Browsing by Author "Salim, Samina"
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Item Behavioral and Biochemical Consequences of Early Life Sleep Deprivation in Rats(2018-08) Atrooz, Fatin Yousef; Salim, Samina; Alkadhi, Karim A.; Eriksen, Jason; Alfano, Candice A.; Risbrough, Victoria B.Adequate sleep is essential for normal brain function, especially during the critical period of early developmental stages (childhood and adolescence). Many epidemiological and clinical studies have linked early life sleep deprivation (SD) with the occurrence of later life behavioral impairment. However, the mechanism by which early life SD causes behavioral impairment is not fully understood. Animal studies have provided useful insights. Previous reports from our laboratory have suggested a potential role for oxidative stress in induction of behavioral impairments in a rat model of acute sleep deprivation. Others have reported that extended wakefulness increases cellular metabolism and induces formation of reactive oxygen species leading to oxidative stress. Moreover, synaptic pruning and neuronal myelination occurs during early life. These processes are essential for neural circuitry maturation which underlies the behavioral changes. Sleep enhances synaptic pruning and neuronal myelination, strengthening neuronal connections. Therefore, we suggested that sleep deprivation during early life, by engaging stress pathway(s), adversely affects neuronal development and function leading to long-lasting behavioral impairment. We examined the effect of early life SD in rats. The rats at postnatal day (PND) 19 were exposed to SD 6-8h/day for 14 days. The behavioral consequences of SD were examined at different developmental stages; early adolescent: PND33, late adolescent: PND60, and adulthood: PND90. The biochemical markers of stress and synaptic density/ plasticity were measured in different brain regions at PND33 and PND90. We found that anxiety-like behavior was induced in SD rats at early life (PND33 and 60). However, at later life (PND90), anxiety-like behavior disappeared and depression-like behavior developed. Interestingly, we found a reduction in synaptic density and plasticity in prefrontal cortex (PFC) of SD rats at PND33 and PND90 as compared to control rats. The protein level of the stress response phosphatase (MKP1), was upregulated while the protein level of the neurotrophic factor (BDNF) was down-regulated in PFC of SD rats. The results suggest that PND 19-32 in rats (2-11 years in humans), is a sensitive period to SD. Sleep deprivation during this developmental stage alters cortical maturation most likely by reducing synaptic density and plasticity contributing to the behavioral deficits.Item Behavioral and Biochemical Consequences of Simulated Vehicle Exhaust Exposure in Rats(2017-08) Salvi, Ankita Abhay; Salim, Samina; Eikenburg, Douglas C.; Bond, Richard A.; Rappenglueck, Bernhard; Kaphalia, Bhupendra SinghAir pollution is one of the most serious environmental threats to mankind. According to a report by the World Health Organization, urban air pollutants, specifically gasoline and diesel emissions from internal combustion engines of automobiles, trucks, locomotives and ships, contribute to a wide range of adverse health effects including cardiovascular, respiratory and neurological complications. While there has been a significant amount of research on the effect of vehicle exhaust exposure on heart and lungs, and some surveys have reported occurrence of mental co-morbidities with air pollution; adverse effects of exhaust emissions on the brain and its psychological impact, has been largely ignored. Interestingly, gaseous constituents of vehicle exhaust, namely, carbon dioxide (CO2), carbon monoxide (CO) and nitrogen dioxide (NO2), are pro-oxidants in nature. This is important considering the recently established causal link between oxidative stress in the brain and behavioral and cognitive impairments. Our postulation is that pro-oxidants in vehicle exhaust potentially increase oxidative stress in the brain damaging neuronal circuits and networks that modulate behavior and cognition. Therefore, we believe that it is critical to examine whether chronic exposure to vehicle exhaust emissions elevates oxidative stress and compromises our psychological health. In this project, we examined the neurobiological effect of prolonged exposure to pro-oxidant constituents of vehicle exhaust in rats using a simulated vehicle exhaust exposure (SVEE) model. We hypothesized that sub-chronic and chronic exposure to simulated exhaust leads to increased oxidative stress in the brain eventually resulting in behavioral and cognitive deficits. Our second hypothesis was that interventions that attenuate oxidative stress such as mitochondria-targeted antioxidant, Mito-Q prevent SVEE-induced increase in oxidative stress and consequently prevent occurrence of behavioral and cognitive deficits. First, we developed a model using adult male Sprague Dawley (SD) rats and utilized a simulated mixture of vehicle exhaust comprising of pro-oxidant exhaust constituents, namely, carbon dioxide (13%), carbon monoxide (0.68%) and nitrogen dioxide (1000 ppm) in air. Rats were exposed either to a high dose with brief duration (1:10 dilution {CO2: 1.3%, CO: 0.068%, NO2: 100 ppm}, 30 min/day) or low dose with prolonged duration (~1:1000 dilution {CO2: 0.04%, CO: 3 ppm, NO2: 0.9 ppm}, 5 h/day) of simulated exhaust in separate experiments for a duration of 2 weeks (sub-chronic) or 6 weeks (chronic). Durations of exposures were 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, a comprehensive behavioral and cognitive analysis was performed to assess anxiety- and depression-like behavior, as well as cognitive function and intelligence quotient (IQ) in rats. Later, rats were sacrificed for biochemical analysis to determine the effect of SVEE on oxidative stress and oxidative stress-associated pathways such as mitochondrial impairment. It was revealed that at both sub-chronic and chronic level of high dose-brief and low dose-prolonged duration SVEE, exposed rats exhibited an increased anxiety-like, depression-like behavior, impaired memory and lowered IQ. At the biochemical level, SVEE led to increase in oxidative stress in specific regions of the brain including pre-frontal cortex, hippocampus and amygdala as indicated by increased level of oxidative stress markers and reduced antioxidant function. SVEE-induced oxidative stress also led to mitochondrial impairment in the form of lowered oxygen consumption, suppressed ATP synthesis and alteration in mitochondrial fission/fusion. In order to test the second hypothesis that antioxidant interventions have a protective role in preventing SVEE-induced impairments, SD rats were pre-treated with Mito-Q/ drinking water for 4 weeks prior to SVEE following which behavioral and biochemical analysis were performed. It was revealed that Mito-Q treated rats were protected from SVEE-induced increased anxiety- and depression-like behavior. Mito-Q also prevented learning-memory and IQ impairment. This protective effect of Mito-Q was extended at the molecular level where it prevented SVEE-induced increased oxidative stress levels in the three brain regions. Mito-Q pre-treated rats were also protected from SVEE-induced mitochondrial impairment. In summary, our study suggests that prolonged exposure to pro-oxidant constituents of vehicle exhaust emissions is associated with behavioral and cognitive deficits. Targeted antioxidant intervention such