Abstract
Stress plays a crucial role in several psychiatric disorders, including anxiety. However, the underlying mechanisms remain poorly understood. Here, we used acute stress (AS) and chronic restraint stress (CRS) models to develop anxiety-like behavior and investigate the role of miR-150 in the hippocampi of mice. Corticosterone levels as well as glutamate receptors in the hippocampus were evaluated. We found that anxiety-like behavior was induced after either AS or CRS, as determined by the open-field test (OFT) and elevated plus-maze test (EPM). Increased corticosterone levels were observed in the blood of AS and CRS groups, while the expression of miR-150 mRNA in the hippocampus was significantly decreased. The expressions of GluN2A, GluR1, GluR2, and V-Glut2 in the hippocampus were decreased after either AS or CRS. Hippocampal GAD67 expression was increased by AS but not CRS, and GluN2B expression was decreased by CRS but not AS. Adult miR-150 knockout mice showed anxiety-like behavior, as assessed by the OFT and EPM. The expressions of GluN2A, GluN2B, GluR1, and GluR2 were also downregulated, but the expression of V-Glut2 was upregulated in the hippocampi of miR-150 knockout mice compared with wild-type mice. Interestingly, we found that the miR-150 knockout mice showed decreased dendrite lengths, dendrite branchings, and numbers of dendrite spines in the hippocampus compared with wild-type mice. These results suggest that miR-150 may influence the synaptic plasticity of the hippocampus and play a significant role in stress-induced anxiety-like behavior in adult mice.
Similar content being viewed by others
References
Abdallah CG, Coplan JD, Jackowski A, Sato J, Mao X, Shungu D, Mathew SJ (2013) A pilot study of hippocampal volume and N-acetylaspartate(NAA) as response biomarkers in riluzole-treated patients with GAD. Eur Neuropsychopharmacol 23:276–284
Agirre X, Jiménez-Velasco A, San José-Enériz E, Garate L, Bandrés E, Cordeu L, Aparicio O, Saez B, Navarro G et al (2008) Down-regulation of hsa-miR-10a in chronic myeloid leukemia CD34 + cells increases USF2-mediated cell growth. Mol Cancer Res 6:1830–1180
Alsharafi WA, Xiao B, Li J (2016) MicroRNA-139-5p negatively regulates GluN2A-containingNMDA receptor in the ratpilocarpine model andpatientswith temporal lobeepilepsy. Full-Length Orig Res 57:1931–1940
Ambros V (2001) MicroRNAs: tiny regulators with great potential. Cell 107:823–826
Ayfer D, Ferihan C, Ali RS, Ilkay A, Aysegul T, Sevil G, Nazan U (2015) The effects of oxytocin on cognitive defect caused by chronic restraint stress applied to adolescent rats and on hippocampal VEGF and BDNF levels. Med Sci Monit 21:69–75
Bannerman DM, Deacon RM, Brady S, Bruce A, Sprengel R, Seeburq PH, Rawlins JN (2004a) A comparison of GluR-A-deficient and wild-type mice on a test battery assessing sensorimotor, affective, and cognitive behaviors. Behav Neurosci 118(3):643–647
Bannerman DM, Rawlins JNP, McHugh SB, Deacon RMJ, Yee BK, Bast T, Zhang WN, Pothuizen HHJ, Feldon J (2004b) Regional dissociations within the hippocampus—memory and anxiety. Neurosci Biobehav Rev 28:273–283
Barber BA, Kohl KL, Nancy KA, Jeffrey I. Gold (2014) Acute stress, depression, and anxiety symptoms among English and Spanish speaking children with recent trauma exposure. HHS Public Access, 21:66–71
Carlos RBS, Mercedes PR, Concepcion VL, Enrique BG (2012) New perspectives in glutamate and anxiety. Pharmacol Biochem Behav 100:752–774
Choi GH, Ko KH, Kim JO, Kim JW, Oh SH, Han IB, Cho KG, Kim OJ, Bae J, KimNK (2016) Association of miR-34a, miR-130a, miR-150 and miR-155 polymorphisms with the risk of ischemic stroke. Int J Mol Med, 1:345–356
