Background COVID-19 vaccination has averted a significant number of deaths in the United States, ... more Background COVID-19 vaccination has averted a significant number of deaths in the United States, but vaccination hesitancy continues to be a problem. Therefore, examining vaccination acceptance and/or hesitancy in local communities is critical. Methods A quantitative survey and a multivariable logistic regression model was utilized to determine predictors of COVID-19 vaccination in Middle Eastern and North African (MENA) origin Houston residents. The outcome of interest was COVID-19 vaccination status (vaccinated versus not vaccinated). Covariates included: demographics, health, and COVID-19 factors. Statistical analyses included SAS version 9.4 at a priori significance level of 0.05. Results The overall vaccine acceptance rate was significantly high in this population subset (N = 366), with 77.60% vaccinated, and 22.40% not vaccinated. MENA individuals with some college degrees were less likely to report vaccination than those with a graduate degree [Odds Ratio (OR): 0.18; 95% Conf...
International Journal of Environmental Research and Public Health
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
The COVID-19 pandemic has contributed to anxiety and depression in many communities across the Un... more The COVID-19 pandemic has contributed to anxiety and depression in many communities across the United States. Here, we have focused on a sample of Houston-based Middle Eastern and North African (MENA) residents and assessed the prevalence of anxiety and depression in this community. The 7-item Generalized Anxiety Disorder and the 9-item Patient Health Questionnaires were used to identify the prevalence and severity of anxiety and depression, respectively. A sociodemographic, general health, and COVID-19 survey was used for a multivariable logistic regression model to determine predictors of anxiety and depression. The outcome of interest was “minimal/mild” versus “moderate/severe” anxiety and depression. A total of 368 participants completed the survey, with 24.73% reporting “moderate/severe” anxiety and 31.79% reporting “moderate/severe” depression. Male participants were less likely (OR = 0.29, 95% CI = 0.12, 0.75) to have “moderate/severe” anxiety compared to females. Respondents...
International Journal of Environmental Research and Public Health
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Through incorporating both physical and psychological forms of stressors, a variety of rodent mod... more Through incorporating both physical and psychological forms of stressors, a variety of rodent models have provided important insights into the understanding of stress physiology. Rodent models also have provided significant information with regards to the mechanistic basis of the pathophysiology of stress-related disorders such as anxiety disorders, depressive illnesses, cognitive impairment and post-traumatic stress disorder. Additionally, rodent models of stress have served as valuable tools in the area of drug screening and drug development for treatment of stress-induced conditions. Although rodent models do not accurately reproduce the biochemical or physiological parameters of stress response and cannot fully mimic the natural progression of human disorders, yet, animal research has provided answers to many important scientific questions. In this review article, important studies utilizing a variety of stress models are described in terms of their design and apparatus, with specific focus on their capabilities to generate reliable behavioral and biochemical read-out. The review focusses on the utility of rodent models by discussing examples in the literature that offer important mechanistic insights into physiologically relevant questions. The review highlights the utility of rodent models of stress as important tools for advancing the mission of scientific research and inquiry.
Benzodiazepines and SSRIs are considered as standard treatment options for anxiety and depression... more Benzodiazepines and SSRIs are considered as standard treatment options for anxiety and depression, hallmarks of Post-Traumatic Stress Disorder (PTSD), although their use is often limited by adverse effects. While promising evidence emerged with β-adrenergic receptor (β-AR) antagonists (or 'β-blockers') and PTSD relief, efficacy issues dampened the excitement. However, we believe it is premature to completely eliminate a beneficial role of β-blockers. Our previous work has suggested that social defeat (SD) results in anxiety-like and depression-like behaviors in rats. Here, using the SD paradigm, we examined the effect of several β-adrenergic receptor antagonists (propranolol, nadolol, bisoprolol) on these behaviors in rats. Following acclimatization, Sprague-Dawley rats received no treatment (for control groups) or treated with ; propranolol (50 mg/kg/day in water), or nadolol (18 mg/kg/day in rats' chow), or bisoprolol (15 mg/kg/day in water). The treatment lasted for 36 days, following which rats were subjected to SD/control exposures (1 week). Later, anxiety-like and depression-like behaviors, social interaction and learning-memory function tests were conducted. SD rats exhibited anxiety- and depression-like behavior as well as learning-memory impairment. Propranolol and nadolol protected SD rats from exhibiting anxiety-or depression-like behaviors. Bisoprolol treatment did not mitigate SD-induced behavioral impairments in rats. Nadolol, propranolol or bisoprolol have no effect in attenuating SD-induced memory function tests. These results suggest that certain 'β-blockers' have the potential to mitigate the negative psychological effects of traumatic events.
Advances in Protein Chemistry and Structural Biology
Adequate sleep is essential for normal brain function, especially during early life developmental... more Adequate sleep is essential for normal brain function, especially during early life developmental stages as postnatal brain maturation occurs during the critical period of childhood and adolescence. Therefore, sleep disturbance and/or deficit during this period can have detrimental consequences. Many epidemiological and clinical studies have linked early life sleep disturbance with occurrence of later life behavioral and cognitive impairments. Role of oxidative stress and inflammation has been implicated in sleep deprivation-related impairments. This review article presents a detailed description of the current state of the literature on the subject.
