PPAR-α Hypermethylation in the Hippocampus of Mice Exposed to Social Isolation Stress Is Associated with Enhanced Neuroinflammation and Aggressive Behavior

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.

Understanding the Role of Oxidative Stress, Neuroinflammation and Abnormal Myelination in Excessive Aggression Associated with Depression: Recent Input from Mechanistic Studies

“…As mentioned above, neural circuits that modulate aggressive behaviour also include the hippocampus and hypothalamus [ 121 , 122 , 123 , 124 , 125 ]. Specifically, atypical hippocampal anatomical asymmetries that disrupt prefrontal–hippocampal circuitry may result in emotion dysregulation with increased aggressiveness because hippocampal neurons have robust projections that originate from hippocampal CA1 and terminate in the orbital and medial frontal cortices [ 126 ].…”

The Role of MeCP2 in Regulating Synaptic Plasticity in the Context of Stress and Depression

“…Moreover, it has recently been shown that Nrf2 activation in microglia is associated with an improvement in dendritic spine morphology in stressed mice [ 118 ]. Finally, a study looking at hippocampal sections of mice stressed by social isolation supported a role of MeCP2 in modulating oxidative stress [ 119 ], which has already been seen in RTT [ 120 , 121 ]. This can be explained by the actions of MeCP2 on genes essential in antioxidant and radical scavenger pathways.…”

The Beneficial Effects of Ultramicronized Palmitoylethanolamide in the Management of Neuropathic Pain and Associated Mood Disorders Induced by Paclitaxel in Mice

“…The activation of PPAR-α receptor initiates a cascade of events that causes the suppression of pain and inflammation, including decreases in pro-inflammatory cytokines such as IL-1β and IL-6, and TNF-α [ 57 ]. Moreover, low levels of PPAR-α are also responsible of several pathological conditions, neurodegenerative diseases, and stress-related disorders [ 66 ].…”

“…Moreover, here we found that the effects of um-PEA were significantly inhibited by the administration of either AM281 (CB1 antagonist) or GW6471 (PPAR-α antagonist). As already mentioned, the reduction in or the absence of CB1 and PPAR-α could lead to neuroinflammation [ 66 , 74 , 75 , 76 , 77 ].…”