Concepción I, Navarro-Francés M, Arenas C (2014) Influence of trait anxiety on the effects of acute stress on learning and retention of the passive avoidance task in male and female mice. Behav Process 105:6–14
Daudelin-Peltier C, Forget H, Blais C, Deschênes A, Fiset D (2017) The effect of acute social stress on the recognition of facial expression of emotions. Sci Rep 7:1–12
Dhingra MS, Dhingra S, Kumria R, Chadha R, Singh T, Kumar A, Karan M (2014) Effect of trimethylgallic acid esters against chronic stress-induced anxiety-like behavior and oxidative stress in mice. Pharmacol Rep 66:606–612
Eisch AJ, Petrik D (2012) Depression and hippocampal neurogenesis: a road to remission? SCIENCE 5:72–75
Fan JM, Ding L, Dm X, Dy C, Jiang P, Ge W, Zhao R, Guo J, Xf F, Xue F, Wang Y, Mao S, Hu L, Gong Y (2017) Amelioration of apelin-13 in chronic normobaric hypoxia-inducedanxiety-likebehavior is associated with an inhibition of NF-κB in thehippocampus. Brain Res Bull 130:67–74
Fonken LK, Gaudet AD, Gaier KR, Nelson RJ, Popovich PG (2016) MicroRNA-155 deletion reduces anxiety- and depressive-likebehaviorsin mice. Psychoneuroendocrinology 63:362–369
Griebel G, Holmes A (2013) 50 years of hurdles and hope in anxiolytic drug discovery. Nat Rev Drug Discov 12:667–687
Harraz MM, Eacker SM, Wang X, Dawson TM, Dawson VL (2012) MicroRNA-223 is neuroprotective by targetingglutamate receptors. PNAS 109:18962–18967
Hashimoto K, Malchow B, Falkai P, Schmitt A (2013) Glutamate modulators as potential therapeutic drugs in schizophrenia and affective disorders. Eur Arch Psychiatry Clin Neurosci 263:367–377
Hettema JM, Kettenmann B, Ahluwalia V, Christopher MC, Kates WR, Schmitt JE, Silberg JL, Neale MC, Kendler KS, Fatouros P (2012) A pilot multimodal twin imaging study of generalized anxiety disorder. Depress Anxiety 29:202–209
Hill MN, Hellemans KGC, Verma P, Gorzalka BB, Weinberg J (2012) Neurobiology of chronic mild stress: parallels to major depression. Neurosci Biobehav Rev 36:2085–2117
Ignacio NO, Miguel AP, Gonzalo T, Pablo M, Alexies DS (2014) Effects of chronic stress in adolescence on learned fear, anxiety, and synaptic transmission in the rat prelimbic cortex. Behav Brain Res 259:342–353
Inta D, Vogt MA, Pfeiffer N, Köhr G, Gass P (2013) Dichotomy in the anxiolytic versus antidepressant effect ofC-terminal truncation of the GluN2A subunit of NMDA receptors. Behav Brain Res 247:227–231
Jiao GL, Pan B, Zhou ZG, Zhou L, Liz Z, Zhang ZY (2015) MicroRNA-21 regulates cell proliferation and apoptosis in H 2 O 2-stimulated rat spinal cord neurons. Mol Med Rep 5:7011–7016
Jin J, Kim SN, Xq L, Hj Z, Zhang C, Seo JS, Kim Y, Sun T (2016) miR-17-92 cluster regulates adult hippocampal neurogenesis, anxiety and depression. Cell Rep 16:1653–1663
Kessels HW, Malinow R (2009) Synaptic AMPA receptor plasticity and behavior. Neuron 61:340–350
Kheirbek MA, Hen R (2011) Dorsal vs ventral hippocampal neurogenesis: implications for cognition and mood. Neuropsychopharmacology 36:373–374
Kosik KS (2006) The neuronal microRNA system. Nature Publish Group NEUROSCIENCE 7:911–920
Ku TH, Lee YJ, Wang SJ, Fan CH, Tian LT (2011) Effect of honokiol on activity of GAD65 and GAD67 in the cortex and hippocampus of mice. Phytomedicine 18:1126–1129
Li F, Mb L, Cao Wy XY, Luo Y, Xl Z, Zhang JY, Rp D, Zhou X-F, Zy L, Cq L (2012) Anterior cingulate cortical lesion attenuates food foraging in rats. Brain Res Bull 88:602–608
Li CQ, Luo YW, Bi FF, Cui TT, Song L, Cao WY, Zhang JY, Li F, Xu JM, Hao W et al (2014) Development of anxiety-like behavior via hippocampalIGF-2 signaling in the offspring of parental morphine exposure: effect of enriched environment. Neuropsychopharmacology 12:2777–2787
