It is becoming increasingly recognized that post-traumatic stress disorder (PTSD) can be acquired vicariously from witnessing traumatic events. Recently, we published an animal model called the “Trauma witness model” (TWM) which mimics PTSD-like symptoms in rats from witnessing daily traumatic events (social defeat of cage mate) [15]. Our TWM does not result in any physical injury. This is a major procedural advantage over the typical intruder paradigm in which it is difficult to delineate the inflammatory response of tissue injury and the response elicited from emotional distress. Using TWM paradigm, we examined behavioral and cognitive effects in rats [15] however, the long-term persistence of PTSD-like symptoms or a time-course of these events (anxiety and depression-like behaviors and cognitive deficits) and the contribution of olfactory and auditory stress vs visual reinforcement were not examined. This study demonstrates that some of the features of PTSD-like symptoms in rats are reversible after a significant time lapse of the witnessing of traumatic events. We also have established that witnessing is critical to the PTSD-like phenotype and cannot be acquired solely due to auditory or olfactory stresses.

These results support the hypothesis of continuity between preverbal precursors and vocabulary development in a population with atypical development.

Background:Persistent psychological stress often leads to anxiety disorders and depression. Benzodiazepines and selective serotonin reuptake inhibitors are popular treatment options but have limited efficacy, supporting the need for alternative treatment. Based on our recent preclinical work suggesting a causal link between neurobehavioral deficits and elevated oxidative stress, we hypothesized that interventions that mitigate oxidative stress can attenuate/overcome neurobehavioral deficits.Methods:Here, we employed the rat social defeat model of psychological stress to determine whether increasing antioxidant levels using grape powder would prevent and/or reverse social defeat-induced behavioral and cognitive deficits. Furthermore, a hippocampal-derived HT22 cell culture model of oxidative stress was employed to identify the individual beneficial constituent(s) of grape powder and the underlying mechanism(s) of action.Results:Grape powder treatment prevented and reversed social defeat-induced behavioral and cognitive deficits and also decreased social defeat-induced increase in plasma corticosterone and 8-isoprostane (systemic and oxidative stress markers, respectively). And grape powder treatment replenished social defeat-induced depleted pool of key antioxidant enzymes glyoxalase-1, glutathione reducatse-1, and superoxide dismutase. Grape powder constituents, quercetin and resveratrol, were most effective in preventing oxidative stress-induced decreased cellular antioxidant capacity. Grape powder protected oxidative stress-induced cell death by preventing calcium influx, mitochondrial dysfunction, and release of cytochrome c.Conclusions:Grape powder treatment by increasing antioxidant pool and preventing cell damage and death prevented and reversed social defeat-induced behavioral and cognitive deficits in rats. Quercetin and resveratrol are the major contributors towards beneficial effects of grape powder.

Background Children subjected to traumatic events during childhood are reported to exhibit behavioral and cognitive deficits later in life, often leading to post-traumatic stress disorder (PTSD) and major depression. Interestingly, some children continue to remain normal despite being exposed to the same risk factors. These trauma-related behavioral and cognitive profiles across different stages of life are not well understood. Animal studies can offer useful insights. Objective The goal of this study was to determine the impact of early life exposure to traumatic events on behavioral and cognitive profile in rats by tracking the behavior of each rat at different ages. Methods We utilized the single prolonged stress (SPS), a rodent model of PTSD, to study the effects of early life stress. Male Sprague-Dawley rats were exposed to SPS on post-natal day (PND) 25. Tests to assess anxiety- and depression-like behavior, as well as learning and memory function were performed at PND32, 60 and 90. Results Rats exposed to SPS exhibited both anxiety- and depression-like behavior at PND32. And, short-term (STM) but not long-term memory (LTM) was impaired. Rats exposed to SPS at PND60 exhibited anxiety- but not depression-like behavior. STM but not LTM was impaired. Rats exposed to SPS at PND90 exhibited fearful (as indicated by elevated plus maze test) but not an overall anxiety-like behavior (in light and dark test). These rats also displayed significant depression-like behavior with no changes in STM or LTM. Interestingly, when data was further analyzed, two subsets of PND90 rats exposed to SPS were identified, “suscep tible”: with depression-like behavior and “resilient”: without depression-like behavior. Importantly, while resilient group expressed early signs of anxiety- (at PND32 and PND60) and depression-like behavior (at PND32), these behavioral deficits were absent at PND90. On the other hand, susceptible PND90 rats exposed to SPS expressed later onset of anxiety-like behavior (at PND60), while depression-like phenotype was evident only later on at PND90. Conclusions Our findings suggest that early life stress caused co-occurrence of anxiety and depression-like behavior at PND32 (mimics human early-adolescent period). This co-occurrence was lost at PND60 with demonstration of anxiety- but not depression-like behavior. Later, depression but not anxiety-like behavior was observed at PND90. It seems that behavioral adaptations occur at the critical PND60 stage (mimics human late-adolescent period), where behavioral and cognitive switching occurs, thereby, expressing susceptible and resilient phenotypes.

