Mouse Model of Weak Depression Exhibiting Suppressed cAMP Signaling in the Amygdala, Lower Lipid Catabolism in Liver, and Correlated Gut Microbiota

Kousuke Shimada; Masakatsu Nohara; Akihito Yasuoka; Asuka Kamei; Fumika Shinozaki; Kaori Kondo; Ryo Inoue; Takashi Kondo; Keiko Abe

doi:10.3389/fnbeh.2022.841450

Mouse Model of Weak Depression Exhibiting Suppressed cAMP Signaling in the Amygdala, Lower Lipid Catabolism in Liver, and Correlated Gut Microbiota

Front Behav Neurosci. 2022 May 19:16:841450. doi: 10.3389/fnbeh.2022.841450. eCollection 2022.

Authors

Kousuke Shimada¹, Masakatsu Nohara¹, Akihito Yasuoka^{1

2}, Asuka Kamei¹, Fumika Shinozaki¹, Kaori Kondo^{1

3}, Ryo Inoue⁴, Takashi Kondo^{1

3}, Keiko Abe^{1

2}

Affiliations

¹ Group for Food Functionality Assessment, Kanagawa Institute of Industrial Science and Technology, Kawasaki, Japan.
² Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
³ Division of Disease Systems Biology, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁴ Laboratory of Animal Science, Kyoto Prefectural University, Kyoto, Japan.

Abstract

To establish a mouse model of weak depression, we raised 6-week-old C57BL/6N mice in single (SH) or group housing (GH) conditions for 2 weeks. The SH group showed less social interaction with stranger mice, learning disability in behavioral tests, and lower plasma corticosterone levels. The cecal microbiota of the SH group showed significant segregation from the GH group in the principal coordinate analysis (PCoA). Transcriptome analysis of the amygdala and liver detected multiple differentially expressed genes (DEGs). In the amygdala of SH mice, suppression of the cyclic adenine monophosphate (cAMP) signal was predicted and confirmed by the reduced immunoreactivity of phosphorylated cAMP-responsive element-binding protein. In the liver of SH mice, downregulation of beta-oxidation was predicted. Interestingly, the expression levels of over 100 DEGs showed a significant correlation with the occupancy of two bacterial genera, Lactobacillus (Lactobacillaceae) and Anaerostipes (Lachnospiraceae). These bacteria-correlated DEGs included JunB, the downstream component of cAMP signaling in the amygdala, and carnitine palmitoyltransferase 1A (Cpt1a), a key enzyme of beta-oxidation in the liver. This trans-omical analysis also suggested that nicotinamide adenine dinucleotide (NAD) synthesis in the liver may be linked to the occupancy of Lactobacillus through the regulation of nicotinamide phosphoribosyltransferase (NAMPT) and kynureninase (KYNU) genes. Our results suggested that SH condition along with the presence of correlated bacteria species causes weak depression phenotype in young mice and provides a suitable model to study food ingredient that is able to cure weak depression.

Keywords: amygdala; corticosterone; cyclic adenosine monophosphate (cAMP); depression; microbiota; nicotinamide adenine dinucleotide.