Li BJ, Liu P, Chu Z, Shang Y, Huan MX, Dang YH, Gao CG (2017) Social isolation induces schizophrenia-like behavior potentially associated with HINT1, NMDA receptor 1,and dopamine receptor 2. Neuropharmacology 8:1–7
Lima-ojeda JM, Voqt MA, Pfeiffer N, Dormann C, Köhr G, Sprengel R, Gass P, Inta D (2013) Pharmacological blockade of GluN2B-containing NMDA receptors induces antidepressant-like effects lacking psychotomimetic action and neurotoxicity in the perinatal and adult rodent brain. Prog Neuro-Psychopharmacol Biol Psychiatry 45:28–33
Luo YW, Xu Y, Cao WY, Zhong XL, Duan J, Wang XQ, Hu ZL, Li F, Zhang JY, Zhou M, Dai RP, Li CQ (2015) Insulin-like growth factor 2 mitigates depressive behavior in a rat model of chronic stress. Neuropharmacology 89:318–324
Lussier AL, Romay NR, Caruncho HJ, Kalynchuk LE (2013) Altered GABAergic and glutamatergic activity within the rat hippocampus and amygdala in rats subjected to repeated corticosterone administration but not restraint stress. Neuroscience 231:38–48
Martin V, Allaïli N, Euvrard M, Marday T, Riffaud A, Franc B, Elisabeth M, Gabriel C, Fossati P, Lehericy S, Lanfumey L (2017) Effect of agomelatine on memorydeficits and hippocampal geneexpression induced by chronicsocial defeat stress in mice. Sci Rep 7:1–11
Marty V, Labialle S, Marie LBC, Medeiros GFD, Moisan MP, Florian C, Cavaillé J (2016) Deletion of the miR-379/miR-410 gene cluster at the imprinted Dlk1-Dio3 locus enhancesanxiety-related behavior. Hum Mol Genet 25:728–739
McNaughton N, Gray JA (2000) Anxiolytic action on the behavioural inhibition system impliesmultiple types of arousal contribute to anxiety. J Affect Disord 61:161–176
Meza-Sosa KF, Valle-Garcı D, Pedraza-Alva G, Pérez-Martınez L (2012) Role of microRNAs in central nervous system development and pathology. J Neurosci Res 90:1–12
Miller OH, Yang LL, Wang CC, Hargroder EA, Zhang YH, Delpire E, Hall BJ (2014) GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine. Elife 3:e03581
Möhler H (2012) The GABA system in anxiety and depression and its therapeutic potential. Neuropharmacology 62:42–53
Mueller SC, Aouidad A, Gorodetsky E, David G, Pine DS, Ernst M (2013) Grey matter volume in adolescent anxiety: an impact of the brain-derived neurotropic factor Val 66 met polymorphism? J Am Acad Child Adolesc Psychiatry 52:184–195
Musazzi L, Treccani G, Mallei A, Popoli M (2012) The action of antidepressants on the glutamate system: regulation of glutamate release and glutamate receptors. Biol Psychiatry 73:1180–1188
Ouhaz Z, Ba-M’hamed S, Bennis M (2017) Morphological, structural, and functional alterations of the prefrontal cortex and the basolateral amygdala after early lesion of the rat mediodorsal thalamus. Brain Struct Funct 222:2527–2545
Pascuan CG, Rubinstein MR, Palumbo ML, Genaro AM (2014) Prenatal stress induces up-regulation of glucocorticoid receptors on lymphoid cells modifying the T-cell response after acute stress exposure in the adult life. Physiol Behav 128:141–147
Pristerà A, Saraulli D, Stefano FV, Strimpakos G, Costanzi M, Certo MG, Cannas S, Ciotti MT, Tirone F, Mattei E et al (2013) Impact of N-tau on adult hippocampal neurogenesis, anxiety, and memory. Neurobiol Aging 11:2551–2562
Qin ZH, Zhou X, Pandey NR, Vecchiarelli HA, Stewart CA, Zhang X, Lagace DC, Brunel JM, Beique JC, Stewart AFR, Hill MN, Chen HH (2015) Chronic stress induces anxiety via an amygdalar intracellular cascade that impairs endocannabinoid signaling. Neuron 85:1319–1331