Air pollution resulting from exhaust emissions of vehicles has risen in the recent years, reportedly causing major adverse effects on the heart, lungs and the brain. Though respiratory and cardiovascular effects of these emissions are well identified, psychological and neurobiological complications of prolonged exposure to vehicle emissions remain unknown. Pro-oxidants are considered as major constituents of vehicle emissions. This is important considering causal link between oxidative stress and behavioral and cognitive impairments. We hypothesized that prolonged exposure to pro-oxidants in vehicle emissions result in behavioral and cognitive deficits. We developed a simulated vehicle exhaust exposure model in rats. The model used a simulated mixture of vehicle exhaust that comprised of pro-oxidant constituents of exhaust, namely, carbon dioxide (13%), carbon monoxide (0.68%) and nitrogen dioxide (1000 ppm) in air. Rats were exposed either to a high (1:10 dilution) or low (~1:1000 dilution) physiologically relevant dose of simulated mixture in air for two weeks in separate experiments followed by a comprehensive behavioral and cognitive analysis. We observed that prolonged exposure to pro-oxidants in vehicle exhaust increased anxiety-and depression-like behavior as well as led to impaired memory in rats. This is important preclinical evidence, particularly relevant to human population exposed to high vehicular traffic.

We have published that pharmacological induction of oxidative stress (OS) causes anxiety-like behavior in rats. Using animal models, we also have established that psychological stress induces OS and leads to anxiety-like behaviors. All evidence points towards the causal role of OS in anxiety-like behaviors. To fully ascertain the role of OS in anxiety-like behaviors, it is reasonable to test whether the pro-anxiety effects of anxiogenic drugs caffeine or N-methyl-beta-carboline-3-carboxamide (FG-7142) can be mitigated using agents that minimize OS. In this study, osmotic pumps were either filled with antioxidant tempol or saline. The pumps were attached to the catheter leading to the brain cannula and inserted into the subcutaneous pocket in the back pocket of the rat. Continuous i.c.v. infusion of saline or tempol in the lateral ventricle of the brain (4.3mmol/day) was maintained for 1 week. Rats were intraperitoneally injected either with saline or an anxiogenic drug one at a time. Two hours later all groups were subjected to behavioral assessments. Anxiety-like behavior tests (open-field, light-dark and elevated plus maze) suggested that tempol prevented anxiogenic drug-induced anxiety-like behavior in rats. Furthermore, anxiogenic drug-induced increase in stress examined via plasma corticosterone and increased oxidative stress levels assessed via plasma 8-isoprostane were prevented with tempol treatment. Protein carbonylation assay also suggested preventive effect of tempol in the prefrontal cortex brain region of rats. Antioxidant protein expression and pro-inflammatory cytokine levels indicate compromised antioxidant defense as well as an imbalance of inflammatory response.

Purpose: In this study, we investigated the effect of a slow-releasing hydrogen sulfide (H 2 S) donor, GYY 4137, on intraocular pressure (IOP) in normotensive rabbits. Furthermore, we compared the IOP-lowering action of GYY 4137 with those elicited by other H 2 S-producing compounds, l-cysteine and ACS67 (a hybrid compound of latanoprost with an H 2 S-releasing moiety). Methods: IOP was measured in New Zealand normotensive male albino rabbits using a pneumatonometer (model 30 classic; Reichert Ophthalmic Instruments, Depew, NY). At 0 h, 50 mL of test compounds were applied topically to 1 eye of each animal, while the contralateral eye received the same quantity of vehicle (saline). IOP was measured hourly until baseline IOP readings were attained and animal eyes monitored for potential side effects (i.e., tearing, hyperemia). Results: GYY 4137 (0.1%-2%) produced a dose-dependent decrease in IOP reaching a maximum of 27.8% -3.14% (n = 5) after 6 h. Interestingly, a significant contralateral effect was observed in vehicle-treated controls eyes at all doses tested. l-cysteine (5%) and ACS67 (0.005%) also elicited a significant (P < 0.01) decrease in IOP that achieved a maximum of 28.84% -1.53% (n = 5) and 23.27% -0.51% (n = 5), respectively, after 3 h. All 3 H 2 S-producing compounds also caused a significant contralateral effect in vehicle-treated control eyes. Conclusion: We conclude that GYY 4137 and other H 2 S-producing donors can reduce IOP in normotensive rabbits. However, the profile of IOP-lowering action of GYY 4137 was different from the other H 2 S donors affirming its ability to act as a slow-releasing gas donor.

Traffic-related air pollution (TRAP) is a major contributor to global air pollution. The World Health Organization (WHO) has reported that air pollution due to gasoline and diesel emissions from internal combustion engines of automobiles, trucks, locomotives, and ships leads to 800,000 premature deaths annually due to pulmonary, cardiovascular, and neurological complications. It has been observed that individuals living and working in areas of heavy vehicle traffic have high susceptibility to anxiety, depression, and cognitive deficits. Information regarding the mechanisms that potentially lead to detrimental mental health effects of TRAP is gradually increasing. Several studies have suggested that TRAP is associated with adverse effects in the central nervous system (CNS), primarily due to increase in oxidative stress and neuroinflammation. Animal studies have provided further useful insights on the deleterious effects of vehicle exhaust emissions (VEEs). The mechanistic basis for these effects is unclear, although gasoline and diesel exhaust-induced neurotoxicity seems the most plausible cause. Several important points emerge from these studies. First, TRAP leads to neurotoxicity. Second, TRAP alters neurobehavioral function. Exactly how that happens remains unclear. This review article will discuss current state of the literature on this subject and potential leads that have surfaced from the preclinical work.