Association Between Stress-Induced Weight Loss and Autophagy-Related Gene Expression in the Hippocampus and Midbrain of Depression Model Mice

Overview

Journal Neuropsychopharmacol Rep

Specialties Neurology
Pharmacology

Date 2024 Dec 23

PMID 39715728

Authors

Hiroaki Mori

Yuta Yoshino

Mariko Okano

Yu Funahashi

Hiroshi Kumon

Shinichiro Ochi

Jun-Ichi Iga

Shu-ichi Ueno

Affiliations

Soon will be listed here.

Abstract

Aim: Recent studies have implicated autophagy in both weight regulation and depression. This study aimed to investigate the relationship between stress-induced weight loss and autophagy-related gene expression in a mouse model of depression.

Method: Male C57BL/6 mice were subjected to a chronic immobilization stress (CIS) protocol for 14 days to induce depressive-like behavior. Body weight was measured before and after the CIS, and depressive-like behavior was assessed using the tail suspension test (TST). The expression levels of autophagy-related genes (Atg5, Atg7, Atg12, Becn1, Mmp9, Fkbp5, and Map1lc3b) in the hippocampus and midbrain were evaluated using reverse transcription-quantitative PCR (RT-qPCR). Serum cortisol levels were also measured.

Results: The CIS resulted in significant weight loss and increased immobility time in the TST, indicating depressive-like behavior. Serum cortisol levels were not different between CIS-depression model and control mice. In the hippocampus, the expression levels of Fkbp5, Mmp9, and Map1lc3b were significantly higher in CIS-depression model mice than in control mice. In the midbrain, the expression levels of Fkbp5 and Mmp9 were significantly higher in CIS-depression model mice than in control mice. Increased autophagy-related gene expressions in CIS-depression model mice were consistent with the previous studies in the postmortem brains of patients with depression. A significant negative correlation was also found between Fkbp5 mRNA expression in the hippocampus and the weight change ratio before and after the CIS.

Conclusion: The findings suggest that enhanced autophagy may be related to the pathology of depression and that Fkbp5, an autophagy regulator, mediates stress-induced weight loss.

References

Lin L, Herselman M, Zhou X, Bobrovskaya L . Effects of corticosterone on BDNF expression and mood behaviours in mice. Physiol Behav. 2022; 247:113721. DOI: 10.1016/j.physbeh.2022.113721. View

Martinelli S, Anderzhanova E, Bajaj T, Wiechmann S, Dethloff F, Weckmann K . Stress-primed secretory autophagy promotes extracellular BDNF maturation by enhancing MMP9 secretion. Nat Commun. 2021; 12(1):4643. PMC: 8324795. DOI: 10.1038/s41467-021-24810-5. View

Levine A, Morley J . Stress-induced eating in rats. Am J Physiol. 1981; 241(1):R72-6. DOI: 10.1152/ajpregu.1981.241.1.R72. View

Malekpour M, Shekouh D, Safavinia M, Shiralipour S, Jalouli M, Mortezanejad S . Role of FKBP5 and its genetic mutations in stress-induced psychiatric disorders: an opportunity for drug discovery. Front Psychiatry. 2023; 14:1182345. PMC: 10313426. DOI: 10.3389/fpsyt.2023.1182345. View

Nectow A, Schneeberger M, Zhang H, Field B, Renier N, Azevedo E . Identification of a Brainstem Circuit Controlling Feeding. Cell. 2017; 170(3):429-442.e11. DOI: 10.1016/j.cell.2017.06.045. View

Fang X, Ge K, Song C, Ge Y, Zhang J . Effects of n-3PUFAs on autophagy and inflammation of hypothalamus and body weight in mice. Biochem Biophys Res Commun. 2018; 501(4):927-932. DOI: 10.1016/j.bbrc.2018.05.084. View

Cryan J, Mombereau C, Vassout A . The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice. Neurosci Biobehav Rev. 2005; 29(4-5):571-625. DOI: 10.1016/j.neubiorev.2005.03.009. View