as Mito-Q seem to be protective against vehicle exhaust-induced deficits at behavior, cognitive as well as at molecular level. This suggests that exhaust emissions most likely cause excessive generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the emotion and cognition regulating brain regions. This buildup of oxidative stress adversely affects neuronal circuitry leading to the development of an altered behavioral and cognitive phenotype. This is the first preclinical evidence suggesting negative neurobiological impact of pro-oxidant constituents of vehicle exhaust emissions, a finding highly relevant to human populations exposed to high vehicular traffic. Furthermore, our study provides a novel and innovative model that can not only be used to study behavioral and psychological effects of a variety of laboratory simulations but it can also be used to probe underlying neurobiological mechanisms.Item Behavioral, Cognitive, and Biochemical Consequences of Early Life Stress in Later Life: Insights from an Animal Model(2017-12) Liu, Hesong; Salim, Samina; Eikenburg, Douglas C.; Hurd, Yasmin; Eriksen, Jason; Bawa-Khalfe, TasneemAdverse experiences during early life contribute to the development of psychiatric conditions in later life. In fact, young children who directly experience or witness traumatic event(s) during early life, a sensitive developmental period, are considered highly vulnerable to psychiatric disorders during adult life. Interestingly, not all children who experience traumatic events are equally at risk of developing later life psychiatric disorders. Some are resilient despite being exposed to the same risk factors, while others are susceptible. The relationship between early life trauma exposure and development of later life psychiatric symptoms is not fully understood, and the mechanistic basis for resilience is also not clear. Clinical and preclinical studies have suggested that defects in stress-adaptive mechanisms potentially contribute to etiology of later life psychiatric conditions. Preclinical data from our laboratory has indicated poor oxidative/antioxidative balance as a critical component of maladaptive stress responsiveness in rodents. Our published work has demonstrated that induction of psychological stress leads to behavioral and cognitive deficits in rats. These impairments correlate with an increase in oxidative stress markers in the periphery as well as in selected regions of the brain including the hippocampus, amygdala, and the prefrontal cortex. Moreover, heightened oxidative stress was associated with decreased levels of key antioxidant enzymes. It seems like that early life stress causes behavioral and cognitive deficits via an oxidative stress-mediated weakening of neuronal connections. The central hypothesis of this Dissertation is that the ability to acquire susceptibility or resistance to stress-induced behavioral and cognitive deficits resides in oxidative-antioxidative balance within the CNS. This balance is maintained by transcriptional and epigenetic mechanisms. Therefore, our long-term goal is to investigate a) the role of early life stress on behavior and cognition across different ages in rats, b) reveal resilience and susceptible phenotypes and c) to identify the role of oxidative mechanisms in the regulation of behavioral and cognitive function and resilience. We propose to utilize a comprehensive approach to address our goals. In Aim 1, the effect of induction of early life trauma was examined using a rat model of early-life stress on later life behaviors. Sprague Dawley (SD) rats were exposed to single prolonged stress (SPS) at postnatal day (PND) 25. Behavior tests to assess anxiety-like behavior, depression-like behavior, and learning and memory function were performed at different stages of development during PND 32, 60 and 90. Resilience and susceptibility phenotypes also were examined. In Aim 2 we examined the effect of early life stress on oxidative stress mechanisms as well as transcriptional and epigenetic regulation of specific genes that presumably control antioxidative capacity. We focused explicitly on Keap1-Nrf2 and NF-κB pathway. SD rats were exposed to SPS at PND25. One group of rats were sacrificed at PND32, the other group of rats was sacrificed at PND90. Blood was collected, and plasma was used to examine systemic markers of oxidative stress and physiological stress. Brains were harvested, and specific brain areas were isolated, and homogenates were prepared for conducting biochemical analysis to determine the effect of early life SPS on oxidative-antioxidant balance, and activation of redox-sensitive pathways such as Nrf2 and NF-κB pathways. Studies proposed in aim 1 revealed that rats exposed to SPS exhibited both anxiety- and depression-like behavior at PND32. Moreover, 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. At the biochemical level, SPS exposure at PND25 led to an increase in oxidative stress in specific regions of the brain (pre-frontal cortex), as indicated by the increased level of oxidative stress marker at PND32 and PND90. SPS exposure at PND25 also led to an initial increase in antioxidant enzyme expression at PND32 and a decrease in antioxidant enzyme expression at PND90. The increase in oxidative stress and the decrease in antioxidant enzymes at PND90 correlates with the depressive phenotypes in SPS rats at PND90. Further biochemical studies revealed a state of a compromised Nrf2 pathway and activated NF-κB pathway in the pre-frontal cortex (PFC) homogenates. The state of compromised Nrf2 pathway and activated NF-κB pathway was indicated by a decrease in the levels of Nrf2 and increased levels of NF-κB, as well as NF-κB-mediated increased levels of interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) in PFC. In summary, 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 a demonstration of anxiety- but not depression-like behavior. Later, depression but not the anxiety-like behavior was observed at PND90. It seems that behavioral adaptations occur at the critical PND60 stage (mimics human late-adolescent period) (Sengupta 2013), where behavioral and cognitive switching occurs, thereby, expressing susceptible and resilient phenotypes. Moreover, susceptible phenotype correlates with an increase in oxidative stress and a decrease in antioxidant enzymes in the emotion-regulating brain region of the PFC. The correlation between susceptible phenotype and increased oxidative stress markers suggests that the early life stress causes a buildup of oxidative stress, which negatively affects neuronal circuitry that contributes to depressive phenotypes. The increase in oxidative stress induced by early life stress activates NF-κB pathway, which triggers cellular inflammatory responses.Item Breast Cancer Awareness, Screening Attitudes, and Biochemical Profile in a Sample of Houston-Based Afghan Refugee Women(2023-04-13) Zamil, JennaBackground: Breast cancer is the second-leading cause of cancer death in US women, and Afghan women exhibit low screening rates. Our study evaluates breast cancer awareness and risk among Afghan refugee women in Houston through demographic survey data and biochemical measurement of inflammatory markers associated with chronic stress and breast cancer risk, C-reactive protein (CRP), cortisol, and interleukin-6. Methods: Houston-based 501(C)(3) non-profit organizations assisted with recruitment of Afghan refugee women (n=67), who answered these psychometrically valid online surveys with language and culturally