Chronic exposure to vehicle exhaust emissions are known to cause several adverse health effects. In this study, we examined the impact of several parameters of behavioral, cardiovascular and biochemical functions upon exposure of pro-oxidants CO2, NO2 and CO (simulated vehicle exhaust exposure: SVEE) in male and female rats. Adult rats were subjected to SVEE or ambient air in whole body chambers (5 h/day, 2 weeks). Male, but not female, rats developed memory deficits, and exhibited anxiety- and depression-like behavior, accompanied with significantly high levels of serum corticosterone, oxidative stress, and inflammatory markers (CRP and TNF alpha), associated with lower levels of total antioxidant capacity, glutathione, glyoxalase and superoxide dismutase (SOD) activities. Brain region-specific downregulation of Cu/Zn SOD, Mn SOD, GSR, PKC alpha, ERK1/2, CaMKIV, CREB, BDNF and NMDAR subunit protein expression were also observed in male, but not female, rats. Blood pressure, heart rate and eGFR were not negatively impacted by SVEE. Our results suggest that SVEE, through its pro-oxidant content, induces oxido-inflammation in susceptible brain regions in a sex-dependent manner.

Purpose: Vehicle exhaust emissions primarily comprise of nitrogen, oxygen, water, CO2, NO2, CO, hydrocarbons and particulate matter. While adverse effects of hydrocarbon and particulate matter on cardiovascular functions are known, the effect of pro-oxidants CO2, NO2 and CO are not clear. Methods: Here, using an animal model of a simulated mixture of pro-oxidants (0.04% CO2, 0.9 ppm NO2 and 3 ppm CO with air as a base), we examined the effect of simulated vehicle exhaust exposure (SVEE) on various cardiovascular parameters. Male Sprague-Dawley rats were exposed to SVEE or ambient air (Control: CON) for 30 min/day for 2 weeks. Thereafter, systolic and diastolic blood pressure, heart rate and glomerular filtration rate were measured. Later, rats were sacrificed, blood plasma and kidneys were collected. Results: The systolic and diastolic blood pressure, heart rate and glomerular filtration rate remained unchanged. Plasma corticosterone increased in SVEE rats when compared to CON group. Plasma 8-isoprostane, a systemic marker of oxidative stress, increased while total antioxidant capacity decreased in SVEE but not in CON. Kidney cortical tissue homogenates exhibited increase in superoxide, hydrogen peroxide and protein carbonylation in SVEE but not CON, all indicative of heightened oxidative stress. Renal cortical mitochondrial SOD activity was significantly reduced in SVEE than CON. Conclusion: Significant decline in mitochondrial respiration and oxygen consumption was observed, in addition to low ATP, reduced ATP synthase and cytochrome C oxidase levels, as well as accelerated mitochondrial fission, and reduced fusion processes, were observed in SVEE than CON rats, all indicative of renal mitochondrial impairment.

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.

BACKGROUND:Vehicle exhaust emissions are known to be significant contributors to physical and psychological stress. Vehicle exhaust-induced stress and associated respiratory and cardiovascular complications are well-known, but the impact of this stress on the brain is unclear. Simulated vehicle exhaust exposure (SVEE) in rats causes behavioral and cognitive deficits. In the present study, the underlying mechanisms were examined. Our postulation is that SVEE, a simulation of physiologically relevant concentrations of pro-oxidants (0.04% carbon dioxide, 0.9 ppm nitrogen dioxide, 3 ppm carbon monoxide) creates a toxic stress environment in the brain that results in an imbalance between production of reactive oxygen species and the counteracting antioxidant mechanisms. This impairs mitochondrial function in the high bioenergetic demand areas of the brain including the hippocampus (HIP), amygdala (AMY) and the prefrontal cortex (PFC), disrupting neuronal network, and causing behavioral deficits. Mitochondria-targeted antioxidant Mito-Q protects against these impairments. METHODS:Sprague Dawley rats were provided with Mito-Q (250 μM) in drinking water for 4 weeks followed by SVEE 5 h/day for 2 weeks, followed by behavioral and biochemical assessments. RESULTS:SVEE resulted in anxiety- and depression-like behavior, accompanied with increased oxidative stress, diminished antioxidant response and mitochondrial impairment reflected from electron transport chain (ETC) disruption, reduced oxygen consumption, low adenosine tri-phosphate (ATP) synthesis and an alteration in the mitochondrial biochemical dynamics assessed via protein expression profiles of mitochondrial fission marker, dynamin-related protein-1 and fusion markers, mitofusin-1/2 in the HIP, AMY and the PFC. Mito-Q treatment prevented SVEE-induced behavioral deficits, attenuated rise in oxidative stress and also prevented SVEE-induced mitochondrial impairment. CONCLUSION:This study demonstrates a causal mechanism mediating SVEE-induced behavioral deficits in rats. We further established that SVEE is a toxicological stressor that induces oxidative stress and results in mitochondrial impairment, which by disrupting neural circuitry impairs cognitive and behavioral functions.

