Mitochondrial dysfunction in animal models of PTSD: Relationships between behavioral models, neural regions, and cellular maladaptation

Abstract

Post-traumatic stress disorder (PTSD) is a trauma-related condition that produces distressing fear memory intrusions, avoidance behaviors, hyperarousal, stress responses, insomnia and other symptoms. This review of rodent models of PTSD examines trauma effects on fear-related learning, cognition, and avoidance, emotional and arousal behaviors and on mitochondrial dysfunction in relevant neural pathways. The review focuses on research that includes four elements: consensus PTSD rodent models, behavioral phenotyping, mitochondrial dysfunction within key neural regions. This approach allows for the integration of behavioral, neural and cellular findings in PTSD models. The PTSD models reviewed include fear conditioning, predator/social stress, chronic restraint stress, single prolonged stress, social isolation, chronic unpredictable stress and early life stress. These models produce a variety of PTSD-related behaviors that include associative and non-associative fear- and stress-related responses, hyperarousal, avoidance behaviors, cognitive disturbances, social withdrawal, compulsive behaviors, anhedonia-, anxiety- and depression-related behaviors. Neural regions included fear- and stress-related regions of the prefrontal cortex, hippocampal, amygdala, nucleus accumbens and hypothalamus. PTSD models produced mitochondrial dysfunction that includes dysregulation of oxidative phosphorylation and other metabolic pathways including β-oxidation of fatty acids and the tricarboxylic acid pathway. These models generative neural reactive oxygen species that damage DNA, proteins, and lipids. Trauma models further altered mitochondrial stucture and replication and affected neuroinflammatory responses, signal transduction and apoptosis. Antidepressant medications used for the treatment of PTSD reversed stress-induced changes in some PTSD-like behaviors and many elements of brain mitochondrial dysfunction. Future studies can develop PTSD models which are ecologically valid and result in a broader manifestation of PTSD-related behaviors as it is clinically defined. This review highlights mitochondrial mechanisms associated with PTSD-like behaviors that have been produced in an array of consensus PTSD models and identifies putative circuit-based targets for more effective treatment for this debilitating disorder.

Neurological Mechanisms and Therapeutic Strategies for Post-Traumatic Stress Disorder (PTSD)

“…The analysis of mitochondrial markers makes it possible to explore brain circuits and study the role of the hippocampus in contextualizing fear experiences. Investigations focused on different brain regions and their connections in functional circuits can include measures such as assessment of ATP production, oxidative metabolism, mtDNA, synaptic plasticity, inflammatory responses of the nervous system and biomarkers of apoptosis (KAPLAN B. et al, 2023).…”

Unveiling the Link: Exploring Mitochondrial Dysfunction as a Probable Mechanism of Hepatic Damage in Post-Traumatic Stress Syndrome

“…Here, for the first time, we have demonstrated mitochondrial dysfunction in the liver of experimental PTSD rats. Until now, mitochondrial dysfunction has been demonstrated only in the brain [ 24 ]. Analysis of the current results allows us to suggest probable mechanisms of the observed damage of liver and hepatic mitochondrial damage and to discuss the consequences of the subsequent hepatic mitochondrial dysfunction.…”

“…After acclimation, the rats were randomly divided into two groups: a control group (n = 10) and an experimental group (n = 20) that was exposed to cat urine scent for 15 min daily for 10 days. To allow the experimental PTSD to develop, the rats were then rested for 14 days under stress-free conditions [ 24 ]. During this time, one rat lost mass and was eliminated from the study.…”

“…Considering the unique role of mitochondria in supporting cell viability, it is quite logical to investigate the role of mitochondrial dysfunction in the pathogenesis of stress-related illnesses, including PTSD. Notably, animal models of PTSD have shown mitochondrial dysfunction, e.g., dysregulation of oxidative phosphorylation and other metabolic pathways, including β-oxidation of fatty acids and the tricarboxylic acid pathway [ 24 ]. These PTSD models generated neural reactive oxygen species that damage DNA, proteins, and lipids [ 25 ].…”

Potential oxidative stress related targets of mitochondria-focused therapy of PTSD

“…3 Role of mitochondria in preventing/ treatment of oxidative stress in PTSD Available data indicate that mitochondrial dysfunction, or suboptimal functioning, inherited or acquired, contribute to the manifestation of PTSD symptoms and can increase susceptibility to PTSD (for review, see, e.g., Preston et al, 2018;Mellon et al, 2018;Kaplan et al, 2023;Sumner et al, 2023). Reduction of oxidative stress appears to be a reasonable therapeutic approach in the treatment or prevention of PTSD.…”