tailored versions: Self-Report Questionnaire (SRQ), Afghan Symptom Checklist (ASC), Perceived Stress Scale (PSS), Refugee Post-Migration Stress Scale (RPMSS), and Breast Cancer Screening Beliefs Questionnaire (BCSBQ) assessing general well-being, mental health, stress levels, and breast cancer awareness via REDCap ($25 Target gift card compensation). Descriptive statistics and correlation analysis between Demographics, ASC, RPMS, and BCSBQ responses were evaluated. Saliva samples were deidentified before inflammatory marker examination using commercially available kits (Salimetrics, USA). Results: ASC scores correlated with many factors including time spent in the US, perceived discrimination, and economic strain (p<0.05). Women exhibited low attitude toward general health checkups, limited breast cancer knowledge, and high barriers toward mammogram screening (BCSBQ). Approximately half and 71.4% reported not knowing about clinical-breast examinations and mammograms, respectively. Conclusions: High stress levels, determined through ASC and RPMS, in susceptible Afghan women correlated with elevated CRP and IL-6 levels. Targeted interventions into stress reduction and breast cancer awareness for Afghan refugee women are warranted.Item CHRONIC STRESS REVEALS COGNITIVE IMPAIRMENT IN A SUBTHRESHOLD AMYLOID-BETA MODEL OF ALZHEIMER’S DISEASE(2010-05) Tran, Trinh T. 1982-; Alkadhi, Karim A.; De Biasi, Mariella; Lau, Yuen-Sum; Rea, Michael A.; Salim, SaminaAlthough it is generally accepted that Aβ contributes to the pathogenesis of Alzheimer's disease (AD), other factors that impact the severity and time of onset of the disease are not well known. Aside from genetic factors, environmental factors, such as stress, may also play a critical role in the manifestation of AD. Epidemiological studies indicate that individuals suffering from chronic stress are at an increased risk for developing AD. The present study investigated the effect of chronic psychosocial stress in an at-risk, subthreshold Aβ (subAβ) rat model of AD by three techniques: learning and memory tests in the radial arm water maze, electrophysiological recordings of long-term potentiation (LTP) and long-term depression (LTD) in anesthetized rats, and immunoblot analyses of learning- and memory-related signaling and AD-related molecules. Chronic psychosocial stress was induced using a rat intruder model. The subAβ rat model of AD was induced by continuous i.c.v. infusion of 160 pmol/day Aβ1-42 via a 14-day mini-osmotic pump. Behavioral tests, electrophysiological recordings, and molecular analyses showed that subAβ rats were not significantly different from control rats, thus validating this model as an at-risk model of AD without phenotypic characteristics or cognitive deficits commonly associated with AD. However, chronically stressed subAβ-infused rats showed significantly greater impairment of cognitive functions and synaptic plasticity than that caused by stress alone. Molecular analyses of essential signaling molecules showed that animals subjected to stress have reduced basal levels of p-CaMKII, decreased p-CaMKII/CaMKII ratio, and increased basal levels of calcineurin. The infusion of subAβ into the cerebral ventricle of chronically stressed rats also decreased basal levels of p-CREB, total CREB and BDNF and increased basal levels of BACE. Furthermore, multiple high frequency stimulation failed to increase levels of p-CREB and BDNF during the late-phase of long-term potentiation. However, paired pulse stimulation produced a decrease in levels of BDNF during long-term depression in the stress/subAβ animals. Together, the results of our behavioral, electrophysiological, and molecular studies suggest that prior and concomitant exposure of subAβ-infused rats to chronic stress intensify the severity of stress-induced cognitive and synaptic plasticity deficits. Thus, chronic stress may accelerate the impairment of learning, memory, and synaptic plasticity in individuals “at-risk” for AD.Item Effects of Regulating Rac1 in a Mouse Model of Fragile X Syndrome(2016-08) Martinez, Luis A.; Tejada-Simon, Maria V.; Eriksen, Jason; Salim, Samina; Leasure, J. Leigh; Ziburkus, JokubasAutism is a complex neurodevelopmental disorder characterized by social deficits, communication and language impairments, and restricted or stereotyped patterns of behavior. Intellectual disability (ID), reported in nearly 70% of those with autism, is a pervasive co-morbidity that exacerbates cognitive functions and impedes behavioral development. The most effective treatment for autism and ID are behavior-based interventions such as Applied Behavior Analysis (ABA) that require rigorous training methodologies. Furthermore, treatment must be started early and must be continuous and consistent for optimal efficiency. The high cost of behavior therapies and demanding schedule often precludes a successful outcome. Over the years, studies have revealed structural and functional synaptic impairments in autism and ID in areas important for cognitive functions such as learning and memory formation. The observation in these learning disabilities that repeated training can overcome cognitive deficiencies suggests that mechanisms of learning and memory are not entirely defective. Autism and ID have been found to share dysregulation of molecular signaling cascades involved in synaptogenesis, spinogenesis and synaptic plasticity. The structural integrity of synapses and dendritic spines within those synapses relies on the underlying actin cytoskeleton. Examination of post-mortem brain tissue of autistic individuals reveals not just an unusually high number of dendritic spines but a high density of immature spines. Post-mortem brain tissue also exhibits high levels of the small Rho GTPase Rac1, a well-recognized regulator of actin dynamics at the synapse. The integral role of Rac1 in dendritic spine development, synaptic plasticity, and learning and memory has been extensively studied. Together these studies present Rac1 as an intriguing target in the treatment of cognitive deficits associated with autism and ID. Herein, we studied whether regulation of Rac1 might represent a promising treatment for cognitive impairment in autism, using Fragile X syndrome (FXS) as a model. FXS is the leading single gene cause of autism and ID. Neurons express a high density of underdeveloped dendritic spines in FXS humans and animal models. Synaptic plasticity deficits are prevalent throughout the brains of FXS mouse models including the cortex and hippocampus, areas critical for various forms of learning and memory. Moderate to severe learning deficiencies are also characteristic in FXS patients and is paralleled in mouse models. Therefore, FXS is an ideal model in the clinical and laboratory setting to investigate therapies aimed at autism and ID. In FXS mouse models, hyperactive Rac1 has been demonstrated in hippocampus and cortex where dendritic spine abnormalities are a common feature. Our results show that in the Fmr1 KO mice (an animal model of FXS) deficits in memory and synaptic plasticity are associated with the presence and localization of Rac1. Furthermore, treatment of Fmr1 KO mice with a specific Rac1 inhibitor improves memory and increases hippocampal LTP. Taken together these observations show that Rac1 may contribute to FXS related learning and memory impairments in humans. Importantly, this study suggests that targeting Rac1 in FXS may rescue cognitive impairments. Such a therapy may be translated into broader applications in