6569 An Increase, Rather Than Absolute Amount, Of Corticotropin-Releasing Hormone (Crh) Drives Mouse Anxiety-Like Behavior

Abstract Disclosure: H.R. Friedman: None. L. Gaston: None. L. Chan: None. J.A. Majzoub: None. Approximately 300 million people have an anxiety disorder. We previously found that anxiety-like behavior (AB) is decreased in mice which lack hypothalamic (HT) Crh (1), so we hypothesized that increased HT Crh, due to primary adrenal insufficiency (PAI), would induce increased AB. To evaluate this, we compared AB in wildtype (WT) mice to those with global deletion of either the Crh gene (CrhKO) or the Mrap gene (MrapKO, causing PAI (2)), measuring: 1) HT Crh mRNA by in situ RNAscope, 2) stress-induced (after 15 min of restraint) plasma corticosterone (CORT) and adrenocorticotropin hormone (ACTH) by ELISA, and 3) AB with elevated plus maze (EPM), and open field (OF) automatically-recorded behaviors. Comparisons were evaluated by ANOVA with post hoc Bonferroni corrections vs. WT. As expected, Crh mRNA was highest in MrapKO (n=16) compared to WT (n=11), and undetectable in CrhKO (n=10), and post-restraint CORT was highest in WT (11±2 mcg/dL), and undetectable in CrhKO and MrapKO. CrhKO mice displayed decreased AB (increased EPM open arm duration) vs. WT animals (140±11 vs. 68±8 s, respectively, P<0.0001). However, AB was comparable between MrapKO (97±10 s) vs. WT (68±8 s; P=0.0807) despite higher HT Crh mRNA in the former. To determine if chronically high vs. a dynamic rise in Crh mRNA is associated with increased AB, we treated MrapKO mice with dexamethasone (DEX) for 5-8 weeks to suppress HT Crh mRNA and assayed hypothalamic-pituitary-adrenal axis function and behavior both on DEX (MrapKO-D; N=4) and 1-week post-withdrawal (MrapKO-DW; N=5). As expected, ACTH was highest in the MrapKO-DW vs. WT (1689±535 vs. 378±35 pg/mL, respectively; P<0.0001) and undetectable in MrapKO-D. Notably, MrapKO-DW mice displayed increased AB (decreased OF center duration) vs. WT animals (56±3 s vs. 114±10 s; P=0.0439). In summary, AB was not present in MrapKO mice with chronically elevated HT Crh mRNA but only developed after they were DEX-treated followed by withdrawal from treatment. These data suggest that in mice, a dynamic rise in HT Crh, but not a chronically elevated level, drives AB, and suggest that Crh is a possible target for anxiety treatment. References: (1) Zhang R et al., Mol Psychiatry. 2017 May;22(5):733-744. (2) Novoselova TV et al., FASEB J. 2018 Jun 7;32(11):fj201701274RR Presentation: 6/2/2024