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 1

The IL is implicated in anxiety-like behavior.

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The IL is implicated in anxiety-like behavior. (A) Expression of ChR2 in...
(A) Expression of ChR2 in the IL. Scale bar: 500 μm. M2,secondary motor cortex; Cg1, cingulate cortex, area 1; PL, prelimbic cortex. (B) Brief blue light pulses at 5 Hz, 20 Hz, and 40 Hz precisely activated ChR2 cells. (C) Schematic protocol for investigating the behavioral impact of optogenetic activation of IL somata. (D) Representative animal track across epochs in the EPM for a ChR2 mouse. Mice were tested in 3-minute epochs across a 9-minute session. (E) ChR2 mice (n = 10) spent less time in the open arms than did eYFP mice (n = 8) during photostimulation [Finteraction (2,32) = 3.959, P = 0.0291]. (F) ChR2 mice showed a lower probability of entering the open arms than did eYFP mice during photostimulation [Finteraction (2,32) = 10.88, P = 0.0002]. (G) Representative animal track across epochs in the OFT for a ChR2 mouse. (H) During the illumination epoch, ChR2 mice spent less time exploring the center of the open field than did eYFP mice [Finteraction (2,32) = 21.12, P < 0.0001]. (I) Photostimulation did not alter the distance traveled for mice in either group. (J) Expression of eNpHR in the IL. Scale bar: 500 μm. (K) Yellow light illumination of eNpHR cells in the IL blocked evoked spiking. (L) Schematic protocol for investigating the behavioral impact of optogenetic inhibition of IL somata. (M) Same as in E but for eNpHR mice [n = 7 per group, Finteraction (2,24) = 4.452, P = 0.0227]. (N) Same as in F but for eNpHR mice [Finteraction (2,24) = 7.726, P = 0.0026]. (O) Same as in H but for eNpHR mice [Finteraction (2,24) = 11.76, P = 0.0003]. (P) Same as in I but for eNpHR mice. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-way, repeated-measures ANOVA with Bonferroni’s post hoc analysis (E–I and M–P). Data are presented as the mean ± SEM. See Supplemental Table 1 for statistical details.