Progress in Neuro-Psychopharmacology and Biological Psychiatry
Background-Post-traumatic stress disorder (PTSD) is a serious psychological condition, which can ... more Background-Post-traumatic stress disorder (PTSD) is a serious psychological condition, which can develop both from physically experiencing and also from witnessing traumatic events. There is evidence that physical exercise can have a positive impact on the symptoms of PTSD. Relevant to this, in our previous pre-clinical work, beneficial effects of treadmill exercise were reported on PTSD-like behaviors in a social defeat paradigm, a rat model of direct physical trauma. However, the role of exercise on vicariously acquired PTSD-like phenotype was not examined. Objective-In this study, we utilized a rodent PTSD model, which mimics both the physical as well as the witness experience of trauma, and examined the impact of moderate treadmill exercise in mitigating vicariously acquired PTSD-like behaviors in rats. Methods-Our PTSD model is a modified social defeat paradigm, which involves aggressive encounters between a large Long-Evans male rat (resident) and a smaller Sprague-Dawley male rat (intruder), resulting in intruder social defeat. The cage mate of the intruder is positioned to witness intruder defeat. Rats were grouped as control (CON), social defeat (SD), exercise (EX), trauma witness (TW), and exercise prior to trauma witness (EX-TW). After acclimatization for 7 days, the exercised groups were subjected to a daily 30-min treadmill exercise regimen for 14 days. On day 21, the SD group was exposed for 7 days of social defeat, while the TW groups witnessed social defeat. On days 28-34, behavioral and cognitive tests including short-term (STM) and long-term (LTM) memory function, anxiety-and depression-like behaviors were conducted. Results-TW and SD rats demonstrated the highest levels of anxiety-and depression-like behaviors, while EX-TW rats did not exhibit anxiety-and depression-like behaviors. TW and SD rats showed no impairments in STM. However, TW and SD rats showed impairments in LTM, and exercise rescued LTM impairments in EX-TW rats.
We have published that pharmacological induction of oxidative stress (OS) causes anxiety-like beh... more 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...
Previously, using the single-prolonged stress (SPS) rat model of post-traumatic stress disorder, ... more Previously, using the single-prolonged stress (SPS) rat model of post-traumatic stress disorder, we reported that moderate treadmill exercise, via modulation of oxidative stress related mechanisms, rescued anxiety and depression-like behaviors and reversed SPS-induced memory impairment. In this study using the SPS model (2 h restrain, 20 min forced swimming, 15 min rest, and 1-2 min diethyl ether exposure), we hypothesized that antioxidant rich grape powder (GP) prevents SPSinduced behavioral and memory impairment in rats. Male Sprague Dawley rats were randomly assigned into: Control (CON; provided tap water), SPS (provided tap water), GP-SPS (provided 15 g/L GP in tap water for 3 wk followed by SPS), or GP-CON (3 wk of GP followed by control exposure). Anxiety and depression-like behaviors were significantly greater in SPS rats when compared to CON or GP treated rats and GP reversed these behavioral deficits. SPS rats made significantly more errors in both short-and long-term memory tests compared to CON or GP treated rats, which were prevented in GP-SPS rats. GP prevented SPS-induced increase in plasma corticosterone level. Furthermore, brain derived neurotrophic factor (BDNF) levels were significantly decreased in amygdala of SPS rats but not in GP-SPS rats compared to CON or GP-CON rats. Additionally, GP significantly increased acetylated Histone3, Histone deacetylase 5 (HDAC 5) in hippocampus and amygdala of SPS rats as compared to CON or GP-CON rats. In conclusion, we suggest protective role of GP in SPS-induced behavioral, cognitive and biochemical impairments in rats. Perhaps, epigenetic regulation of BDNF enables GP-mediated prevention of SPS-induced deficits in rats.
Gravin, an A-kinase anchoring protein, targets protein kinase A (PKA), protein kinase C (PKC), ca... more Gravin, an A-kinase anchoring protein, targets protein kinase A (PKA), protein kinase C (PKC), calcineurin and other signaling molecules to the beta2-adrenergic receptor (β 2 -AR). Gravin mediates desensitization/resensitization of the receptor by facilitating its phosphorylation by PKA and PKC. The role of gravin in β-AR mediated regulation of cardiac function is unclear. The purpose of this study was to determine the effect of acute β-AR stimulation on cardiac contractility in mice lacking functional gravin. Using echocardiographic analysis, we observed that contractility parameters such as left ventricular fractional shortening and ejection fraction were increased in gravin mutant (gravin-t/t) animals lacking functional protein compared to wild-type (WT) animals both at baseline and following acute isoproterenol (ISO) administration. In isolated gravin-t/t cardiomyocytes, we observed increased cell shortening fraction and decreased intracellular Ca 2+ in response to 1 µmol/L ISO stimulation. These physiological responses occurred in the presence of decreased β 2 -AR phosphorylation in gravin-t/t hearts, where PKA-dependent β 2 -AR phosphorylation has been shown to lead to receptor desensitization. cAMP production, PKA activity and phosphorylation of phospholamban and troponin I was comparable in WT and gravin-t/t hearts both with and without ISO stimulation. However, cardiac myosin binding protein C (cMyBPC) phosphorylation site at position 273 was significantly increased in gravin-t/t versus WT hearts, in the absence of ISO. Additionally, the cardioprotective heat shock protein 20 (Hsp20) was significantly more phosphorylated in gravin-t/t versus WT hearts, in response to ISO. Our results suggest that disruption of gravin's scaffold mediated signaling is able to increase baseline cardiac function as well as to augment contractility in response to acute β-AR stimulation by decreasing β 2 -AR phosphorylation and thus attenuating receptor desensitization and perhaps by altering PKA localization to increase the phosphorylation of cMyBPC and the nonclassical PKA substrate Hsp20.