autism and ID.Item Human Signaling Scaffold Protein (mAKAP) Polymorphisms: Role in Heart Failure(2013-05) Rababa'H, Abeer 1981-; McConnell, Bradley K.; Salim, Samina; Hussain, Tahir; Hwa, John; Gunaratne, Preethi H.; Tikunova, Svetlana B.Protein kinase-A (PKA) substrate phosphorylation is facilitated through its co-localization with its signaling partner by A-kinase anchoring proteins (AKAPs). mAKAP (muscle-selective AKAP) localizes PKA and its substrates such as phosphodiesterase-4D3 (PDE4D3), ryanodine receptor and protein phosphatase (PP2A) to the cardiomyocytes sarcoplasmic reticulum and perinuclear space. We have recently identified potentially important human mAKAP coding non-synonymous polymorphisms located within or near key protein binding sites critical to β-adrenergic receptor signaling. Three mutations (P1400S, S2195F and L717V) were cloned and transfected into a mammalian cell line for the purpose of comparing whether those substitutions disrupt mAKAP binding to both the PKA or PDE4D3 binding domain and understanding their role in altered signaling. Our immunopreciptation study of mAKAP-P1400S, a mutation in the mAKAP-PDE4D3 binding site, displayed a significant reduction in binding affinity to PDE4D3 after stimulation, with no significant change in PKA binding and activity. Conversely, mAKAP-S2195F, a mutation located in mAKAP-PP2A binding site and flanking PKA-RII binding domain, showed significant increase in both binding affinity to PKA as well as PKA activity. Although, mAKAP-L717V (a mutation flanking the mAKAP-spectrin repeat domain) exhibited an enhanced binding propensity to PKA, it showed similar pattern of PKA activity as the wild-type mAKAP. All three mutations have similar total phosphodiesterase enzyme activity. Binding results were quantified using surface plasmon resonance (Biacore-2000). We demonstrated specific binding of wild-type mAKAP to PDE4D3. Additionally, human mAKAP mutants S2195F and L717V displayed increased expression for downstream PKA substrates and hypertrophic markers such as CREB and calcineurin. These data suggest that S2195F or L717V-mAKAP may enhance cardiac hypertrophy through persistent binding of mAKAP to PKA. Furthermore, these mutants increased the phosphorylation of ERK5 compared to the wild-type mAKAP suggesting that mAKAP also orchestrates the cross-talk of mitogen activated protein kinase (MAPK) signaling pathway with cAMP/PKA signaling pathways. Generally, PKA-PDE4D3-mAKAP complexes exemplify how protein kinases and phosphodiesterase may contribute in molecular signaling to dynamically normalize localized intracellular signaling. Consequently, comparative analysis of the binding responses of mutations to mAKAP could provide important information about how these mutations modulate signaling.Item Mechanistic Role of Human mAKAP Polymorphisms in Cardiovascular Diseases(2017-12) Suryavanshi, Santosh; McConnell, Bradley K.; Bond, Richard A.; Salim, Samina; Dauwalder, Brigitte; Chatterjee, Sujash S.Cardiovascular diseases (CVDs) are the no. 1 cause of deaths in the world. CVDs can affect any individual irrespective of his/her age and gender. Despite the continuous improvement in the clinical research, there is no reduction in a number of deaths and/or hospitalizations from CVDs. We believe that comprehensive understanding of basic cardiac signaling is crucial in finding new therapeutic targets for CVDs. One of such vital cardiac signaling pathways is cAMP-dependent PKA signal transduction which is tempered by a family of scaffolding proteins called A-kinase anchoring proteins. By anchoring key enzymes along with their upstream and downstream signaling partners, AKAPs create order in intracellular signal transduction. Heart-specific muscle AKAP (mAKAP, AKAP6, AKAP100) controls cyclic AMP / PKA signals downstream by binding to PKA, PDE4D3, and PP2A. mAKAP is a master scaffold that governs cardiac hypertrophic pathways. SNPs in different genes encoding essential cardiac proteins have been proven to increase the risk of CVDs in humans. Polymorphic analysis of disease-causing human mAKAP has been unexplored so far. The goal of this work is to study human mAKAP SNPs found in CVDs databases (S1653R and E2124G). We performed immunoprecipitation analysis to see whether SNPs affect binding of mAKAP to PKA, PDE4D3, and PP2A. In immunoprecipitation studies, S1653R mutant exhibited increased binding with PDE4D3 at baseline but significantly reduced binding after stimulation as compared to WT. E2124G mutant displayed significantly lower PKA binding at baseline and higher binding after stimulation. Both the mutants show no change in binding with PP2A as compared to WT. Intracellular cAMP was significantly lower at baseline but higher after stimulation in S1653R mutant cells as compared to the WT. PKA activity assay revealed identical results for the S1653R mutant. E2124G expressed cells showed no change in cAMP levels. PKA activity was significantly lower at baseline but the sharp increase was observed after stimulation. PDE activity assay showed significantly higher activity in S1653R mutant before stimulation which was considerably lowered after stimulation as compared to WT. E2124G mutant showed similar changes as WT with respect to PDE activity. Immunoblotting revealed altered expression of PKA-mediated hypertrophic markers in mAKAP mutants. Notably, E2124G mutant also showed increased intracellular calcium after stimulation as compared with WT in red fluorescence quantification assay. In summary, human mAKAP SNPs might predispose individuals to the risk of developing CVDs by altering AKAP-PKA signaling and affecting cAMP and/or calcium dynamics. mAKAP can be further targeted as a candidate gene for identifying disease-causing SNPs in CVDs.Item MeCP2 Transgenic Mouse as A New Disease Model for Neuropsychiatric Lupus(2021-05) Li, Yaxi; Wu, Tianfu; Mohan, Chandra; Shevkoplyas, Sergey S.; Zhang, Yingchun; Salim, SaminaNeuropsychiatric lupus (NPSLE) impacts a large cohort of lupus patients and is an important driver of disease morbidity and mortality. The complexity and heterogeneity of clinical presentations impede the investigation of disease etiology directly in patients. Several mouse models have been used for the NPSLE study, however, there is no unifying model to fully represent the disease pathogenesis yet. This study aims to determine whether C57BL/6 mice transgenic for human MeCP2 (B6.MECP2Tg1) could serve as a new mouse model for NPSLE, which could be used for uncovering disease mechanisms and the identification of novel therapeutic targets. First, we found MeCP2 protein expression level was significantly increased in the brain and spleen in a spontaneous lupus mouse model MRL/lpr as well as a female B6.MECP2Tg1 mice, when compared to B6. In addition, the B6.MECP2Tg1 transgenic mice exhibited elevated proteinuria, and increased autoantibody production including total IgG, IgG anti-dsDNA antibody and other autoantibodies as revealed by an autoantigen array. Furthermore, immunofluorescence analysis revealed that IgG deposition and macrophage infiltration were more severe in the kidney of female B6.MECP2Tg1 compared to B6. Interestingly, the effector memory T cells, activated germinal center B cells and plasma B cells were markedly increased in the female B6.MeCP2Tg1 mice. In the neuropsychiatric aspects, B6.MECP2Tg1 mice exhibited anxiety and depression-like behavior, as well as cognitive disorders at young age. These abnormal behaviors may be explained by the altered neurogenesis and