TY - JOUR
T1 - High-fat diet induces depression-like phenotype via astrocyte-mediated hyperactivation of ventral hippocampal glutamatergic afferents to the nucleus accumbens
AU - Tsai, Sheng Feng
AU - Hsu, Pei Ling
AU - Chen, Yun Wen
AU - Hossain, Mohammad Shahadat
AU - Chen, Pei Chun
AU - Tzeng, Shun Fen
AU - Chen, Po See
AU - Kuo, Yu Min
N1 - Funding Information:
We are grateful for the support and services from 1) Laboratory Animal Center, College of Medicine, National Cheng Kung University, Taiwan, 2) Bioimaging Core Facility of the National Core Facility for Biopharmaceuticals, Ministry of Science and Technology, Taiwan, 3) National Laboratory Animal Center, NARLabs, Taiwan, 4) National RNAi Core Facility at Academia Sinica, Taiwan. This project was funded by Ministry of Science and Technology, Taiwan (Grant #: 106-2320-B-006-049, 107-2320-B-006-013, 108-2320-B-006-001, 109-2320-B-006-043-MY3, 110-2320-B-006-021, 107-2811-B-006-532, 108-2811-B-006-533, 109-2811-B-006-520, and 110-2811-B-006-546).
Funding Information:
We are grateful for the support and services from 1) Laboratory Animal Center, College of Medicine, National Cheng Kung University, Taiwan, 2) Bioimaging Core Facility of the National Core Facility for Biopharmaceuticals, Ministry of Science and Technology, Taiwan, 3) National Laboratory Animal Center, NARLabs, Taiwan, 4) National RNAi Core Facility at Academia Sinica, Taiwan. This project was funded by Ministry of Science and Technology, Taiwan (Grant #: 106-2320-B-006-049, 107-2320-B-006-013, 108-2320-B-006-001, 109-2320-B-006-043-MY3, 110-2320-B-006-021, 107-2811-B-006-532, 108-2811-B-006-533, 109-2811-B-006-520, and 110-2811-B-006-546).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/11
Y1 - 2022/11
N2 - Comorbidity exists between metabolic disorders and depressive syndrome with unclear mechanisms. To characterize the causal relationship, we adopted a 12-week high-fat diet (HFD) to induce metabolic disorder and depressive phenotypes in mice. Initially, we identified an enhanced glutamatergic input in the nucleus accumbens of HFD mice. Retrograde tracing and chemogenetic inhibition showed that the hyperactive ventral hippocampal glutamatergic afferents to the nucleus accumbens determined the exhibition of depression-like behavior in HFD mice. Using lentiviral knockdown and overexpression approaches, we proved that HFD-induced downregulation of glial glutamate transporters, GLAST and GLT-1, contributed to the observed circuit maladaptations and subsequent depression-like behaviors. Finally, we identified a potential therapeutic agent, riluzole, which could mitigate the HFD-induced behavioral deficits by normalizing the expressions of GLAST and GLT-1 and ventral hippocampal glutamatergic afferents to the nucleus accumbens. Overall, astrocyte-mediated disturbance in glutamatergic transmission underlies the metabolic disorder-related depressive syndrome and represents a therapeutic target for this subtype of depressive mood disorders.
AB - Comorbidity exists between metabolic disorders and depressive syndrome with unclear mechanisms. To characterize the causal relationship, we adopted a 12-week high-fat diet (HFD) to induce metabolic disorder and depressive phenotypes in mice. Initially, we identified an enhanced glutamatergic input in the nucleus accumbens of HFD mice. Retrograde tracing and chemogenetic inhibition showed that the hyperactive ventral hippocampal glutamatergic afferents to the nucleus accumbens determined the exhibition of depression-like behavior in HFD mice. Using lentiviral knockdown and overexpression approaches, we proved that HFD-induced downregulation of glial glutamate transporters, GLAST and GLT-1, contributed to the observed circuit maladaptations and subsequent depression-like behaviors. Finally, we identified a potential therapeutic agent, riluzole, which could mitigate the HFD-induced behavioral deficits by normalizing the expressions of GLAST and GLT-1 and ventral hippocampal glutamatergic afferents to the nucleus accumbens. Overall, astrocyte-mediated disturbance in glutamatergic transmission underlies the metabolic disorder-related depressive syndrome and represents a therapeutic target for this subtype of depressive mood disorders.
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U2 - 10.1038/s41380-022-01787-1
DO - 10.1038/s41380-022-01787-1
M3 - Article
C2 - 36180573
AN - SCOPUS:85139123834
SN - 1359-4184
VL - 27
SP - 4372
EP - 4384
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 11
ER -