BACKGROUND:Earlier, we have reported that post-traumatic stress disorder (PTSD)-like behaviors developed in rats that witnessed their cage mates undergo repeated traumatic stress. More recently, we published that early life physical traumatic stress leads to later life depression-like behaviors in rats. Whether early life trauma witness causes later life PTSD-like behaviors is not known. Also unclear are sex-specific stress-induced behavioral variations in later life. The early life witness component of stress is an important aspect of stress-induced psychopathologies and must be investigated.OBJECTIVE:Here, we have examined the impact of early life repeated witnessing of traumatic events by pups from post-natal day (PND) 21-PND27, on later life behaviors at PND60, and the behavioral impact of postpartum traumatic stress in female rats.METHODS:We used a modified version of rodent social defeat model to induce postpartum stress in female rats and trauma witness stress in pups. One female Sprague-Dawley rat (intruder) was introduced into the cage of an aggressive Long-Evans male rat (resident). The encounter between the two resulted in attacks between the female rat and the Long-Evans male rat. Three exposures of social defeat (attacks) were given for 7 consecutive days. The social defeat traumatic events were witnessed by 6 pups (offspring of the intruder female rat, PND21-27), placed in six separate enclosures surrounding the cage. The objective of this experiment was three-fold: 1) to test later life behavioral effects in pups from witnessing maternal defeat, 2) to examine gender susceptibility of pups in maternal defeat witness-induced behaviors, 3) to test behavioral effect in female rats 24h after receiving the last social defeat exposure.RESULTS:We observed that while anxiety-like behavior assessed in open-field and elevated plus-maze tests, was not affected in male or female rats upon witnessing repeated maternal traumatic stress, depression-like behavior in forced-swim test was observed at PND60 in both male and female rats, with greater effect in male rats. No change was observed in learning and memory functions using radial arm water maze test in both male and female rats. Interestingly, socially defeated female rats (dams: mother of the pups) developed both anxiety and depression-like behavior with no change in learning-memory function when compared to control female rats.CONCLUSIONS:Our findings suggest that early life maternal stress witness history leads to depression-like behavior in both male and female adult rats, and dams developed both anxiety and depression-like behaviors.

We investigated the pharmacological actions of a slow-releasing H2S donor, GYY 4137; a substrate for the biosynthesis of H2S, l-cysteine and its precursor, N-acetylcysteine on potassium (K+; 50 mM)-evoked [3H]D-aspartate release from bovine isolated retinae using the Superfusion Method. GYY 4137 (10 nM–10 µM), l-cysteine (100 nM–10 µM) and N-acetylcysteine (10 µM–1 mM) elicited a concentration-dependent decrease in K+-evoked [3H]D-aspartate release from isolated bovine retinae without affecting basal tritium efflux. At equimolar concentration of 10 µM, the rank order of activity was as follows: l-cysteine > GYY 4137 > N-acetylcysteine. A dual inhibitor of the biosynthetic enzymes for H2S, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), amino-oxyacetic acid (AOA; 3 mM) reversed the inhibitory responses caused by GYY 4137, l-cysteine and N-acetylcysteine on K+-evoked [3H]D-aspartate release. Glibenclamide (300 µM), an inhibitor of KATP channels blocked the inhibitory action of GYY 4137 and l-cysteine but not that elicited by N-acetylcysteine on K+-induced [3H]D-aspartate release. The inhibitory effect of GYY 4137 and l-cysteine on K+-evoked [3H]D-aspartate release was reversed by the non-specific inhibitor of nitric oxide synthase (NOS), l-NAME (300 µM). Furthermore, a specific inhibitor of inducible NOS (iNOS), aminoguanidine (10 µM) blocked the inhibitory action of l-cysteine on K+-evoked [3H]D-aspartate release. We conclude that both donors and substrates for H2S production can inhibit amino acid neurotransmission in bovine isolated retinae, an effect that is dependent, at least in part, upon the intramural biosynthesis of this gas, and on the activity of KATP channels and NO synthase.

