Stress-induced GHS-R1a Expression in Medial Prefrontal Cortical Neurons Promotes Vulnerability to Anxiety in Mice

Overview

Journal Commun Biol

Specialty Biology

Date 2025 Mar 14

PMID 40082560

Authors

Liu Yang

Meng Zhang

Xiaomin Sun

Anqi Du

Jiajia Jia

Nan Li

Gonghui Hu

Yingchang Lu

Sihan Wang

Jingsai Zhang

Wenjie Chen

Hanbing Yu

Yu Zhou

Affiliations

Soon will be listed here.

Abstract

The neural basis of anxiety is unclear, which hinders the treatment of anxiety disorders. Here, we found that αCaMKII neurons in the medial prefrontal cortex (mPFC) responded to stressors with increased activity both under physiological conditions and after repeated restraint stress (RRS) in mice. Chemogenetic activation of mPFC neurons ameliorated stress-induced anxiety. A delayed increase in the expression of growth hormone secretagogue receptor 1a (GHS-R1a), the receptor of the peripheral metabolic hormone ghrelin, in mPFC neurons coincided with reduced excitatory synaptic transmission and the development of RRS-induced enhancement of anxiety-related behavior. Virus-mediated GHS-R1a upregulation in mPFC neurons exaggerated the excitation/inhibition (E/I) imbalance and promoted anxiety-related behavior, whereas GHS-R1a knockdown had the opposite effect. We conclude that GHS-R1a signaling contributes to the development of stress-induced anxiety by shaping synaptic activity of mPFC neurons. GHS-R1a may be a new therapeutic target for treating anxiety disorders.

References

Shaw G, Hyer M, Targett I, Council K, Dyer S, Turkson S . Traumatic stress history interacts with sex and chronic peripheral inflammation to alter mitochondrial function of synaptosomes. Brain Behav Immun. 2020; 88:203-219. PMC: 9380700. DOI: 10.1016/j.bbi.2020.05.021. View

Tang M, Huang H, Li S, Zhou M, Liu Z, Huang R . Hippocampal proteomic changes of susceptibility and resilience to depression or anxiety in a rat model of chronic mild stress. Transl Psychiatry. 2019; 9(1):260. PMC: 6797788. DOI: 10.1038/s41398-019-0605-4. View

Lutter M, Sakata I, Osborne-Lawrence S, Rovinsky S, Anderson J, Jung S . The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress. Nat Neurosci. 2008; 11(7):752-3. PMC: 2765052. DOI: 10.1038/nn.2139. View

Huang H, Zhu X, Han Q, Wang Y, Yue N, Wang J . Ghrelin alleviates anxiety- and depression-like behaviors induced by chronic unpredictable mild stress in rodents. Behav Brain Res. 2017; 326:33-43. DOI: 10.1016/j.bbr.2017.02.040. View

Meyer R, Burgos-Robles A, Liu E, Correia S, Goosens K . A ghrelin-growth hormone axis drives stress-induced vulnerability to enhanced fear. Mol Psychiatry. 2013; 19(12):1284-94. PMC: 3988273. DOI: 10.1038/mp.2013.135. View

Yousufzai M, Harmatz E, Shah M, Malik M, Goosens K . Ghrelin is a persistent biomarker for chronic stress exposure in adolescent rats and humans. Transl Psychiatry. 2018; 8(1):74. PMC: 5895712. DOI: 10.1038/s41398-018-0135-5. View

Stone L, Harmatz E, Goosens K . Ghrelin as a Stress Hormone: Implications for Psychiatric Illness. Biol Psychiatry. 2020; 88(7):531-540. DOI: 10.1016/j.biopsych.2020.05.013. View

Yanagi S, Sato T, Kangawa K, Nakazato M . The Homeostatic Force of Ghrelin. Cell Metab. 2018; 27(4):786-804. DOI: 10.1016/j.cmet.2018.02.008. View

Spencer S, Emmerzaal T, Kozicz T, Andrews Z . Ghrelin's Role in the Hypothalamic-Pituitary-Adrenal Axis Stress Response: Implications for Mood Disorders. Biol Psychiatry. 2014; 78(1):19-27. DOI: 10.1016/j.biopsych.2014.10.021. View

10.

Mahbod P, Smith E, Fitzgerald M, Morano R, Packard B, Ghosal S . Desacyl Ghrelin Decreases Anxiety-like Behavior in Male Mice. Endocrinology. 2017; 159(1):388-399. PMC: 5761608. DOI: 10.1210/en.2017-00540. View

11.

Huang H, Chen X, Han Q, Wang J, Pilot A, Yu R . The protective effects of Ghrelin/GHSR on hippocampal neurogenesis in CUMS mice. Neuropharmacology. 2019; 155:31-43. DOI: 10.1016/j.neuropharm.2019.05.013. View

12.

Guo L, Niu M, Yang J, Li L, Liu S, Sun Y . GHS-R1a Deficiency Alleviates Depression-Related Behaviors After Chronic Social Defeat Stress. Front Neurosci. 2019; 13:364. PMC: 6478702. DOI: 10.3389/fnins.2019.00364. View

13.

Huang W, Zucca A, Levy J, Page D . Social Behavior Is Modulated by Valence-Encoding mPFC-Amygdala Sub-circuitry. Cell Rep. 2020; 32(2):107899. PMC: 7410267. DOI: 10.1016/j.celrep.2020.107899. View

14.

Sun X, Liu L, Song Y, Wu T, Zheng T, Hao J . Two parallel medial prefrontal cortex-amygdala pathways mediate memory deficits via glutamatergic projection in surgery mice. Cell Rep. 2023; 42(7):112719. DOI: 10.1016/j.celrep.2023.112719. View

15.

Capuzzo G, Floresco S . Prelimbic and Infralimbic Prefrontal Regulation of Active and Inhibitory Avoidance and Reward-Seeking. J Neurosci. 2020; 40(24):4773-4787. PMC: 7294792. DOI: 10.1523/JNEUROSCI.0414-20.2020. View

16.

Wang G, Cen C, Li C, Cao S, Wang N, Zhou Z . Deactivation of excitatory neurons in the prelimbic cortex via Cdk5 promotes pain sensation and anxiety. Nat Commun. 2015; 6:7660. PMC: 4518290. DOI: 10.1038/ncomms8660. View

17.

Hare B, Duman R . Prefrontal cortex circuits in depression and anxiety: contribution of discrete neuronal populations and target regions. Mol Psychiatry. 2020; 25(11):2742-2758. PMC: 7442605. DOI: 10.1038/s41380-020-0685-9. View

18.

Duman R, Sanacora G, Krystal J . Altered Connectivity in Depression: GABA and Glutamate Neurotransmitter Deficits and Reversal by Novel Treatments. Neuron. 2019; 102(1):75-90. PMC: 6450409. DOI: 10.1016/j.neuron.2019.03.013. View

19.

Duman R, Aghajanian G . Synaptic dysfunction in depression: potential therapeutic targets. Science. 2012; 338(6103):68-72. PMC: 4424898. DOI: 10.1126/science.1222939. View

20.

Tiwari P, Fanibunda S, Kapri D, Vasaya S, Pati S, Vaidya V . GPCR signaling: role in mediating the effects of early adversity in psychiatric disorders. FEBS J. 2021; 288(8):2602-2621. DOI: 10.1111/febs.15738. View