Single Prolonged Stress Induces Behavior and Transcriptomic Changes in the Medial Prefrontal Cortex to Increase Susceptibility to Anxiety-like Behavior in Rats

Overview

Journal Front Psychiatry

Specialty Psychiatry

Date 2024 Dec 4

PMID 39628496

Authors

Javed Iqbal

Geng-Di Huang

Dan Shen

Yan-Xue Xue

Mei Yang

Xiao-Jian Jia

Affiliations

Soon will be listed here.

Abstract

Introduction: Transcriptomic studies offer valuable insights into the pathophysiology of traumatic stress-induced neuropsychiatric disorders, including generalized anxiety disorder and post-traumatic stress disorder (PTSD). The medial prefrontal cortex (mPFC) has been implicated in emotion, cognitive function, and psychiatric disorders. Alterations in the function of mPFC have been observed in PTSD patients. However, the specific transcriptomic mechanisms governed by genes within the mPFC under traumatic stress remain elusive.

Methods: In this study, we conducted transcriptome-wide RNA-seq analysis in the prelimbic (PL) and infralimbic (IL) cortices. We employed the single prolonged stress (SPS) animal model to simulate anxiety-like behavior, which was assessed using the open field and elevated plus maze tests.

Results: We identified sixty-two differentially expressed genes (DEGs) (FDR adjusted < 0.05) with significant expression changes in the PL and IL mPFC. In the PL cortex, DEGs in the susceptible group exhibited reduced enrichment for cellular, biological, and molecular functions such as postsynaptic density proteins, glutamatergic synapses, synapse formation, transmembrane transport proteins, and actin cytoskeleton reorganization. In contrast, the IL-susceptible group displayed diminished enrichment for synapse formation, neuronal activity, dendrite development, axon regeneration, learning processes, and glucocorticoid receptor binding compared to control and insusceptible groups. DEGs in the PL-susceptible group were enriched for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways related to Parkinson's disease, Huntington's disease, Alzheimer's disease, and neurodegeneration processes. In the IL cortex, the susceptible group demonstrated enrichment for KEGG pathways involved in regulating stress signaling pathways and addiction-like behaviors, compared to control and insusceptible groups.

Conclusion: Our findings suggest that SPS activates distinct transcriptional and molecular pathways in PL and IL cortices of mPFC, enabling differential coping mechanisms in response to the effects of traumatic stress. The enhanced enrichment of identified KEGG pathways in the PL and IL mPFC may underlie the anxiety-like behavior observed in susceptible rats.

References

Tang W, Wang Y, Lu L, Lu Y, Xu J . Post-traumatic growth among 5195 adolescents at 8.5 years after exposure to the Wenchuan earthquake: Roles of post-traumatic stress disorder and self-esteem. J Health Psychol. 2020; 26(13):2450-2459. DOI: 10.1177/1359105320913947. View

Xue Y, Zhu Z, Han H, Liu J, Meng S, Chen C . Overexpression of Protein Kinase Mζ in the Prelimbic Cortex Enhances the Formation of Long-Term Fear Memory. Neuropsychopharmacology. 2015; 40(10):2487. PMC: 4538343. DOI: 10.1038/npp.2015.136. View

Iqbal J, Bibi M, Huang G, Xue Y, Khatttak J, Yang M . Differential regulation of hippocampal transcriptome by circulating estrogen. Funct Integr Genomics. 2023; 23(4):309. DOI: 10.1007/s10142-023-01234-6. View

Ouerchefani R, Ouerchefani N, Allain P, Rejeb M, Le Gall D . Relationships between executive function, working memory, and decision-making on the Iowa Gambling Task: Evidence from ventromedial patients, dorsolateral patients, and normal subjects. J Neuropsychol. 2018; 13(3):432-461. DOI: 10.1111/jnp.12156. View

Milad M, Pitman R, Ellis C, Gold A, Shin L, Lasko N . Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder. Biol Psychiatry. 2009; 66(12):1075-82. PMC: 2787650. DOI: 10.1016/j.biopsych.2009.06.026. View

Huckins L, Chatzinakos C, Breen M, Hartmann J, Klengel T, da Silva Almeida A . Analysis of Genetically Regulated Gene Expression Identifies a Prefrontal PTSD Gene, SNRNP35, Specific to Military Cohorts. Cell Rep. 2020; 31(9):107716. PMC: 7359754. DOI: 10.1016/j.celrep.2020.107716. View