Rallis S, Skouteris H, McCabe M, Milgrom J (2014) A prospective examination of depression, anxiety and stress throughout pregnancy. Women Birth 27:36–42
Sanacora G, Zarate CA, Krystal J, Manji HK (2008) Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov 7:426–437
Sempere LF, Freemantle S, Rowe IP, Moss E, Dmitrovsky E, Ambros V (2004) Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation. Genome Biol 5:1–10
Shen X, Ys L, Xu S, Qs Z, Wu H, Guo X, Shen R, Wang F (2014) Menin regulates spinal glutamate-GABA balance through GAD65contributing to neuropathic pain. Pharmacol Rep 66:49–55
Shepard R, Coutellier L (2017) Changes in the prefrontal glutamatergic and parvalbumin systems of mice exposed to unpredictable chronic stress. Mol Neurobiol
Siegel (2012) Pharmacology biochemistry and behavior, vol 100, pp 653–655
Simons L, Elman I, Borsook D (2014) Psychological processing in chronic pain: a neural systems approach. Neurosci Biobehav Rev 39:61–78
Soztutar E, Colak E, Ulupinar E (2016) Gender- and anxiety level-dependent effects of perinatal stress exposure on medial prefrontal cortex. Exp Neurol 275:274–284
Sun H, Jia N, Guan Lx SQ, Wang D, Li H, Zhu Z (2013) Involvement of NR1, GluN2A different expression in brain regions in anxiety-like behavior of prenatally stressed offspring. Behav Brain Res 275:1–7
Tsang SWY, Vinters HV, Cummings JL, Wong PTH, Chen C, Lai MKP (2008) Alterations in NMDA receptor subunit densities and ligand binding to glycine recognition sites are associated with chronic anxiety in Alzheimer’s disease. Neurobiol Aging 29(10):1524–1532
Umemori J, Takao K, Koshimizu H, Hattori S, Furuse T, Wakana S, Miyakawa T (2013) ENU-mutagenesis mice with a non-synonymous mutation in Grin1 exhibit abnormal anxiety-like behaviors, impaired fear memory, and decreased acoustic startle response. BMC Res Notes 6:1–23
Wang KC, Lee YJ, Fan LW, Yang PP, Tao PL, Ho IK, Tien LT (2013) Mu-opioid receptor knockout mice are more sensitive to chlordiazepoxide-induced anxiolytic behavior. Brain Res Bull 90:137–141
Wang XQ, Zhong XL, Li RB, Wang HT, Zhang J, Li F, Zhang JY, Dai RP, Zhou XF et al (2015a) Differential roles of hippocampal glutamatergic receptors in neuropathic anxiety-like behavior after partial sciatic nerve ligation in rats. BMC Neurosci 16:14
Wang Y, Ma Y, Hu J, Chen GW, Jiang H, Zhang X, Li M, Ren J, Li X (2015b) Prenatal chronic mild stress induces depression-like behavior and sex-specific changes glutamate receptor expression patterns in adult rats. Neuroscience 2015(301):363–374
Wang T, Guan RL, Liu MC, Shen XF, Chen JY, Zhao MG, Luo WJ (2016) Lead exposure impairs hippocampus related learning and memory by altering synaptic plasticity and morphology during juvenile period. Mol Neurobiol 53:3740–3752
Wang HT, Huang FL, Hu ZL, Zhang WJ, Qiao XQ, Huang YQ, Dai RP, Li F, Li CQ (2017) Early-life social isolation-induced depressive-like behavior in rats results in microglial activation and neuronal histone methylation that are mitigated by minocycline. Neurotox Res 31(4):505–520
Watanabe A, Tagawa H, Yamashita J, Teshima K, Nara M, Iwamoto K, Kume M, Kameoka Y, Takahashi N, Nakagawa T, Shimizu N, Sawada K (2011) The role of microRNA-150 as a tumor suppressor in malignant lymphoma. Leukemia 25:1324–1334
Wittmann A, Schlagenhauf F, John T, Guhn A, Rehbein H, Siegmund A, Stoy M, Held D, Schulz I, Fehm L et al (2001) A new paradigm (Westphal-Paradigm) to study the neural correlates of panic disorder with agoraphobia. Eur Arch Psychiatry Clin Neurosci 3:185–194
Wohleb ES, McKim DB, Shea DT, Powell ND, Tarr AJ, Sheridan JF, Godbout JP (2014) Re-establishment of anxiety in stress-sensitized mice is caused by monocyte trafficking from the spleen to the brain. A RCHIVAL R EPORT 75:970–981
