Post-traumatic stress disorder (PTSD) is associated with cognitive deficits, oxidative stress, and inflammation. Animal models have recapitulated features of PTSD, but no comparative RNA sequencing analysis of differentially expressed genes (DEGs) in the brain between PTSD and animal models of traumatic stress has been carried out. We compared DEGs from the prefrontal cortex (PFC) of an established stress model to DEGs from the dorsolateral PFC (dlPFC) of humans. We observed a significant enrichment of rat DEGs in human PTSD and identified 20 overlapping DEGs, of which 17 (85%) are directionally concordant. N,N-dimethyltryptamine (DMT) is a known indirect antioxidant, anti-inflammatory, and neuroprotective compound with antidepressant and plasticity-facilitating effects. We tested the capacity of DMT, the monoamine oxidase inhibitor (MAOI) harmaline, and “pharmahuasca” (DMT + harmaline) to reduce reactive oxygen species (ROS) production and inflammatory gene expression and to modulate neuroplasticity-related gene expression in the model. We administered DMT (2 mg/kg IP), harmaline (1.5 mg/kg IP), pharmahuasca, or vehicle every other day for 5 days, following a 30 day stress regiment. We measured ROS production in the PFC and hippocampus (HC) by electron paramagnetic resonance spectroscopy and sequenced total mRNA in the PFC. We also performed in vitro assays to measure the affinity and efficacy of DMT and harmaline at 5HT_2AR compared to 5-HT. DMT and pharmahuasca reduced ROS production in the PFC and HC, while harmaline had mixed effects. Treatments normalized 9, 12, and 14 overlapping DEGs, and pathway analysis implicated that genes were involved in ROS production, inflammation, growth factor signaling, neurotransmission, and neuroplasticity.

Conventional methods of studying posttraumatic stress disorder (PTSD) have proven to be insufficient for diagnosis. We have reviewed clinical and preclinical imaging techniques as well as molecular, cellular, and behavioral indicators for PTSD.

Psychiatric, cardiometabolic, and immune disorders are highly comorbid, and are precipitated by psychological stress. To explain why these conditions co-occur and how stress triggers their pathogenesis, we introduce the Allostatic Triage Model of Psychopathology (ATP Model) that explains psychopathogenesis, and these bidirectional associations through a bioenergetic lens. Stress increases the energy demand on biological systems, which operate on a finite energy budget, increasing the risk of energy scarcity, especially in the brain, which faces high energy needs and limited access to energetic resources. Allostatic processes anticipate stress-induced increases in energy demand and regulate systemic and brain energy allocation from mind-to-mitochondria, a process that we call "allostatic triage". The brain allostatic-interoceptive system generates internal models of systemic and brain metabolism and energy output that are used to produce affective states, which regulate allostasis. In turn, we propose that affect regulates allostatic triage among functional brain networks. Chronic and traumatic stress dysregulates the mitochondrial and brain networks that regulate affect by reducing metabolic efficiency. We propose that stress-induced energy scarcity and affective dysregulation exacerbates allostatic triage to the networks most necessary for short-term survival, at the expense of non-vital processes contributing to long-term optimization and well-being, dysregulating allostasis and driving transdiagnostic disease pathogenesis. Persistent network activation patterns underlying psychiatric symptoms can then become entrenched as psychiatric disorders through activity-dependent neuroplasticity, also known as canalization. Altogether, we propose that stress dysregulates mitochondria, affect, and allostatic triage, impairing allostasis, and driving transdiagnostic pathological states, which are canalized over time into transdiagnostic disease.