Diminished estrogen influence at menopause is reported to be associated with cognitive decline, h... more Diminished estrogen influence at menopause is reported to be associated with cognitive decline, heightened anxiety and hypertension. While estrogen therapy is often prescribed to overcome these behavioral and physiological deficits, antioxidants which have been shown beneficial are gaining nutritional intervention and popularity. Therefore, in the present study, utilizing the antioxidant properties of grapes, we have examined effect of 3 weeks of grape powder (GP; 15 g/L dissolved in tap water) treatment on anxiety-like behavior, learning-memory impairment and high blood pressure in ovariectomized (OVX) rats. Four groups of female Wistar rats were used; sham control, sham-GP treated, OVX and OVX+GP treated. We observed a significant increase in systolic and diastolic blood pressure in OVX rats as compared to shamcontrols. Furthermore, ovariectomy increased anxiety-like behavior and caused learning and memory impairment in rats as compared to sham-controls. Interestingly, providing grape powder treated water to OVX rats restored both systolic and diastolic blood pressure, decreased anxiety-like behavior and improved memory function. Moreover, OVX rats exhibited an impaired long term potentiation which was restored with grape powder treatment. Furthermore, ovariectomy increased oxidative stress in the brain, serum and urine, selectively decreasing antioxidant enzyme, glyoxalase-1 protein expression in the hippocampus but not in the cortex and amygdala of OVX rats, while grape powder treatment reversed these effects. Other antioxidant enzyme levels, including manganese superoxide dismutase (SOD) and Cu/Zn SOD remained unchanged. We suggest that grape powder by regulating oxidative stress mechanisms exerts its protective effect on blood pressure, learning-memory and anxiety-like behavior. Our study is the first to examine behavioral, biochemical, physiological and electrophysiological outcome of estrogen depletion in rats and to test protective role of grape powder, all in the same study.
Social defeat (SD) induced stress causes physiological and behavioral deficits in rodents, includ... more Social defeat (SD) induced stress causes physiological and behavioral deficits in rodents, including depression and anxiety-like behaviors, as well as memory impairment. Anxiolytic and mood elevating effects of physical exercise are also known. However, rescue effect of physical exercise in social defeat-induced anxiety, depression or memory impairment has not been addressed. Role of epigenetic mechanisms that potentially contribute to these rescue or protective effects are also not known. Present study investigated the effect of moderate treadmill exercise on anxiety-like behavior and memory function in rats subjected to SD using a modified version of the resident-intruder model for social stress (defeat). Changes in histone acetylation and histonemodifying enzymes were examined in hippocampus, amygdala and frontal cortex which are considered critical for anxiety, depression and cognition. Sprague Dawley rats were randomly assigned in four groups; control, exercised, social defeat, social defeat and exercise. At the end of the SD or control exposure lasting 30 min daily for 7 days, one group of SD rats was subjected to treadmill exercise for 2 weeks, whereas the other SD group was handled without exercise. Anxiety-like behavior tests and radial arm water maze test suggested that moderate treadmill exercise rescued social defeat induced anxiety-like behavior and memory impairment. Moreover, exercise normalized SD-induced increase in oxidative stress, most likely by adjusting antioxidant response. Our data suggests involvement of epigenetic mechanisms including histone acetylation of H3 and modulation of methyl-CpG-binding in the hippocampus that might contribute to the rescue effects of exercise in SD-induced behavioral deficits in rats.
In the present study, we have examined the behavioral and biochemical effect of induction of psyc... more In the present study, we have examined the behavioral and biochemical effect of induction of psychological stress using a modified version of the resident-intruder model for social stress (social defeat). At the end of the social defeat protocol, body weights, food and water intake were recorded, depression and anxiety-like behaviors as well as learning-memory function was examined. Biochemical analysis including oxidative stress measurement, inflammatory markers and other molecular parameters, critical to behavioral effects were examined. We observed a significant decrease in the body weight in the socially defeated rats as compared to the controls. Furthermore, social defeat increased anxiety-like behavior and caused memory impairment in rats (P<0.05). Socially defeated rats made significantly more errors in long term memory tests (P<0.05) as compared to control rats. Furthermore, brain extracellular signal-regulated kinase-1/2 (ERK1/2), and an inflammatory marker, interleukin (IL)-6 were activated (P<0.05), while the protein levels of glyoxalase (GLO)-1, glutathione reductase (GSR)-1, calcium/calmodulindependent protein kinase type (CAMK)-IV, cAMP-response-element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) were significantly less (P<0.05) in the hippocampus, but not in the prefrontal cortex and amygdala of socially defeated rats, when compared to control rats. We suggest that social defeat stress alters ERK1/2, IL-6, GLO1, GSR1, CAMKIV, CREB, and BDNF levels in specific brain areas, leading to oxidative stress-induced anxiety-depressionlike behaviors and as well as memory impairment in rats.