Traumatic experiences are reported to cause Post Traumatic Stress Disorder (PTSD). Benzodiazepines and Selective Serotonin Re‐Uptake Inhibitors are considered as standard treatments. Although clinically useful, chronic use causes drastic side effects. Thus, there remains a necessity for improving treatment and finding preventive pharmacological interventions. While promising evidence emerged with administration of b‐adrenergic receptor antagonist Propranolol and PTSD relief, methodological limitations of the studies and efficacy issues dampened the excitement. We believe it is premature to completely eliminate the role of b‐antagonists in PTSD. Using the social defeat paradigm, we examined the effect of two b‐adrenergic receptor antagonists Propranolol and Nadolol on PTSD‐like behavior in Sprague Dawley rats. Propranolol was administered in drinking water at ~18 mg/rat/day for 36 days. Nadalol was provided in rat chow (50 g/rat/day). Social defeat (SD) was performed for 7 consecutive days. In SD, the Sprague Dawley rat was introduced into the home cage of a larger, aggressive male Long Evans (LE) rat. The LE rat perceived the Sprague Dawley rat as an intruder, leading to an attack on the rat. The Sprague Dawley rat was forced into a supine postion repeatedly, inducing depression‐like behavior. We used four rat groups; SD group, SD+ Propranolol, SD+ Nadalol, and naïve control. We performed depression‐like behavior tests 24 hours after SD or control exposures, including forced swim test (FST) and social interaction (SIT). In FST, the rat was placed into a cylindrical water‐filled container for five minutes. The total time spent immobile was recorded. Higher immobility time in the water indicates depression‐like behavior. SD rats had significantly more immobility time as compared to control rats in FST. SD rats treated with Propranolol or Nadolol did not exhibit high immobility in FST. SIT measures animal sociability. The Sprage Dawley rats were placed into an apparatus containing two chambers; an empty chamber and a chamber housing a novel rat. SD rats exhibited higher depression‐like behavior (less interaction time with the novel rat as compared to an empty cup) compared to controls. SD rats pretreated with Propranolol or Nadolol did not exhibit low social interaction when compared to SD rats alone. These results suggest that depression‐like behavior induced by SD was prevented when rats were pre‐treated with Propranolol and Nadolol.Support or Funding InformationGrant Support: 2R15MH093918‐02

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, "susceptible": 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.

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.

Air pollution from vehicle exhaust is a serious environmental threat, known to contribute to cardiovascular, respiratory and neurological complications. While the effect of vehicle exhaust exposure on heart and lungs is well known, adverse effects of these emissions on the brain and its psychological impact has been ignored. Here, we examined exhaust‐induced psychological and neurobiological alterations in rats using a simulated vehicle exhaust exposure (SVEE) model. Prolonged exposures to the gaseous constituents of vehicle exhaust, carbon dioxide (CO 2 ), carbon monoxide (CO) and nitrogen dioxide (NO 2 ) are known to increase oxidative stress. And, our previous studies have established a causal link between oxidative stress and behavioral as well as cognitive deficits. Therefore, we hypothesized that prolonged exposures to pro‐oxidants from vehicle exhaust elevate oxidative stress leading to behavioral and cognitive deficits. And, interventions that limit/prevent oxidative stress such as a mitochondria‐permeable antioxidant, MitoQ, can protect SVEE‐induced impairments. Four groups of Sprague Dawley rats were included: Control+Vehicle (C+V), Control+MitoQ (C+M), Exposure+Vehicle (E+V) and Exposure+MitoQ (E+M). The MitoQ groups received 250μM of MitoQ for 4 weeks via drinking water. Vehicle groups received normal drinking water during this period. Following the treatment, exposure rats were exposed to a simulated mixture of vehicle exhaust containing 0.04% CO 2 , 0.9 ppm NO 2 and 3 ppm CO. Exposures were performed in whole body exposure chambers 5h daily for 2 weeks. Duration of exposures was comparable to daily exposure of exhaust levels in areas of high traffic. Control rats were exposed to normal air for the same duration. Following SVEE, anxiety‐ and depression‐like behavior, as well as cognitive function and intelligence quotient (IQ) levels were assessed. An increase in anxiety‐like and depression‐like behavior as well as impaired memory and low IQ was observed in E+V rats as compared to C+V and C+M rats. However these deficits were not seen in E+M rats. At the biochemical level, effect of SVEE on mitochondrial function (one of the targets of increased oxidative stress) was assessed. Mitochondrial oxygen consumption in three brain regions, namely, prefrontal cortex, hippocampus and amygdala was determined using high resolution respirometry. SVEE led to decreased mitochondrial oxygen consumption in rats suggesting SVEE‐induced mitochondrial dysfunction. Oxygen consumption was unaltered in rats that received MitoQ. Thus our study has identified behavioral and biochemical impairments associated with exposure to vehicle exhaust in rats and identified a potential role of the antioxidant MitoQ in preventing these impairments. Support or Funding Information Grant Support: 2R15MH093918‐02

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.