inflammation in the hippocampus, immune cell infiltration in the choroid plexus, as well as the disrupted blood-brain barrier (BBB) and activated microglia, as demonstrated by immunofluorescence microscopy. Collectively, this work demonstrates that B6.MECP2Tg1 mice exhibit lupus-like phenotypes as well as clear CNS dysfunctions, suggesting it may represent a new animal model for NPSLE.Item NEURAL CORRELATES OF EMOTION REGULATION IN A SAMPLE OF SYRIAN REFUGEE CHILDREN: AN ERP STUDY(2022-08-11) Mohamad, HanaIntroduction: The Syrian War led to millions of displaced families all around the world. A large portion of those refugees were children, who had to grow up abroad. The United States opened its doors to Syrian refugees, many of which resettled in Texas. As a result, many of these families, including the children, suffer challenges that may include depression and post-traumatic stress disorder. This study focuses on differences in regulation of emotions in these refugee children, whether they have symptoms of post-traumatic stress disorder (PTSD), and if they show resilience. Methods: Using a multi-method approach, the study consisted of the Emotion Regulation Task that measures event-related potentials (ERP) from an electroencephalograph (EEG) reading, and two surveys. The Emotion Regulation Task consists of three trial conditions (while measuring the ERP): look-neutral, look-negative, and decrease-negative. One survey is the Children’s Impact of Event Scale 13 measure (CRIES-13), which assesses the children for symptoms of PTSD, and the Child and Youth Resilience Measure (CYRM-R) which measures resiliency. Results: Age has a significant correlation with condition for the area under the curve (F (2,22) =4.02, p=.03). Repeated measures analysis of variance (ANOVA) with ERP trials conditions within-subject factors and max value as the outcome approached significance (F (2,24) = 2.80, p=.08). No other variables were significant. Discussion: The main significant effect was between age and condition, which indicated that the participants reacted differently, or had different abilities in regulating emotion when interacting with the various tasks due to age. Further research is to be conducted with a larger sample, language modifications, and stricter age classifications among others.Item Providing Enrichment for Syrian Refugee Adolescents in the Greater Houston Area(2021-04-01) Akbar, Zain; Al-Rousan, Ghalya; Atrooz, Fatin; Salim, SaminaAccording to data provided by the United Nations High Commission for Refugees, Syrians are the largest forcibly displaced population in the world with over 13 million people being displaced, 50% of whom are children. An estimated 130 Syrian refugee families with children live in the Houston area. The Syrian refugee children endure extreme amounts of stress in their lives and often face depression, PTSD, generalized anxiety, and traumatic grief as a result. These children further experience the stress of assimilating into the American school system. We reached out to Syrian refugee families in the area through a Houston-based 501(C)(3) non-profit organization, IMPACTs, which facilitates resettlement of Syrian refugees in the Houston area, to gauge their interest in our pilot program. 13 children from 5 families agreed to participate in this project. We grouped the children according to their school grade level (elementary, junior high, and high school). Our goal though this project was to provide an enrichment program for Syrian refugee children to help improve their academic performance and social skills by offering online mentorship once a week, including tutoring of English and STEM subjects and game nights (Kahoot, Scribble.io). In a survey offered by us, the parents were asked to provide feedback on the tutoring sessions offered over a period of 2 months (10 sessions), in which they reported improvement in their children’s academic well-being and communication skills and expressed satisfaction with the program and its positive impact on their child.Item Regular treadmill exercise prevents sleep deprivation-induced impairment of hippocampal-dependent memory and synaptic plasticity(2011-08) Zagaar, Munder; Alkadhi, Karim A.; Eriksen, Jason; Salim, Samina; Grill, Raymond J.; Alcantara, Adriana A.Study Objectives: Evidence suggests that regular exercise can protect against learning and memory impairment in the presence of insults such as stroke and neurodegeneration. The purpose of this study was to determine the effect of regular exercise on hippocampus-dependent learning and memory impairment associated with sleep deprivation. Experimental Design: We investigated the effects of 4 weeks of regular treadmill exercise on learning and memory impairment in 24 hour sleep-deprived rats. Sleep deprivation was accomplished using the columns-in-water model. We tested the effects of exercise and/or sleep deprivation using three approaches: the radial arm water maze (RAWM) task to test spatial learning and memory performance; electrophysiological recording in the Cornu Ammonis (CA1) and dentate gyrus (DG) areas of the hippocampus to measure synaptic plasticity; and western blot analysis to quantify the levels of key signaling molecules that are related to memory and synaptic plasticity. Results: In the RAWM, regular exercise prevented the sleep deprivation-induced impairment of spatial learning, short-term memory, and early-phase long-term potentiation (E-LTP) in both CA1 and DG areas. In correlation, exercise prevented the sleep deprivation-associated decrease in basal levels of phosphorylated and total calcium/calmodulin-dependent protein kinase II (P/total-CaMKII) and brain-derived neurotrophic factor (BDNF). High frequency stimulation (HFS), which increased the P-CaMKII and BDNF levels in normal animals, did not change these levels in sleep-deprived rats but did increase levels of the phosphatase calcineurin. In contrast, exercise increased BDNF and P-CaMKII levels in exercised/sleep-deprived rats, probably by preventing increases in calcineurin levels, thus maintaining appropriate P-CaMKII levels. Regular exercise also prevented the sleep deprivation-induced impairment of long-term memory and late-phase LTP. In correlation, exercise increased the basal levels of phosphorylated cAMP response element binding protein (P-CREB) and total-CREB as well as P/total- mitogen activated protein kinase (MAPK/ERK) in CA1 and DG areas of sleep-deprived rats. Also, exercise allowed multiple HFS to increase the levels of BDNF and P/total-CREB during L-LTP expression in sleep-deprived rats. Conclusions: These findings suggest that sleep deprivation impairs both the CA1 and DG areas whereas exercise prevents this impairment. Regular exercise exerts a protective effect against sleep deprivation-induced impairment probably by inducing BDNF expression, which can positively modulate basal and/or stimulated levels of P-CaMKII, P-CREB, P-MAPK/ERK and calcineurin. As a result, exercise-induced BDNF could contribute to the restoration of hippocampus-dependent learning and memory as well as LTP in both CA1 and DG areas.Item Role of Angiotensin II Type 2 Receptor in Blood Pressure Regulation in Obese rats(2011-05) Ali, Quaisar; Hussain, Tahir; Lokhandwala, Mustafa F.; Eikenburg, Douglas C.; Bryan, Robert; Doris, Peter A.; Salim, SaminaRenin angiotensin system (RAS) consists of enzymes, hormones, proteins and peptides. Angiotensin II (Ang II) is an important peptide of RAS. Ang II acts via AT1 receptor (AT1R) and AT2 receptor (AT2R). While AT1R is