Adverse experiences during early life contribute to the development of psychiatric conditions lat... more Adverse experiences during early life contribute to the development of psychiatric conditions later in life. In fact, young children who experience stressful traumatic event(s) during early life, a sensitive developmental period, are considered highly vulnerable to psychiatric disorders in adult life. Interestingly, not all children who experience stressful events are equally at risk of developing later life psychiatric disorders. Some are resilient in spite of being exposed to the same risk factors, while others are susceptible. The mechanistic basis for resilience/susceptibility is not clear. Using an early life stress model of Sprague Dawley rats, the mechanisms governing this phenotype segregation were revealed. Depression-susceptible phenotype is associated with high oxidative stress, low antioxidant status, defective redox-sensitive Nrf2 transcription factor and hyperactive NF-KB transcription factor, selectively in the pre-frontal cortex (PFC) area of the brain. The resistant phenotype displayed low oxidative stress, high antioxidant status, activated Nrf2 and inactivated NF-KB pathways.
Progress in Molecular Biology and Translational Science
Mental health is central to normal health outcomes. A widely accepted theory is that chronic pers... more Mental health is central to normal health outcomes. A widely accepted theory is that chronic persistent stress during adulthood as well as during early life triggers onset of neuropsychiatric ailments. However, questions related to how that occurs, and why are some individuals resistant to stress while others are not, remain unanswered. An integrated, multisystemic stress response involving neuroinflammatory, neuroendocrine, epigenetic and metabolic cascades have been suggested to have causative links. Several theories have been proposed over the years to conceptualize this link including the cytokine hypothesis, the endocrine hypothesis, the oxidative stress hypothesis and the oxido-neuroinflammation hypothesis. The data discussed in this review describes potential biochemical basis of the link between stress, and stress-induced neuronal, behavioral and emotional deficits, providing insights into potentially novel drug targets.
The adverse consequences of early-life sleep deprivation on mental health are well recognized, ye... more The adverse consequences of early-life sleep deprivation on mental health are well recognized, yet many aspects remain unknown, therefore, animal studies can offer useful insights. Male Sprague-Dawley rats at postnatal day (PND) 19 were subjected to sleep deprivation (SD) for 14 days (6-8 hours/day). Control (CON) rats were gently handled. Behavior tests were done on PND33, PND60 and PND90. SD rats exhibited anxiety-like behavior at PND33 and PND60, when compared to CON rats. Depression-like behavior was observed at PND90. Evaluation of oxidative stress and inflammatory markers revealed interesting results. Plasma 8-isoprostane and antioxidant defense enzymes; hemeoxygenase-1, superoxide dismutase, glutathione peroxidase in the prefrontal cortex (PFC), were upregulated in SD rats at PND33 but not at PND90. PFC interleukin-6 protein expression was elevated at PND33 and PND90. PFC mitogen activated protein kinase phosphatase-1 (MKP-1) and p-38 protein expression were upregulated at PND90. PFC expression of glutamate receptor subunits, post synaptic density protein (PSD-95), calcium/calmodulin-dependent protein kinase (CaMKII), and extracellular signal-regulated kinase (ERK1/2), were significantly reduced in SD rats at PND33 and PND90. PFC brain derived neurotrophic factor (BDNF) and cAMP response element binding protein (CREB) were reduced in SD rats at PND90. Our postulation is that SD by increasing PFC oxido-inflammation, negatively affects glutamate receptor subunits and PSD95 expression, which disrupts synapse formation and maturation, potentially causing anxiety-like behavior at PND33. Oxido-inflammation further results in MKP-1 and CaMKII-mediated blockade of ERK1/2 activation, which inhibits CREB dependent BDNF expression. This most likely disrupts neuronal circuit development, leading to depression-like behavior at PND90.
Progress in neuro-psychopharmacology & biological psychiatry, 2017
Children subjected to traumatic events during childhood are reported to exhibit behavioral and co... more 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. 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. 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. Rats exposed to SPS ex...
Earlier, we reported that elevated anxiety-like behavior and high aggression in aged retired bree... more Earlier, we reported that elevated anxiety-like behavior and high aggression in aged retired breeder Long-Evans (L-E) rats was associated with increased plasma corticosterone and elevated oxidative stress levels. In the present study, we examined how this aged aggressive and anxious rat strain responds to acute sleep deprivation (24h) and whether their behaviors can be modulated via antioxidant tempol treatment. Four groups of L-E rats were utilized: naïve control (NC), tempol treated control (T+NC), sleep deprived (SD), tempol treated and sleep deprived (T+SD). Thus, two groups were treated with tempol (1mM in drinking water for 2 weeks) while the other two were not. Two groups were subjected to acute sleep deprivation (24h) using the columns-in-water model while the other two were not. Sleep deprivation induced anxiety-like behavior, led to significant depression-like behavior and short-term memory impairment in SD rats. And, decision-making behavior also was compromised in SD rats. These behavioral and cognitive impairments were prevented with tempol treatment in T+SD rats. Tempol treatment also reduced SD-induced increase in corticosterone and oxidative stress levels in T+SD rats. These results suggest potential involvement of oxidative stress mechanisms in regulation of sleep deprivation induced behavioral and cognitive deficits in male aged-aggressive rats.