Bagherniya M, Butler A, Barreto G, Sahebkar A . The effect of fasting or calorie restriction on autophagy induction: A review of the literature. Ageing Res Rev. 2018; 47:183-197. DOI: 10.1016/j.arr.2018.08.004. View

Matosin N, Arloth J, Czamara D, Edmond K, Maitra M, Frohlich A . Associations of psychiatric disease and ageing with FKBP5 expression converge on superficial layer neurons of the neocortex. Acta Neuropathol. 2023; 145(4):439-459. PMC: 10020280. DOI: 10.1007/s00401-023-02541-9. View

10.

Nakamura S, Yoshimori T . Autophagy and Longevity. Mol Cells. 2018; 41(1):65-72. PMC: 5792715. DOI: 10.14348/molcells.2018.2333. View

11.

Bijata M, Baczynska E, Muller F, Bijata K, Masternak J, Krzystyniak A . Activation of the 5-HT7 receptor and MMP-9 signaling module in the hippocampal CA1 region is necessary for the development of depressive-like behavior. Cell Rep. 2022; 38(11):110532. DOI: 10.1016/j.celrep.2022.110532. View

12.

Speed M, Jefsen O, Borglum A, Speed D, Ostergaard S . Investigating the association between body fat and depression via Mendelian randomization. Transl Psychiatry. 2019; 9(1):184. PMC: 6683191. DOI: 10.1038/s41398-019-0516-4. View

13.

Bobinska K, Szemraj J, Czarny P, Galecki P . Expression and Activity of Metalloproteinases in Depression. Med Sci Monit. 2016; 22:1334-41. PMC: 4844317. DOI: 10.12659/msm.895978. View

14.

Kaushik S, Arias E, Kwon H, Lopez N, Athonvarangkul D, Sahu S . Loss of autophagy in hypothalamic POMC neurons impairs lipolysis. EMBO Rep. 2012; 13(3):258-65. PMC: 3323137. DOI: 10.1038/embor.2011.260. View

15.

Nobis S, Goichon A, Achamrah N, Guerin C, Azhar S, Chan P . Alterations of proteome, mitochondrial dynamic and autophagy in the hypothalamus during activity-based anorexia. Sci Rep. 2018; 8(1):7233. PMC: 5940678. DOI: 10.1038/s41598-018-25548-9. View

16.

Alaiyed S, McCann M, Mahajan G, Rajkowska G, Stockmeier C, Kellar K . Venlafaxine Stimulates an MMP-9-Dependent Increase in Excitatory/Inhibitory Balance in a Stress Model of Depression. J Neurosci. 2020; 40(22):4418-4431. PMC: 7252486. DOI: 10.1523/JNEUROSCI.2387-19.2020. View

17.

Zschocke J, Zimmermann N, Berning B, Ganal V, Holsboer F, Rein T . Antidepressant drugs diversely affect autophagy pathways in astrocytes and neurons--dissociation from cholesterol homeostasis. Neuropsychopharmacology. 2011; 36(8):1754-68. PMC: 3138654. DOI: 10.1038/npp.2011.57. View

18.

Michelsen K, Prickaerts J, Steinbusch H . The dorsal raphe nucleus and serotonin: implications for neuroplasticity linked to major depression and Alzheimer's disease. Prog Brain Res. 2008; 172:233-64. DOI: 10.1016/S0079-6123(08)00912-6. View

19.

Gassen N, Rein T . Is There a Role of Autophagy in Depression and Antidepressant Action?. Front Psychiatry. 2019; 10:337. PMC: 6529564. DOI: 10.3389/fpsyt.2019.00337. View

20.

Shin H, Lee S, Moon H, So Y, Jang H, Lee K . Prolonged stress response induced by chronic stress and corticosterone exposure causes adult neurogenesis inhibition and astrocyte loss in mouse hippocampus. Brain Res Bull. 2024; 208:110903. DOI: 10.1016/j.brainresbull.2024.110903. View