known to cause antinatriuresis and increase in blood pressure, the role of AT2R in renal function and long-term BP regulation is not well defined. Recently our laboratory showed that AT2R are upregulated in the kidney of obese rats and selective activation of these receptors stimulates nitric oxide/cGMP pathway, inhibits proximal tubules Na+/K+-ATPase (NKA) activity and increases urinary sodium excretion. In light of those findings, we undertook this project to investigate the role of AT2R in renal function, long-term blood pressure control and interaction with renal AT1R function in obese Zucker rats, an animal model exhibiting hyperinsulinemia, hyperglycemia and hypertension. Also, we studied the mechanism associated with hyperglycemia induced AT2R upregulation in proximal tubule cells. First, we designed experiment to determine whether AT2R has a protective role in blood pressure increase in obese rats. We treated obese Zucker rats with AT2R antagonist PD123319 (PD) for two weeks and BP was measured. Treatment with PD significantly increased the blood pressure, which was associated with increased renal renin expression in obese rats. This suggested that AT2R protect against increase in blood pressure by keeping renal renin expression low. Then, we designed experiments to determine whether chronic AT2R activation affects Na-balance and lowers BP in obese rats. We treated lean and obese Zucker rats with AT2R agonist CGP42112A (CGP) for two weeks. Two weeks treatment caused a decrease in BP by 19 mmHg and in Na-balance in obese but not in lean rats. The plasma renin activity was significantly decreased in both lean and obese CGP-treated rats. The expression of AT2R, AT1R, angiotensin converting enzyme (ACE) and renin in the kidney cortex was not affected by the CGP-treatment of obese or lean rats. However, ACE2 expression and activity was significantly increased in CGP-treated obese rats and not in lean rats. These studies suggest that long-term activation of AT2R decreases BP in obese rats. The reduction in BP by AT2R agonist treatment may have been contributed by a decrease in Na-balance and an enhanced expression and activity of ACE2 in renal cortex. In order to determine whether the reduction in BP and decrease in Na-balance might have been contributed by the ability of AT2R to antagonize renal AT1R function in CGP-treated obese rats, we again treated the obese Zucker rats with CGP for two weeks. We performed the renal function study after two weeks under anesthesia. We found that CGP-treatment of obese rats caused reduction in Ang II pressor response and blunted the candesartan-induced natriuresis/diuresis in these rats suggesting that chronic activation of AT2R antagonizes the function of AT1R. Earlier studies from our laboratory suggest that AT2R promote Na-excretion but the contribution of different nephron segments in AT2R-induced natriuresis is not known. We investigated the involvement of proximal tubule AT2R in natriuresis by blocking the two important distal tubule Na-transporters (NaCl cotransporter and ENaC). We found that selective activation of AT2R with a novel AT2R agonist C21 promoted natriuresis predominantly via proximal tubules. We also performed in vitro experiments (HK2 cells) to elucidate the potential signaling mechanism involved in the proximal tubule AT2R upregulation in diabetes/hyperglycemia. In this experiment, we exposed HK2 cells with high glucose with and without IRF-1 siRNA. High glucose increased AT2R expression in HK2 cells and is mediated via transcriptional mechanism involving the transcription factor IRF-1. Collectively, the data suggest that long-term treatment with AT2R agonist attenuates positive Na-balance, lowers renal renin expression, antagonizes the function of AT1R and decreases blood pressure in obese Zucker rats. Moreover AT2R upregulation in response to hyperglycemia may be compensatory mechanism to exert a beneficial role in kidney function. These findings highlight the therapeutic potential of AT2R for treating obesity/diabetes related hypertension.Item Role of Angiotensin II Type 2 Receptor in Regulation of Lipid Metabolism and Adiposity(2013-12) Nag, Sourashish; Hussain, Tahir; Mani, Shailaja K.; Clarke, Mark S. F.; Knoll, Brian J.; Salim, SaminaObesity is becoming increasingly common in the United States and worldwide. Abundant supplies of cheap foods and sedentary life styles are predisposing human beings to obesity which is an underlying risk factor for metabolic syndrome and cardiovascular diseases. Adipose tissue is the obligatory site of fat accumulation which causes obesity. Moreover, adipose tissue expresses local renin angiotensin system (RAS) which has been implicated in obesity. Recent studies using angiotensin type 2 receptor (AT2R) knockout mice suggested that AT2R contributes to adiposity and obesity in male mice while prevents adiposity and obesity in female mice. On the other hand, deficiency of AT2R in Apolipoprotein E knockout mice (a model of atherosclerosis) exaggerated adiposity in male mice suggesting that AT2R prevents adiposity in this animal model. Thus, role of AT2R on adiposity in knockout studies was in-conclusive and also indicated a gender specific role of AT2R. Furthermore, the studies showed that the relative expression of AT2R deceases after birth through adolescence and adulthood. Also, there are reports suggesting that estrogen (E2) positively regulates AT2R expression and AT2R affects levels of urinary E2 which is known regulator of adiposity. Hence, we designed the present study to investigate the effect of pharmacological activation of AT2R on adiposity and to study whether the said effect is reduced at adolescence. Male C57BL/6 mice (5 and 12 weeks old) were pretreated with the AT2R agonist C21 (0.3 mg/kg, daily i.p.) for 4 days. Thereafter the animals were placed on normal chow diet (ND) or high-fat diet (HFD) with concurrent drug treatment for the next 10 days. The HFD significantly increased epididymal WAT (eWAT) weight, adipocyte size, plasma free fatty acid (FFA) and triglyceride (TAG) in these mice. The pharmacological activation of AT2R reduced the HFD-induced increase in eWAT weight, adipocyte size, plasma FFA and TAG. Thus, we observed that the pharmacological activation of AT2R reduced the HFD-induced adiposity and plasma parameters in male mice, both in young and adults. To explore the effects of C21 on lipid metabolism we investigated the adipose lipid metabolism (lipogenic and lipolytic) regulators in the eWAT of 5 weeks old male mice only. We observed that HFD increased the protein expressions (measured by western blot) of eWAT lipogenic regulators, namely adipose fatty acid binding protein (FABP4) and fatty acid synthase (FASN). On the other hand, HFD caused a decrease in the protein expression of eWAT adipose triglyceride lipase (ATGL) and an increase in hormone-sensitive lipase (HSL) protein expression 5 weeks old male mice. Interestingly, C21 treatment altered HFD-induced changes in lipogenic and lipolytic regulators. To explore further whether C21 directly impacts eWAT lipogenic/lipolytic regulators or impacts them due to its effect on fatty acid uptake in adipocytes, we performed an in vitro study using isolated primary epididymal adipocytes from 5 weeks old male mice. We observed that C21 acting on epididymal adipocyte AT2R via a NOS/GC/PKG-dependent pathway reduced fatty acid transport in adipocytes. Thus, pharmacological activation of AT2R reduced the fatty acid transport in adipocytes and possibly in consequence