Background COVID-19 vaccination has averted a significant number of deaths in the United States, ... more Background COVID-19 vaccination has averted a significant number of deaths in the United States, but vaccination hesitancy continues to be a problem. Therefore, examining vaccination acceptance and/or hesitancy in local communities is critical. Methods A quantitative survey and a multivariable logistic regression model was utilized to determine predictors of COVID-19 vaccination in Middle Eastern and North African (MENA) origin Houston residents. The outcome of interest was COVID-19 vaccination status (vaccinated versus not vaccinated). Covariates included: demographics, health, and COVID-19 factors. Statistical analyses included SAS version 9.4 at a priori significance level of 0.05. Results The overall vaccine acceptance rate was significantly high in this population subset (N = 366), with 77.60% vaccinated, and 22.40% not vaccinated. MENA individuals with some college degrees were less likely to report vaccination than those with a graduate degree [Odds Ratio (OR): 0.18; 95% Conf...
International Journal of Environmental Research and Public Health
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
The COVID-19 pandemic has contributed to anxiety and depression in many communities across the Un... more The COVID-19 pandemic has contributed to anxiety and depression in many communities across the United States. Here, we have focused on a sample of Houston-based Middle Eastern and North African (MENA) residents and assessed the prevalence of anxiety and depression in this community. The 7-item Generalized Anxiety Disorder and the 9-item Patient Health Questionnaires were used to identify the prevalence and severity of anxiety and depression, respectively. A sociodemographic, general health, and COVID-19 survey was used for a multivariable logistic regression model to determine predictors of anxiety and depression. The outcome of interest was “minimal/mild” versus “moderate/severe” anxiety and depression. A total of 368 participants completed the survey, with 24.73% reporting “moderate/severe” anxiety and 31.79% reporting “moderate/severe” depression. Male participants were less likely (OR = 0.29, 95% CI = 0.12, 0.75) to have “moderate/severe” anxiety compared to females. Respondents...
International Journal of Environmental Research and Public Health
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Through incorporating both physical and psychological forms of stressors, a variety of rodent mod... more Through incorporating both physical and psychological forms of stressors, a variety of rodent models have provided important insights into the understanding of stress physiology. Rodent models also have provided significant information with regards to the mechanistic basis of the pathophysiology of stress-related disorders such as anxiety disorders, depressive illnesses, cognitive impairment and post-traumatic stress disorder. Additionally, rodent models of stress have served as valuable tools in the area of drug screening and drug development for treatment of stress-induced conditions. Although rodent models do not accurately reproduce the biochemical or physiological parameters of stress response and cannot fully mimic the natural progression of human disorders, yet, animal research has provided answers to many important scientific questions. In this review article, important studies utilizing a variety of stress models are described in terms of their design and apparatus, with specific focus on their capabilities to generate reliable behavioral and biochemical read-out. The review focusses on the utility of rodent models by discussing examples in the literature that offer important mechanistic insights into physiologically relevant questions. The review highlights the utility of rodent models of stress as important tools for advancing the mission of scientific research and inquiry.
Benzodiazepines and SSRIs are considered as standard treatment options for anxiety and depression... more Benzodiazepines and SSRIs are considered as standard treatment options for anxiety and depression, hallmarks of Post-Traumatic Stress Disorder (PTSD), although their use is often limited by adverse effects. While promising evidence emerged with β-adrenergic receptor (β-AR) antagonists (or 'β-blockers') and PTSD relief, efficacy issues dampened the excitement. However, we believe it is premature to completely eliminate a beneficial role of β-blockers. Our previous work has suggested that social defeat (SD) results in anxiety-like and depression-like behaviors in rats. Here, using the SD paradigm, we examined the effect of several β-adrenergic receptor antagonists (propranolol, nadolol, bisoprolol) on these behaviors in rats. Following acclimatization, Sprague-Dawley rats received no treatment (for control groups) or treated with ; propranolol (50 mg/kg/day in water), or nadolol (18 mg/kg/day in rats' chow), or bisoprolol (15 mg/kg/day in water). The treatment lasted for 36 days, following which rats were subjected to SD/control exposures (1 week). Later, anxiety-like and depression-like behaviors, social interaction and learning-memory function tests were conducted. SD rats exhibited anxiety- and depression-like behavior as well as learning-memory impairment. Propranolol and nadolol protected SD rats from exhibiting anxiety-or depression-like behaviors. Bisoprolol treatment did not mitigate SD-induced behavioral impairments in rats. Nadolol, propranolol or bisoprolol have no effect in attenuating SD-induced memory function tests. These results suggest that certain 'β-blockers' have the potential to mitigate the negative psychological effects of traumatic events.
Advances in Protein Chemistry and Structural Biology
Adequate sleep is essential for normal brain function, especially during early life developmental... more Adequate sleep is essential for normal brain function, especially during early life developmental stages as postnatal brain maturation occurs during the critical period of childhood and adolescence. Therefore, sleep disturbance and/or deficit during this period can have detrimental consequences. Many epidemiological and clinical studies have linked early life sleep disturbance with occurrence of later life behavioral and cognitive impairments. Role of oxidative stress and inflammation has been implicated in sleep deprivation-related impairments. This review article presents a detailed description of the current state of the literature on the subject.