Bygrave A, Jahans-Price T, Wolff A, Sprengel R, Kullmann D, Bannerman D . Hippocampal-prefrontal coherence mediates working memory and selective attention at distinct frequency bands and provides a causal link between schizophrenia and its risk gene GRIA1. Transl Psychiatry. 2019; 9(1):142. PMC: 6472369. DOI: 10.1038/s41398-019-0471-0. View

Henningsen K, Palmfeldt J, Christiansen S, Baiges I, Bak S, Jensen O . Candidate hippocampal biomarkers of susceptibility and resilience to stress in a rat model of depression. Mol Cell Proteomics. 2012; 11(7):M111.016428. PMC: 3394954. DOI: 10.1074/mcp.M111.016428. View

Nguyen Q, Nicoll R . The GABA Receptor β Subunit Is Required for Inhibitory Transmission. Neuron. 2018; 98(4):718-725.e3. PMC: 6089239. DOI: 10.1016/j.neuron.2018.03.046. View

10.

Fogaca M, Fukumoto K, Franklin T, Liu R, Duman C, Vitolo O . N-Methyl-D-aspartate receptor antagonist d-methadone produces rapid, mTORC1-dependent antidepressant effects. Neuropsychopharmacology. 2019; 44(13):2230-2238. PMC: 6898593. DOI: 10.1038/s41386-019-0501-x. View

11.

Helpman L, Marin M, Papini S, Zhu X, Sullivan G, Schneier F . Neural changes in extinction recall following prolonged exposure treatment for PTSD: A longitudinal fMRI study. Neuroimage Clin. 2016; 12:715-723. PMC: 5065048. DOI: 10.1016/j.nicl.2016.10.007. View

12.

Luine V, Gomez J, Beck K, Bowman R . Sex differences in chronic stress effects on cognition in rodents. Pharmacol Biochem Behav. 2016; 152:13-19. PMC: 5195878. DOI: 10.1016/j.pbb.2016.08.005. View

13.

Nahvi R, Tanelian A, Nwokafor C, Godino A, Parise E, Estill M . Transcriptome profiles associated with resilience and susceptibility to single prolonged stress in the locus coeruleus and nucleus accumbens in male sprague-dawley rats. Behav Brain Res. 2022; 439:114162. PMC: 9812303. DOI: 10.1016/j.bbr.2022.114162. View

14.

Robinson C, Dalal S, Chitneni A, Patil A, Berger A, Mahmood S . A Look at Commonly Utilized Serotonin Noradrenaline Reuptake Inhibitors (SNRIs) in Chronic Pain. Health Psychol Res. 2022; 10(3):32309. PMC: 9239373. DOI: 10.52965/001c.32309. View

15.

Giotakos O . Neurobiology of emotional trauma. Psychiatriki. 2020; 31(2):162-171. DOI: 10.22365/jpsych.2020.312.162. View

16.

Smith K, Kassem M, Clarke D, Kuligowski M, Bedoya-Perez M, Todd S . Microglial cell hyper-ramification and neuronal dendritic spine loss in the hippocampus and medial prefrontal cortex in a mouse model of PTSD. Brain Behav Immun. 2019; 80:889-899. DOI: 10.1016/j.bbi.2019.05.042. View

17.

Kim M, Roh J, Yoon B, Kang L, Kim Y, Aronin N . Huntingtin is degraded to small fragments by calpain after ischemic injury. Exp Neurol. 2003; 183(1):109-15. DOI: 10.1016/s0014-4886(03)00132-8. View

18.

Babenko V, Smagin D, Galyamina A, Kovalenko I, Kudryavtseva N . Altered Slc25 family gene expression as markers of mitochondrial dysfunction in brain regions under experimental mixed anxiety/depression-like disorder. BMC Neurosci. 2018; 19(1):79. PMC: 6288882. DOI: 10.1186/s12868-018-0480-6. View

19.

Shanley M, Miura Y, Guevara C, Onoichenco A, Kore R, Ustundag E . Estrous Cycle Mediates Midbrain Neuron Excitability Altering Social Behavior upon Stress. J Neurosci. 2022; 43(5):736-748. PMC: 9899085. DOI: 10.1523/JNEUROSCI.1504-22.2022. View

20.

Muhie S, Gautam A, Meyerhoff J, Chakraborty N, Hammamieh R, Jett M . Brain transcriptome profiles in mouse model simulating features of post-traumatic stress disorder. Mol Brain. 2015; 8:14. PMC: 4359441. DOI: 10.1186/s13041-015-0104-3. View