Yaka R, Salomon S, Matzner H, Weinstock M (2007) Effect of varied gestational stress on acquisition of spatial memory, hippocampal LTP and synaptic proteins in juvenile male rats. Behav Brain Res 179:126–132
Yamasue H, Abe O, Suga M, Yamada H, Inoue H, Tochigi M, Rogers M, Aoki S, Kato N, Kasai K (2007) Gender common and specific neuroanatomical basis of human anxiety-related personality traits. Cereb Cortex 18:46–52
Zhang YJ, Dq L, Chen X, Li J, Li Lm BZ, Sun F, Lu J, Yin Y, Cai X (2010) Secreted monocytic miR-150 enhances targeted endothelial cell migration. Mol Cell 39:133–144
Zhang J, Luo N, Luo Y, Peng ZP, Zhang T, Li SL (2012) microRNA-150 inhibits human CD133-positive liver cancer stem cells through negative regulation of the transcription factor c-Myb. Int J Oncol 40:747–756
Zhang YL, Xing RZ, Luo XB, Xu H, Chang RC, Zou LY, Liu JJ, Yang XF (2016) Anxiety-like behavior and dysregulation of miR-34a in triple transgenic mice of Alzheimer’s disease. Eur Rev Med Pharmacol Sci 20:2853–2862
Zhao HB, Jiang YM, Li XJ, Liu YY, Bai XH, Li N, Chen JX, Liu Q, Yan ZY, Zhao FZ (2017) Xiao Yao San improves the anxiety-like behaviors of rats induced by chronic immobilization stress: the involvement of the JNK signaling pathway in the hippocampus. Biol Pharm Bull 40:187–194
Zimprich A, Mroz G, Reckendorf CM, Sofia A, Philip F, Lillian G, Sabine M, Lore B, Jan R, Prehn C et al (2017) Serum response factor (SRF) ablation interferes with acute stress-associated immediate and long-term coping mechanisms. Mol Neurobiol 54:8242–8262
Zuckerman C, Blumkin E, Melamed O, Golan HM (2015) Glutamatergic synapse protein composition of wild-type mice is sensitive to in utero MTHFR genotype and the timing of neonatal vigabatrin exposure. Eur Neuropsychopharmacol 10:1787–1802
Acknowledgments
We wish to thank Xin-Fu Zhou from the University of South Australia for his critical reading of the manuscript.
Funding
This study was supported by the National Natural Science Foundation of China (Grant No. 81471372 to Fang Li, Grant No. 31371212 to Chang-Qi Li), the Natural Science Foundation of Hunan Province, China (Grant No. 2018JJ3635 to Fang Li), and the Science and Technology Projects of Hunan Province (Grant No. 2014wk 3025 to Rong Hu).
Author information
Authors and Affiliations
Contributions
WZ performed behavioral testing and Western blot RT-PCR experiments and wrote the manuscript. WC was involved in data collection and data analysis. YH, YC, BT, LW, GZ, YL, and ZH participated in data collection and data analysis. RH and CL provided experimental suggestions and assisted in writing the manuscript. The corresponding authors XX and FL supervised, designed the project, interpreted the work, revised the manuscript, and provided funds. All authors contributed to the study and have approved the final manuscript.
Corresponding authors
Ethics declarations
Conflict of Interest
The authors declare that they have no competing interests.
Consent for Publication
Not applicable.
Ethics Approval and Consent to Participate
All animal procedures performed in this study were reviewed and approved by the Animal Care and Use Committee of Central South University and were conducted in accordance with the guidelines of the International Association for the Study of Depression.
Rights and permissions
About this article
Cite this article
Zhang, WJ., Cao, WY., Huang, YQ. et al. The Role of miR-150 in Stress-Induced Anxiety-Like Behavior in Mice. Neurotox Res 35, 160–172 (2019). https://doi.org/10.1007/s12640-018-9943-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-018-9943-x