Progress in Neuro-Psychopharmacology and Biological Psychiatry
Background-Post-traumatic stress disorder (PTSD) is a serious psychological condition, which can ... more Background-Post-traumatic stress disorder (PTSD) is a serious psychological condition, which can develop both from physically experiencing and also from witnessing traumatic events. There is evidence that physical exercise can have a positive impact on the symptoms of PTSD. Relevant to this, in our previous pre-clinical work, beneficial effects of treadmill exercise were reported on PTSD-like behaviors in a social defeat paradigm, a rat model of direct physical trauma. However, the role of exercise on vicariously acquired PTSD-like phenotype was not examined. Objective-In this study, we utilized a rodent PTSD model, which mimics both the physical as well as the witness experience of trauma, and examined the impact of moderate treadmill exercise in mitigating vicariously acquired PTSD-like behaviors in rats. Methods-Our PTSD model is a modified social defeat paradigm, which involves aggressive encounters between a large Long-Evans male rat (resident) and a smaller Sprague-Dawley male rat (intruder), resulting in intruder social defeat. The cage mate of the intruder is positioned to witness intruder defeat. Rats were grouped as control (CON), social defeat (SD), exercise (EX), trauma witness (TW), and exercise prior to trauma witness (EX-TW). After acclimatization for 7 days, the exercised groups were subjected to a daily 30-min treadmill exercise regimen for 14 days. On day 21, the SD group was exposed for 7 days of social defeat, while the TW groups witnessed social defeat. On days 28-34, behavioral and cognitive tests including short-term (STM) and long-term (LTM) memory function, anxiety-and depression-like behaviors were conducted. Results-TW and SD rats demonstrated the highest levels of anxiety-and depression-like behaviors, while EX-TW rats did not exhibit anxiety-and depression-like behaviors. TW and SD rats showed no impairments in STM. However, TW and SD rats showed impairments in LTM, and exercise rescued LTM impairments in EX-TW rats.
We have published that pharmacological induction of oxidative stress (OS) causes anxiety-like beh... more 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...
Previously, using the single-prolonged stress (SPS) rat model of post-traumatic stress disorder, ... more Previously, using the single-prolonged stress (SPS) rat model of post-traumatic stress disorder, we reported that moderate treadmill exercise, via modulation of oxidative stress related mechanisms, rescued anxiety and depression-like behaviors and reversed SPS-induced memory impairment. In this study using the SPS model (2 h restrain, 20 min forced swimming, 15 min rest, and 1-2 min diethyl ether exposure), we hypothesized that antioxidant rich grape powder (GP) prevents SPSinduced behavioral and memory impairment in rats. Male Sprague Dawley rats were randomly assigned into: Control (CON; provided tap water), SPS (provided tap water), GP-SPS (provided 15 g/L GP in tap water for 3 wk followed by SPS), or GP-CON (3 wk of GP followed by control exposure). Anxiety and depression-like behaviors were significantly greater in SPS rats when compared to CON or GP treated rats and GP reversed these behavioral deficits. SPS rats made significantly more errors in both short-and long-term memory tests compared to CON or GP treated rats, which were prevented in GP-SPS rats. GP prevented SPS-induced increase in plasma corticosterone level. Furthermore, brain derived neurotrophic factor (BDNF) levels were significantly decreased in amygdala of SPS rats but not in GP-SPS rats compared to CON or GP-CON rats. Additionally, GP significantly increased acetylated Histone3, Histone deacetylase 5 (HDAC 5) in hippocampus and amygdala of SPS rats as compared to CON or GP-CON rats. In conclusion, we suggest protective role of GP in SPS-induced behavioral, cognitive and biochemical impairments in rats. Perhaps, epigenetic regulation of BDNF enables GP-mediated prevention of SPS-induced deficits in rats.
Gravin, an A-kinase anchoring protein, targets protein kinase A (PKA), protein kinase C (PKC), ca... more Gravin, an A-kinase anchoring protein, targets protein kinase A (PKA), protein kinase C (PKC), calcineurin and other signaling molecules to the beta2-adrenergic receptor (β 2 -AR). Gravin mediates desensitization/resensitization of the receptor by facilitating its phosphorylation by PKA and PKC. The role of gravin in β-AR mediated regulation of cardiac function is unclear. The purpose of this study was to determine the effect of acute β-AR stimulation on cardiac contractility in mice lacking functional gravin. Using echocardiographic analysis, we observed that contractility parameters such as left ventricular fractional shortening and ejection fraction were increased in gravin mutant (gravin-t/t) animals lacking functional protein compared to wild-type (WT) animals both at baseline and following acute isoproterenol (ISO) administration. In isolated gravin-t/t cardiomyocytes, we observed increased cell shortening fraction and decreased intracellular Ca 2+ in response to 1 µmol/L ISO stimulation. These physiological responses occurred in the presence of decreased β 2 -AR phosphorylation in gravin-t/t hearts, where PKA-dependent β 2 -AR phosphorylation has been shown to lead to receptor desensitization. cAMP production, PKA activity and phosphorylation of phospholamban and troponin I was comparable in WT and gravin-t/t hearts both with and without ISO stimulation. However, cardiac myosin binding protein C (cMyBPC) phosphorylation site at position 273 was significantly increased in gravin-t/t versus WT hearts, in the absence of ISO. Additionally, the cardioprotective heat shock protein 20 (Hsp20) was significantly more phosphorylated in gravin-t/t versus WT hearts, in response to ISO. Our results suggest that disruption of gravin's scaffold mediated signaling is able to increase baseline cardiac function as well as to augment contractility in response to acute β-AR stimulation by decreasing β 2 -AR phosphorylation and thus attenuating receptor desensitization and perhaps by altering PKA localization to increase the phosphorylation of cMyBPC and the nonclassical PKA substrate Hsp20.
