TY - JOUR
T1 - Adolescent social isolation decreases colonic goblet cells and impairs spatial cognition through the reduction of cystine
AU - Tanabe, Moeka
AU - Kunisawa, Kazuo
AU - Saito, Imari
AU - Kosuge, Aika
AU - Tezuka, Hiroyuki
AU - Kawai, Tomoki
AU - Kon, Yuki
AU - Yoshidomi, Koyo
AU - Kagami, Akari
AU - Hasegawa, Masaya
AU - Kubota, Hisayoshi
AU - Ojika, Haruto
AU - Fujii, Tadashi
AU - Tochio, Takumi
AU - Hirooka, Yoshiki
AU - Saito, Kuniaki
AU - Nabeshima, Toshitaka
AU - Mouri, Akihiro
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024
Y1 - 2024
N2 - Negative experiences during adolescence, such as social isolation (SI), bullying, and abuse, increase the risk of psychiatric diseases in adulthood. However, the pathogenesis of psychiatric diseases induced by these factors remain poorly understood. In adolescents, stress affects the intestinal homeostasis in the gut-brain axis. This study determined whether adolescent SI induces behavioral abnormalities by disrupting colonic function. Adolescent mice exposed to SI exhibit spatial cognitive deficits and microglial activation in the hippocampus (HIP). SI decreased the differentiation of mucin-producing goblet cells, which was accompanied by alterations in the composition of the gut microbiota, particularly the depletion of mucin-feeding bacteria. Treatment with rebamipide, which promotes goblet cell differentiation in the colon, attenuated SI-induced spatial cognitive deficits and microglial activation in the HIP and decreased cystine, a downstream metabolite of homocysteine. Treatment with cystine ameliorated SI-induced spatial cognitive deficits and increased microglial C-C motif chemokine ligand 7 (CCL7) levels in the HIP. Inhibition of CCL7 receptors by antagonists of CC motif chemokine receptors 2 (CCR2) and 3 (CCR3) in the HIP prevented spatial cognitive deficits induced by SI. Infusion of CCL7 into the HIP following microglial ablation with clodronate liposome induced spatial cognitive deficits. These findings suggest that adolescent SI decreases serum cystine levels by damaging the colonic goblet cells, resulting in spatial cognitive deficits by triggering microglial activation in the HIP. Our results indicate that increased CCL7 expression in hippocampal microglia may contribute to spatial cognitive deficits by activating CCR2 and CCR3.
AB - Negative experiences during adolescence, such as social isolation (SI), bullying, and abuse, increase the risk of psychiatric diseases in adulthood. However, the pathogenesis of psychiatric diseases induced by these factors remain poorly understood. In adolescents, stress affects the intestinal homeostasis in the gut-brain axis. This study determined whether adolescent SI induces behavioral abnormalities by disrupting colonic function. Adolescent mice exposed to SI exhibit spatial cognitive deficits and microglial activation in the hippocampus (HIP). SI decreased the differentiation of mucin-producing goblet cells, which was accompanied by alterations in the composition of the gut microbiota, particularly the depletion of mucin-feeding bacteria. Treatment with rebamipide, which promotes goblet cell differentiation in the colon, attenuated SI-induced spatial cognitive deficits and microglial activation in the HIP and decreased cystine, a downstream metabolite of homocysteine. Treatment with cystine ameliorated SI-induced spatial cognitive deficits and increased microglial C-C motif chemokine ligand 7 (CCL7) levels in the HIP. Inhibition of CCL7 receptors by antagonists of CC motif chemokine receptors 2 (CCR2) and 3 (CCR3) in the HIP prevented spatial cognitive deficits induced by SI. Infusion of CCL7 into the HIP following microglial ablation with clodronate liposome induced spatial cognitive deficits. These findings suggest that adolescent SI decreases serum cystine levels by damaging the colonic goblet cells, resulting in spatial cognitive deficits by triggering microglial activation in the HIP. Our results indicate that increased CCL7 expression in hippocampal microglia may contribute to spatial cognitive deficits by activating CCR2 and CCR3.
UR - http://www.scopus.com/inward/record.url?scp=85210561463&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85210561463&partnerID=8YFLogxK
U2 - 10.1038/s41380-024-02826-9
DO - 10.1038/s41380-024-02826-9
M3 - Article
AN - SCOPUS:85210561463
SN - 1359-4184
JO - Molecular Psychiatry
JF - Molecular Psychiatry
ER -