prevented HFD-induced adiposity in the male mice. Our studies with AT2R knock out female mice demonstrated that genetic deletion of AT2R causes an increase in adiposity with a parallel decrease in urinary E2 in female mice. Thus to explore whether the pharmacological activation of AT2R using C21 prevents adiposity in female mice and whether the E2 plays a role in C21-mediated effect on adiposity, female C57BL/6 ovary-intact (Ovi) and ovariectomized (Ovx) mice were used. These mice were treated with C21 (0.3 mg/kg, daily i.p.) with(out) E2 (5 µg/day) supplementation and placed on HFD for 10 days. We observed that the C21 treatment prevented the HFD-induced adiposity and plasma parameters, namely FFA, TAG and insulin in female mice independent of E2. In the liver, C21 treatment increased the CPT1A expression (an index of β-oxidation) and prevented liver weight increase under HFD. Interestingly, we also observed that C21 treatment increased the physical activity of female mice. Thus, this study demonstrated that pharmacological activation of AT2R increased physical activity of the female mice and prevented the HFD-induced adiposity in these mice. Overall these studies demonstrate that the pharmacological activation of AT2R reduces fatty acid uptake in adipocytes. This reduction in fatty acid uptake possibly prevents HFD-induced changes in lipid metabolism, adiposity and plasma parameters in mice. Moreover, pharmacological activation of AT2R also increases physical activity which may increase utilization of the fatty acid via oxidation and thus remove fatty acid from the circulation. In light of these studies, we propose that AT2R activation may serve as a potential therapeutic target to control obesity which in turn protects against obesity-associated metabolic disorders.Item Role of Oxidative Stress in Behavioral, Cognitive and Biochemical Impairment in a Rat Model of Social Stress(2016-08) Solanki, Naimesh Natawarlal; Salim, Samina; Alkadhi, Karim A.; Eriksen, Jason; Dauwalder, Brigitte; Wood, Susan K.Psychological stress is known to contribute to anxiety and cognitive impairment in humans. Currently, the drugs of choice for treatment of anxiety disorders are traditional-antidepressants, with modest efficacy and major side effects. Therefore, alternative therapies with higher efficacy and fewer side effects are needed. Recent evidence from our lab has suggested a causal role of oxidative stress (OS) in psychological stress (social defeat)-induced behavioral and cognitive impairments in rats. Basically, psychological stress induces behavioral and cognitive deficits in rats while increasing oxidative stress systemically as well as in the brain. Increase in oxidative stress was associated with reduced systemic and cerebral antioxidant status. Imbalance in oxidant-antioxidant status seemed to have contributed to stress-induced deficits in the social defeat (SD) model. If the rise in oxidative stress causes behavioral and cognitive deficits then interventions mitigating oxidative stress by increasing antioxidant could be useful. In this study, we employed the rat model of social defeat (SD) which closely resembles societal stress in humans to determine whether increasing antioxidant level using grape powder (GP), with its rich antioxidant content, is able to protect and/or reverse SD-induced behavioral and cognitive deficits in rats. Grape powder is a mixture of a variety of antioxidants. Therefore, it is important to know which antioxidant constituent contributes to potentially protective effects of GP. This was determined in a neuronal cell culture model of HT22 cells, a hippocampal derived cell line. Finally, underlying mechanism(s) of action of GP also were determined. Sprague Dawley rats after undergoing 7 days of repeated social defeat developed significant behavioral and cognitive impairments. And, 3 weeks GP treatment (15 g/L in drinking water) protected and reversed SD-induced behavioral and cognitive deficits. Biochemical analysis revealed that GP treatment significantly decreased SD-induced increase in levels of plasma corticosterone (systemic marker of stress), and plasma 8-isoprostane (marker of OS). Furthermore, GP treatment significantly increased SD-induced decrease in cellular pool of key antioxidant enzymes such as glyoxalase-1, glutathione reducatse-1 and superoxide dismutases in specific regions of the brain including the hippocampus and amygdala. Next, utilizing an in-vitro model of oxidative stress, we examined contribution of Quercetin (Q), Resveratrol (R) and Kaempferol (K), key antioxidants present in grapes, in mediating protective effect. HT22 cells were treated with 1mM BSO (L-Buthionine-sulfoximine, pro-oxidant) for 14 hrs to induce oxidative stress. The cells were treated for 4 hrs with Q, R or K prior to BSO treatment. Q and R but not K were the most effective in protecting BSO-induced decreased total antioxidant capacity, suggesting major contribution of Q and R in protective action of grape powder. Further data suggested that GP protected oxidative stress-induced cell death by preventing oxidative stress-induced increased calcium influx, mitochondrial dysfunction and release of cytochrome c. Collectively, animal and cell culture data suggest that GP protected and reversed SD-induced behavioral and cognitive impairments in rats and, that quercetin and resveratrol appear as the most likely major contributors towards beneficial effects of GP. Finally, it seems that GP mitigates oxidative stress by increasing antioxidant pool and preventing cell damage and death.Item The Behavioral Consequences of Early Life Sleep Deprivation(2017) Atrooz, Fatin Yousef; Liu, Hesong; Kochi, Camila; Salim, SaminaSleep, especially at developmental stages of early life, is essential for normal brain function and development. Sleep deprivation at early life stages (childhood and adolescence) is associated with behavioral impairment. The relationship between early life sleep deprivation and development of later life psychiatric symptoms is not clearly understood.Item The Effect of Heterozygous Loss of Progranulin on Alzheimer's Disease(2021-08) Vollert, Craig Thomas; Eriksen, Jason; Salim, Samina; Alkadhi, Karim A.; Leasure, J. Leigh; Taglialatela, GiulioHaploinsufficient loss of progranulin (PGRN) is implicated in both frontotemporal lobar dementia (FTD) and Alzheimer’s disease (AD). Furthermore, Grn polymorphisms have been linked to various other neurodegenerative diseases suggesting PGRN plays an important role in neurodegenerative disease pathways. Although genetic studies have demonstrated that partial loss of PGRN increases the risk of AD there are conflicting reports in mouse studies examining the loss of PGRN and it is unclear how the loss of PGRN modulates AD pathophysiology. Therefore, the present study was designed to elucidate the effect of haploinsufficiency loss of PGRN on the pathophysiology of AD. To this end, we characterized a novel PGRN haploinsufficient mouse model (Grn+/-) across age. Utilizing a battery of cognitive and non-cognitive behavior tests we observed key FTD-related behavior deficits in Grn+/- mice across age in the absence of FTD-related pathology including neuroinflammation and TDP-43 proteinopathy as measured by immunohistochemical and western blot techniques. We observed functional deficits in Grn+/- mice, including impaired long-term potentiation and reduced numbers of GABAergic interneurons. Next, we investigated the role of haploinsufficiency PGRN loss on tau pathology by crossing Grn+/- mice with the