Diminished estrogen influence at menopause is reported to be associated with cognitive decline, h... more Diminished estrogen influence at menopause is reported to be associated with cognitive decline, heightened anxiety and hypertension. While estrogen therapy is often prescribed to overcome these behavioral and physiological deficits, antioxidants which have been shown beneficial are gaining nutritional intervention and popularity. Therefore, in the present study, utilizing the antioxidant properties of grapes, we have examined effect of 3 weeks of grape powder (GP; 15 g/L dissolved in tap water) treatment on anxiety-like behavior, learning-memory impairment and high blood pressure in ovariectomized (OVX) rats. Four groups of female Wistar rats were used; sham control, sham-GP treated, OVX and OVX+GP treated. We observed a significant increase in systolic and diastolic blood pressure in OVX rats as compared to shamcontrols. Furthermore, ovariectomy increased anxiety-like behavior and caused learning and memory impairment in rats as compared to sham-controls. Interestingly, providing grape powder treated water to OVX rats restored both systolic and diastolic blood pressure, decreased anxiety-like behavior and improved memory function. Moreover, OVX rats exhibited an impaired long term potentiation which was restored with grape powder treatment. Furthermore, ovariectomy increased oxidative stress in the brain, serum and urine, selectively decreasing antioxidant enzyme, glyoxalase-1 protein expression in the hippocampus but not in the cortex and amygdala of OVX rats, while grape powder treatment reversed these effects. Other antioxidant enzyme levels, including manganese superoxide dismutase (SOD) and Cu/Zn SOD remained unchanged. We suggest that grape powder by regulating oxidative stress mechanisms exerts its protective effect on blood pressure, learning-memory and anxiety-like behavior. Our study is the first to examine behavioral, biochemical, physiological and electrophysiological outcome of estrogen depletion in rats and to test protective role of grape powder, all in the same study.
Social defeat (SD) induced stress causes physiological and behavioral deficits in rodents, includ... more Social defeat (SD) induced stress causes physiological and behavioral deficits in rodents, including depression and anxiety-like behaviors, as well as memory impairment. Anxiolytic and mood elevating effects of physical exercise are also known. However, rescue effect of physical exercise in social defeat-induced anxiety, depression or memory impairment has not been addressed. Role of epigenetic mechanisms that potentially contribute to these rescue or protective effects are also not known. Present study investigated the effect of moderate treadmill exercise on anxiety-like behavior and memory function in rats subjected to SD using a modified version of the resident-intruder model for social stress (defeat). Changes in histone acetylation and histonemodifying enzymes were examined in hippocampus, amygdala and frontal cortex which are considered critical for anxiety, depression and cognition. Sprague Dawley rats were randomly assigned in four groups; control, exercised, social defeat, social defeat and exercise. At the end of the SD or control exposure lasting 30 min daily for 7 days, one group of SD rats was subjected to treadmill exercise for 2 weeks, whereas the other SD group was handled without exercise. Anxiety-like behavior tests and radial arm water maze test suggested that moderate treadmill exercise rescued social defeat induced anxiety-like behavior and memory impairment. Moreover, exercise normalized SD-induced increase in oxidative stress, most likely by adjusting antioxidant response. Our data suggests involvement of epigenetic mechanisms including histone acetylation of H3 and modulation of methyl-CpG-binding in the hippocampus that might contribute to the rescue effects of exercise in SD-induced behavioral deficits in rats.
In the present study, we have examined the behavioral and biochemical effect of induction of psyc... more In the present study, we have examined the behavioral and biochemical effect of induction of psychological stress using a modified version of the resident-intruder model for social stress (social defeat). At the end of the social defeat protocol, body weights, food and water intake were recorded, depression and anxiety-like behaviors as well as learning-memory function was examined. Biochemical analysis including oxidative stress measurement, inflammatory markers and other molecular parameters, critical to behavioral effects were examined. We observed a significant decrease in the body weight in the socially defeated rats as compared to the controls. Furthermore, social defeat increased anxiety-like behavior and caused memory impairment in rats (P<0.05). Socially defeated rats made significantly more errors in long term memory tests (P<0.05) as compared to control rats. Furthermore, brain extracellular signal-regulated kinase-1/2 (ERK1/2), and an inflammatory marker, interleukin (IL)-6 were activated (P<0.05), while the protein levels of glyoxalase (GLO)-1, glutathione reductase (GSR)-1, calcium/calmodulindependent protein kinase type (CAMK)-IV, cAMP-response-element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) were significantly less (P<0.05) in the hippocampus, but not in the prefrontal cortex and amygdala of socially defeated rats, when compared to control rats. We suggest that social defeat stress alters ERK1/2, IL-6, GLO1, GSR1, CAMKIV, CREB, and BDNF levels in specific brain areas, leading to oxidative stress-induced anxiety-depressionlike behaviors and as well as memory impairment in rats.
