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 generated neural reactive oxygen species that damage DNA, proteins, and lipids. Trauma models further altered mitochondrial structure 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.

Keywords: apoptosis; electron transport chain; hippocampus; mitochondrial dysfunction; oxidative stress; posttraumatic stress disorder; prefrontal cortex; rodent models.

FIGURE 1

The figure illustrates the five main protein complexes in the electron transfer chain (ETC) that located in the inner membrane of the mitochondria. These are labelled Complexes I, II, III, IV and V. The ETC is a series of protein complexes that transfer electrons from donor to acceptor proteins. These complexes transport electrons that are derived from food substrates and initially catabolized by the TCA cycle and β-oxidation pathways. At the enzymatic complexes I, III, and IV, protons are pumped out of the mitochondrial matrix into the intermembrane space, generating an electrochemical gradient used by Complex V (ATP synthase) to drive ATP synthesis. The mitochondrial membrane potential or MMP is produced by these proton pumps and represents a key component in energy storage for oxidative phosphorylation. The MMP works together with the mitochondrial proton gradient which are harnessed to produce ATP. Mitochondria consume most of the cell’s oxygen and are the major site generating reactive oxygen species (ROS) including superoxide, hydrogen peroxide and hydroxyl radicals and are neutralized by antioxidant enzymes. Chronic and severe stress produces maladaption of all of these ETC elements.