Oxidative and lipid homeostasis are altered by stress and trauma and post-traumatic stress disorder (PTSD) is associated with alterations to lipid species in plasma. Stress-induced alterations to lipid oxidative and homeostasis may exacerbate PTSD pathology, but few preclinical investigations of stress-induced lipidomic changes in the brain exist. Currently available techniques for the quantification of lipid species in biological samples require tissue extraction and are limited in their ability to retrieve spatial information. Raman imaging can overcome this limitation through the quantification of lipid species in situ in minimally processed tissue slices. Here, we utilized a predator exposure and psychosocial stress (PE/PSS) model of traumatic stress to standardize Raman imaging of lipid species in the hippocampus using LC-MS based lipidomics and these data were confirmed with qRT-PCR measures of mRNA expression of relevant enzymes and transporters. Electron Paramagnetic Resonance Spectroscopy (EPR) was used to measure free radical production and an MDA assay to measure oxidized polyunsaturated fatty acids. We observed that PE/PSS is associated with increased cholesterol, altered lipid concentrations, increased free radical production and reduced oxidized polyunsaturated fats (PUFAs) in the hippocampus (HPC), indicating shifts in lipid and oxidative homeostasis in the HPC after traumatic stress.

Objective: Exposure to trauma increases the risk of somatic symptoms, as well as acute and chronic physical diseases. However, many individuals display psychological resilience, showing positive psychological adaptation despite trauma exposure. Resilience to prior trauma may be a protective factor for physical health during subsequent stressors, including the COVID-19 pandemic. Methods: Using data from 528 US adults in a longitudinal cohort study, we examined psychological resilience to lifetime potentially traumatic events early in the pandemic and the risk of COVID-19 infection and somatic symptoms across 2 years of follow-up. Resilience was defined as level of psychological functioning relative to lifetime trauma burden, assessed in August 2020. Outcomes included COVID-19 infection and symptom severity, long COVID, and somatic symptoms assessed every 6 months for 24 months. Using regression models, we examined associations between resilience and each outcome adjusting for covariates. Results: Higher psychological resilience to trauma was associated with a lower likelihood of COVID-19 infection over time, with one standard deviation higher resilience score associated with a 31% lower likelihood of COVID-19 infection, adjusting for sociodemographics and vaccination status. Furthermore, higher resilience was associated with lower levels of somatic symptoms during the pandemic, adjusting for COVID-19 infection and long COVID status. In contrast, resilience was not associated with COVID-19 disease severity or long COVID. Conclusions: Psychological resilience to prior trauma is associated with lower risk of COVID-19 infection and lower somatic symptoms during the pandemic. Promoting psychological resilience to trauma may benefit not only mental but also physical health.

Stress is associated with contextual memory deficits, which may mediate avoidance of trauma‐associated contexts in posttraumatic stress disorder. These deficits may emerge from impaired pattern separation, the independent representation of similar experiences by the dentate gyrus‐Cornu Ammonis 3 (DG‐CA3) circuit of the dorsal hippocampus, which allows for appropriate behavioral responses to specific environmental stimuli. Neurogenesis in the DG is controlled by mitochondrial reactive oxygen species (ROS) production, and may contribute to pattern separation. In Experiment 1, we performed RNA sequencing of the dorsal hippocampus 16 days after stress in rats that either develop conditioned place avoidance to a predator urine‐associated context (Avoiders), or do not (Non‐Avoiders). Weighted genome correlational network analysis showed that increased expression of oxidative phosphorylation‐associated gene transcripts and decreased expression of gene transcripts for axon guidance and insulin signaling were associated with avoidance behavior. Based on these data, in Experiment 2, we hypothesized that Avoiders would exhibit elevated hippocampal (HPC) ROS production and degraded object pattern separation (OPS) compared with Nonavoiders. Stress impaired pattern separation performance in Non‐Avoider and Avoider rats compared with nonstressed Controls, but surprisingly, Avoiders exhibited partly preserved pattern separation performance and significantly lower ROS production compared with Non‐Avoiders. Lower ROS production was associated with better OPS performance in Stressed rats, but ROS production was not associated with OPS performance in Controls. These results suggest a strong negative association between HPC ROS production and pattern separation after stress, and that stress effects on these outcome variables may be associated with avoidance of a stress‐paired context.