ArticleInternational journal of molecular sciences2021
PPAR-α Hypermethylation in the Hippocampus of Mice Exposed to Social Isolation Stress Is Associated with Enhanced Neuroinflammation and Aggressive Behavior.
Article in International journal of molecular sciences, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 39 citations in OpenAlex.
- Alterations in GABAergic Interneurons, Neuroinflammation, and Epigenetics: Potential Targets for Therapeutic Strategies in Schizophrenia.Current neuropharmacology · 2026Article
- Low-dose combination of ultramicronized palmitoylethanolamide and docosahexaenoic acid on neurosteroid and neuroinflammatory dysregulation in autism spectrum disorders.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- Review: Suicide and its relationship to aggression and impulsivity.Cognitive, affective & behavioral neuroscience · 2025Review
- Metabolic Modulators in Depression: Emerging Molecular Mechanisms and Therapeutic Opportunities.International journal of molecular sciences · 2025Review
- The Ferroptosis-Mitochondrial Axis in Depression: Unraveling the Feedforward Loop of Oxidative Stress, Metabolic Homeostasis Dysregulation, and Neuroinflammation.Antioxidants (Basel, Switzerland) · 2025Review
- Neuroactive steroids and the pathophysiology of PTSD: Biomarkers for treatment targeting.Neuroscience and biobehavioral reviews · 2025Review
- Genetic, Epigenetic, and Hormonal Regulation of Stress Phenotypes in Major Depressive Disorder: From Maladaptation to Resilience.Cellular and molecular neurobiology · 2025Review
- Ciprofol Alleviates Depressive-Like Behaviors in CUMS Mice Through PPARα-Associated ERK/CREB Signaling Activation.Drug design, development and therapy · 2025Article
- The Role of Insulin Within the Socio-Psycho-Biological Framework in Type 2 Diabetes-A Perspective from Psychoneuroimmunology.Biomedicines · 2024Review
- The Effects ofAnimals : an open access journal from MDPI · 2024Article
- Nurture outpaces nature: fostering with an attentive mother alters social dominance in a mouse model of stress sensitivity.Molecular psychiatry · 2023Article
- The influence of genetic and acquired factors on the vulnerability to develop depression: a review.Bioscience reports · 2023Review
- Review
- Sex-specific immune mechanisms in PTSD symptomatology and risk: A translational overview and perspectives.Brain research bulletin · 2023Review
- Understanding the Role of Oxidative Stress, Neuroinflammation and Abnormal Myelination in Excessive Aggression Associated with Depression: Recent Input from Mechanistic Studies.International journal of molecular sciences · 2023Review
- Functional Nutrition as Integrated Intervention for In- and Outpatient with Schizophrenia.Current neuropharmacology · 2023Article
- Resistance Training Modulates Hippocampal Neuroinflammation and Protects Anxiety-Depression-like Dyad Induced by an Emotional Single Prolonged Stress Model.Molecular neurobiology · 2023Article
- Long-term social isolation stress exacerbates sex-specific neurodegeneration markers in a natural model of Alzheimer's disease.Frontiers in aging neuroscience · 2023Article
- Neurogenetics and Epigenetics of Loneliness.Psychology research and behavior management · 2023Review
- Effects of Cannabidiol in Adolescent and Young Adult Depressive and Anxiety Disorders: A Systematic Review of Clinical and Preclinical Research.Adolescent psychiatry (Hilversum, Netherlands) · 2023Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Social behavioral changes, including social isolation or loneliness, increase the risk for stress-related disorders, such as major depressive disorder, posttraumatic stress disorder (PTSD), and suicide, which share a strong neuroinflammatory etiopathogenetic component. The peroxisome-proliferator activated receptor (PPAR)-α, a newly discovered target involved in emotional behavior regulation, is a ligand-activated nuclear receptor and a transcription factor that, following stimulation by endogenous or synthetic ligands, may induce neuroprotective effects by modulating neuroinflammation, and improve anxiety and depression-like behaviors by enhancing neurosteroid biosynthesis. How stress affects epigenetic mechanisms with downstream effects on inflammation and emotional behavior remains poorly understood. We studied the effects of 4-week social isolation, using a mouse model of PTSD/suicide-like behavior, on hippocampal PPAR-α epigenetic modification. Decreased PPAR-α expression in the hippocampus of socially isolated mice was associated with increased levels of methylated cytosines of PPAR-α gene CpG-rich fragments and deficient neurosteroid biosynthesis. This effect was associated with increased histone deacetylases (HDAC)1, methyl-cytosine binding protein (MeCP)2 and decreased ten-eleven translocator (TET)2 expression, which favor hypermethylation. These alterations were associated with increased TLR-4 and pro-inflammatory markers (e.g., TNF-α,), mediated by NF-κB signaling in the hippocampus of aggressive mice. This study contributes the first evidence of stress-induced brain PPAR-α epigenetic regulation. Social isolation stress may constitute a risk factor for inflammatory-based psychiatric disorders associated with neurosteroid deficits, and targeting epigenetic marks linked to PPAR-α downregulation may offer a valid therapeutic approach.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.