P301S tau transgenic mouse model. There were slight differences in tau-related non-cognitive behavior deficits and reduced AT8 tau phosphorylation in the brain and spinal cord measured by western blot techniques. While we did not observe differences in microglial activation, we observed alterations in the Akt signaling pathway. Lastly, we investigated the role of haploinsufficiency PGRN loss on amyloid pathology by crossing Grn+/- mice with the APdE9 amyloid transgenic mouse model. We observed exacerbated deficits in AD-related cognitive and non-cognitive behavior, including worsened cognitive learning and memory and motor coordination. We also observed biochemical and morphological changes in amyloid pathology. While we did not observe differences in microglial activation, we did observe deficits in synaptic plasticity and loss of GABAergic interneurons with loss of PGRN. In summary, several conclusions can be drawn from the present study. First, heterozygous loss of global progranulin across age replicates critical frontotemporal dementia-related behavioral and functional deficits in the absence of detectable neuroinflammation. Secondly, heterozygous loss of progranulin reduces tau hyperphosphorylation in an Alzheimer’s transgenic mouse model suggesting that loss of progranulin, at least in the context of tau pathology, may be beneficial. Lastly, heterozygous loss of progranulin exacerbates Alzheimer’s disease-related behavior and amyloid-beta pathology in an Alzheimer’s transgenic mouse model, suggesting that loss of progranulin, at least in the context of amyloid pathology, may be detrimental. Our results suggest a dissociation of behavioral and functional deficits from microglial activation, suggesting an essential effect of progranulin deficiency on neurons driving key FTD-related behavioral deficits and potential underlying mechanisms. While progranulin has been suggested to be a potential therapeutic target for Alzheimer’s disease our results suggest this may not be the case due to differential effects on Alzheimer’s’ disease pathology.Item The Effects of Simulated Vehicle Exhaust Exposure on Behavior and Blood Pressure in Male and Female Rats(2020-12) Kochi, Camila Y. S.; Salim, Samina; Banday, Anees Ahmad; Eriksen, Jason; Lutfy, Kabirullah; Rappenglueck, BernhardLong-term exposure to vehicle exhaust pollution is associated with cardiovascular, respiratory and neurological problems. Understanding biological mechanisms responsible for adverse effects of vehicle pollution to human health are critical. Animal studies offer useful insights. Recently, using a simulated vehicle exhaust exposure (SVEE) model we have published that SVEE, by inducing oxidative stress, results in behavioral and cognitive deficits in male rats. SVEE-induced sex-dependent variations in behavior, cognition, and cardiovascular functions were not examined. This is important as behavioral, cognitive and cardiovascular risks vary with gender. Therefore, in this study, male and female rats were subjected to SVEE for 2 weeks (5h/day) in whole body chambers. Our postulation was that, SVEE increases allostatic load (oxidative stress and inflammation), modifying critical signaling cascades, resulting in neurobehavioral deficits and blood pressure changes in a sex-dependent manner. This hypothesis was tested using three specific aims. In AIM 1, we examined if male and female rats would show differential susceptibility to SVEE-induced neurobehavioral deficits. In AIM 2, we assessed the biochemical changes induced by SVEE in male and female rats, and in AIM 3, we determined if SVEE differentially alters blood pressure and related parameters between male and female rats. Results suggest that as compared to control, male but not female SVEE rats developed memory deficits, exhibited anxiety- and depression-like behavior, accompanied with elevated serum corticosterone, oxidative stress, inflammation (CRP and TNF), and declined antioxidant capacity, glutathione, glyoxalase and SOD activities. Similarly, as compared to control, male but not female SVEE rats exhibited low Cu/Zn SOD, Mn SOD, GSR, and PKC expression levels in amygdala but not in the hippocampus. This was accompanied with elevated IL-6 levels and low ERK1/2, CaMKIV, CREB, BDNF and NMDA receptor subunit expression levels. Interestingly, SVEE did not negatively impact blood pressure, heart rate, or glomerular filtration rate in either male or female rats. Together, SVEE increases allostatic load in vulnerable brain regions, causing downregulation of ERK1/2-CREB-BDNF and CaMKIV-CREB-BDNF signaling, which subdues BDNF and NMDA receptor protein levels, thus declining the potential involvement of synaptic plasticity and neurogenesis in male but not female SVEE rats, causing neurobehavioral deficits. Estrogen due to its antioxidant and anti-inflammatory properties maintains BDNF and NMDA receptor levels, offering neurobehavioral protection.Item The Neuroprotective Effects of Moderate Treadmill Exercise in a Rat Model of Alzheimer’s Disease(2013-08) Dao, An Thien 1986-; Alkadhi, Karim A.; Eriksen, Jason; Salim, Samina; Justice, Nicholas J.; Ziburkus, JokubasAlzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory loss, spatial disorientation, and aberrant behaviors. The most important risk factor of AD is aging. Accumulating evidence suggests a neuroprotective role of regular exercise in aging associated memory impairment. In this study, we investigated the ability of regular moderate treadmill exercise to prevent impairment of cognitive and non-cognitive functions, long-term potentiation (LTP), and related signaling pathways in a rat model of AD, which was achieved by i.c.v. infusion of Aβ1-42 peptides (250 pmol/day for 2 weeks). We utilized behavioral assessment, in vivo electrophysiological recording, and immunoblotting in 4 groups of adult Wistar rats: control, treadmill exercise (Ex), β-amyloid-infused (Aβ), and amyloid-infused/treadmill exercised (Ex/Aβ). Our findings indicated that Aβ rats exhibited impaired spatial learning and memory as tested in the radial arm water maze (RAWM). Compared to all other groups, these rats also displayed increased anxiety-like behaviors as indicated by less time spent in the center area of the open field apparatus and the elevated plus maze (EPM), more time in the dark area of the light-dark box, and longer time in the closed arms of the EPM paradigm. Extracellular recordings in urethane-anesthetized rats revealed that these amyloid-infused animals showed suppressed early phase (E-) and late phase (L-) LTP in both CA1 and DG areas, which correlated with deficient signaling pathways in these two brain regions. For example, Western blot analysis indicated that Aβ rats exhibited deleterious alterations in the levels of AD- and LTP-related molecules including amyloid precursor protein (APP), β-secretase enzyme (BACE-1), calcineurin (PP2B), brain derived-neurotrophic factor (BDNF), Ca2+/calmodulin dependent protein kinases II and IV (CaMKII and CaMKIV), cAMP response element binding protein (CREB), and extracellular signal-regulated kinase 1/2 (ERK1/2). Compared to controls, Ex and Ex/Aβ rats showed a similar behavioral performance with normal hippocampal LTP and no detrimental changes in the levels of those LTP- and memory-related molecules in both areas. Thus, regular moderate treadmill exercise may be beneficial in preserving cognitive and non-cognitive functions in the AD brains by preventing the detrimental effects of amyloid toxicity on the synapses and key signaling pathways.