Using a simulated oxidative stress model of hippocampus-derived immortalized cell line (HT22), we report that prooxidant buthionine sulfoximine (BSO, 1 mM, 14 h), without adversely affecting cell viability or morphology, induced oxidative stress by inhibiting glutathione synthesis. BSO treatment also significantly reduced superoxide dismutase (SOD) activity (p<0.05) and significantly lowered total antioxidant capacity (p<0.001) in HT22 cells when compared to vehicle treated control cells. Antioxidant tempol, a piperidine nitroxide considered a SOD mimetic, reversed BSO-induced decline in SOD activity (p<0.01) and also increased BSO-induced decline in total antioxidant capacity (p<0.05). Interestingly, BSO treatment significantly reduced mitochondrial oxygen consumption (p<0.05), decreased mitochondrial membrane potential (p<0.05), and lowered ATP production (p<0.05) when compared to vehicle treated control cells, collectively indicative of mitochondrial impairment. Antioxidant tempol treatment mitigated all three indicators of mitochondrial impairment. We postulate that BSO-induced oxidative stress in HT22 cells caused mitochondrial impairment, and tempol by increasing SOD activity and improving antioxidant capacity presumably protected the cells from BSO-induced mitochondrial impairment. In conclusion, present study provides an interesting simulation of oxidative stress in hippocampal cells, which will serve as an excellent model to study mitochondrial functions.

PURPOSE In this study, we investigated the effect of a slow-releasing hydrogen sulfide (H2S) 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 H2S-producing compounds, l-cysteine and ACS67 (a hybrid compound of latanoprost with an H2S-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 μL 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 H2S-producing compounds also caused a significant contralateral effect in vehicle-treated control eyes. CONCLUSION We conclude that GYY 4137 and other H2S-producing donors can reduce IOP in normotensive rabbits. However, the profile of IOP-lowering action of GYY 4137 was different from the other H2S donors affirming its ability to act as a slow-releasing gas donor.

In the present study, we investigated the effect of three different sources of hydrogen sulfide (H 2 S) on sympathetic neurotransmission from isolated superfused bovine iris-ciliary bodies. The three agents under consideration were: ACS67, a hybrid of latanoprost and a H 2 S-donating moiety; l -cysteine, a substrate for endogenous production of H 2 S and GYY 4137, a slow donor of H 2 S. We also examined the contribution of prostaglandins to the pharmacological actions of the H 2 S donors on release of [ 3 H]-norepinephrine ([ 3 H]NE) triggered by electrical field stimulation. ACS67, l -cysteine and GYY 4137 caused a concentration-dependent inhibition of electrically-evoked [ 3 H]NE release from isolated bovine iris-ciliary bodies without affecting basal [ 3 H]NE efflux. The cyclooxygenase inhibitor, flurbiprofen enhanced the inhibitory action of ACS67 and l -cysteine on stimulated [ 3 H]NE release. Both aminooxyacetic acid, an inhibitor of cystathionine-β-synthase and glibenclamide, a K ATP channel blocker reversed the inhibition of evoked NE release induced by the H 2 S donors. We conclude that H 2 S donors can inhibit sympathetic neurotransmission from isolated bovine iris-ciliary bodies, an effect partially dependent on the in situ production of H 2 S and prostanoids, and is mediated by an action on K ATP channels.

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.

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) [14]. 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 [14] 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.

Recent studies from our lab have shown that post‐traumatic stress disorder (PTSD)‐like behaviors are triggered not only in rats that physically experienced traumatic events of social defeat, but also in rats that witnessed their cage mates undergo traumatic exposure. Extending this line of research we have attempted to establish a rat model to study the consequences of early‐life exposure of witnessing maternal abuse (MAW). In this MAW model we introduced a female Spraugue‐Dawley rat (mother) into the cage of a male Long Evans (LE) rat. The female rat undergoes defeat from the LE rat. Natural litters at postnatal day 21 were placed in separate chambers surrounding the cage to witness 3 attacks per day, for 7 consecutive days. One month later, when the pups became 60 day old (considered adults), cognitive and behavioral outcomes of witnessing maternal abuse during early life were examined. MAW rats exhibited depression‐like behavior (examined via forced‐swim test) when compared to age matched controls. No changes were noted in anxiety‐like behavior (examined via open‐field and elevated plus maze tests) or learning and memory function (Radial arm water maze test) in MAW rats. Elevated levels of oxidative stress correlate with depressive phenotype of MAW rats. Studies to investigate the underlying neurobiology of MAW phenotype are currently ongoing.