.000] and center exploration in the open field [E, Finteraction (2,30) = 3.392, P = 0.0470]. Neither light stimulation nor injection of AP5 plus NBQX altered the total distance traveled [F, Finteraction (2,30) = 0.2107, P = 0.8112]. (G–K) Same as in B–F, but for IL-CeA projections. After intra-CeA glutamate receptor blockade, photoactivation of ChR2-expressing IL terminals in the CeA failed to increase open-arm exploration [H, Finteraction (2,38) = 3.100, P = 0.0566; I, Finteraction (2,38) = 13.84, P < 0.0001], center exploration in the open field [J, Finteraction (2,34) = 7.009, P = 0.0028], or locomotion [K, Finteraction (2,34) = 0.08985, P = 0.7863]. n = 11 and n = 13 mice for C and D; n = 9 and n = 8 mice for E and F; n = 11 and n = 10 mice for H and I; n = 10 and n = 9 mice for J and K. *P < 0.05 and ***P < 0.001., by 2-way, repeated-measures ANOVA with Bonferroni’s post hoc analysis (C–F and H–K). Data are presented as the mean ± SEM. See Supplemental Table 1 for statistical details.