Adverse experiences during early life contribute to the development of psychiatric conditions lat... more Adverse experiences during early life contribute to the development of psychiatric conditions later in life. In fact, young children who experience stressful traumatic event(s) during early life, a sensitive developmental period, are considered highly vulnerable to psychiatric disorders in adult life. Interestingly, not all children who experience stressful events are equally at risk of developing later life psychiatric disorders. Some are resilient in spite of being exposed to the same risk factors, while others are susceptible. The mechanistic basis for resilience/susceptibility is not clear. Using an early life stress model of Sprague Dawley rats, the mechanisms governing this phenotype segregation were revealed. Depression-susceptible phenotype is associated with high oxidative stress, low antioxidant status, defective redox-sensitive Nrf2 transcription factor and hyperactive NF-KB transcription factor, selectively in the pre-frontal cortex (PFC) area of the brain. The resistant phenotype displayed low oxidative stress, high antioxidant status, activated Nrf2 and inactivated NF-KB pathways.
Progress in Molecular Biology and Translational Science
Mental health is central to normal health outcomes. A widely accepted theory is that chronic pers... more Mental health is central to normal health outcomes. A widely accepted theory is that chronic persistent stress during adulthood as well as during early life triggers onset of neuropsychiatric ailments. However, questions related to how that occurs, and why are some individuals resistant to stress while others are not, remain unanswered. An integrated, multisystemic stress response involving neuroinflammatory, neuroendocrine, epigenetic and metabolic cascades have been suggested to have causative links. Several theories have been proposed over the years to conceptualize this link including the cytokine hypothesis, the endocrine hypothesis, the oxidative stress hypothesis and the oxido-neuroinflammation hypothesis. The data discussed in this review describes potential biochemical basis of the link between stress, and stress-induced neuronal, behavioral and emotional deficits, providing insights into potentially novel drug targets.
The adverse consequences of early-life sleep deprivation on mental health are well recognized, ye... more The adverse consequences of early-life sleep deprivation on mental health are well recognized, yet many aspects remain unknown, therefore, animal studies can offer useful insights. Male Sprague-Dawley rats at postnatal day (PND) 19 were subjected to sleep deprivation (SD) for 14 days (6-8 hours/day). Control (CON) rats were gently handled. Behavior tests were done on PND33, PND60 and PND90. SD rats exhibited anxiety-like behavior at PND33 and PND60, when compared to CON rats. Depression-like behavior was observed at PND90. Evaluation of oxidative stress and inflammatory markers revealed interesting results. Plasma 8-isoprostane and antioxidant defense enzymes; hemeoxygenase-1, superoxide dismutase, glutathione peroxidase in the prefrontal cortex (PFC), were upregulated in SD rats at PND33 but not at PND90. PFC interleukin-6 protein expression was elevated at PND33 and PND90. PFC mitogen activated protein kinase phosphatase-1 (MKP-1) and p-38 protein expression were upregulated at PND90. PFC expression of glutamate receptor subunits, post synaptic density protein (PSD-95), calcium/calmodulin-dependent protein kinase (CaMKII), and extracellular signal-regulated kinase (ERK1/2), were significantly reduced in SD rats at PND33 and PND90. PFC brain derived neurotrophic factor (BDNF) and cAMP response element binding protein (CREB) were reduced in SD rats at PND90. Our postulation is that SD by increasing PFC oxido-inflammation, negatively affects glutamate receptor subunits and PSD95 expression, which disrupts synapse formation and maturation, potentially causing anxiety-like behavior at PND33. Oxido-inflammation further results in MKP-1 and CaMKII-mediated blockade of ERK1/2 activation, which inhibits CREB dependent BDNF expression. This most likely disrupts neuronal circuit development, leading to depression-like behavior at PND90.
Progress in neuro-psychopharmacology & biological psychiatry, 2017
Children subjected to traumatic events during childhood are reported to exhibit behavioral and co... more 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. 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. 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. Rats exposed to SPS ex...
Earlier, we reported that elevated anxiety-like behavior and high aggression in aged retired bree... more Earlier, we reported that elevated anxiety-like behavior and high aggression in aged retired breeder Long-Evans (L-E) rats was associated with increased plasma corticosterone and elevated oxidative stress levels. In the present study, we examined how this aged aggressive and anxious rat strain responds to acute sleep deprivation (24h) and whether their behaviors can be modulated via antioxidant tempol treatment. Four groups of L-E rats were utilized: naïve control (NC), tempol treated control (T+NC), sleep deprived (SD), tempol treated and sleep deprived (T+SD). Thus, two groups were treated with tempol (1mM in drinking water for 2 weeks) while the other two were not. Two groups were subjected to acute sleep deprivation (24h) using the columns-in-water model while the other two were not. Sleep deprivation induced anxiety-like behavior, led to significant depression-like behavior and short-term memory impairment in SD rats. And, decision-making behavior also was compromised in SD rats. These behavioral and cognitive impairments were prevented with tempol treatment in T+SD rats. Tempol treatment also reduced SD-induced increase in corticosterone and oxidative stress levels in T+SD rats. These results suggest potential involvement of oxidative stress mechanisms in regulation of sleep deprivation induced behavioral and cognitive deficits in male aged-aggressive rats.
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