The Effect of Environmental Enrichment on Glutathione-Mediated Xenobiotic Metabolism and Antioxidation in Normal Adult Mice

Olfactory bulb (OB) plays an important role in protecting against harmful substances via the secretion of antioxidant and detoxifying enzymes. Environmental enrichment (EE) is a common rehabilitation method and known to have beneficial effects in the central nervous system. However, the effects of EE in the OB still remain unclear. At 6 weeks of age, CD-1® (ICR) mice were assigned to standard cages or EE cages. After 2 months, we performed proteomic analysis. Forty-four up-regulated proteins were identified in EE mice compared to the control mice. Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes Pathway demonstrated that the upregulated proteins were mainly involved in metabolic pathways against xenobiotics. Among those upregulated proteins, 9 proteins, which participate in phase I or II of the xenobiotic metabolizing process and are known to be responsible for ROS detoxification, were validated by qRT-PCR. To explore the effect of ROS detoxification mediated by EE, glutathione activity was measured by an ELISA assay. The ratio of reduced glutathione to oxidized glutathione was significantly increased in EE mice. Based on a linear regression analysis, GSTM2 and UGT2A1 were found to be the most influential genes in ROS detoxification. For further analysis of neuroprotection, the level of iNOS and the ratio of Bax to Bcl-2 were significantly decreased in EE mice. While TUNEL+ cells were significantly decreased, Ki67+ cells were significantly increased in EE mice, implicating that EE creates an optimal state for xenobiotic metabolism and antioxidant activity. Taken together, our results suggested that EE protects olfactory layers via the upregulation of glutathione-related antioxidant and xenobiotic metabolizing enzymes, eventually lowering ROS-mediated inflammation and apoptosis and increasing neurogenesis. This study may provide an opportunity for a better understanding of the beneficial effects of EE in the OB

The Effect of Environmental Enrichment on Glutathione-Mediated Xenobiotic Metabolism and Antioxidation in Normal Adult Mice

Olfactory bulb (OB) plays an important role in protecting against harmful substances via the secretion of antioxidant and detoxifying enzymes. Environmental enrichment (EE) is a common rehabilitation method and known to have beneficial effects in the central nervous system. However, the effects of EE in the OB still remain unclear. At 6 weeks of age, CD-1(R) (ICR) mice were assigned to standard cages or EE cages. After 2 months, we performed proteomic analysis. Forty-four up-regulated proteins were identified in EE mice compared to the control mice. Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes Pathway demonstrated that the upregulated proteins were mainly involved in metabolic pathways against xenobiotics. Among those upregulated proteins, 9 proteins, which participate in phase I or II of the xenobiotic metabolizing process and are known to be responsible for ROS detoxification, were validated by qRT-PCR. To explore the effect of ROS detoxification mediated by EE, glutathione activity was measured by an ELISA assay. The ratio of reduced glutathione to oxidized glutathione was significantly increased in EE mice. Based on a linear regression analysis, GSTM2 and UGT2A1 were found to be the most influential genes in ROS detoxification. For further analysis of neuroprotection, the level of iNOS and the ratio of Bax to Bcl-2 were significantly decreased in EE mice. While TUNEL(+) cells were significantly decreased, Ki67(+) cells were significantly increased in EE mice, implicating that EE creates an optimal state for xenobiotic metabolism and antioxidant activity. Taken together, our results suggested that EE protects olfactory layers via the upregulation of glutathione-related antioxidant and xenobiotic metabolizing enzymes, eventually lowering ROS-mediated inflammation and apoptosis and increasing neurogenesis. This study may provide an opportunity for a better understanding of the beneficial effects of EE in the OB.ope

Alcohol, tobacco and other drugs: clinical guidelines for nurses and midwives

Version 3edited by C. de Crespigny & J. Talme

Environmental and genetic correlates of neuropsychiatric diseases and the role of erythropoietin/hypoxia in the brain as potential treatment targets

Neuropsychiatric disorders are relatively frequent and present a considerable burden to affected individuals and society. Disease etiology is often complex and patients exhibit large heterogeneity regarding disease causing factors, presentation and progression. Available treatment options are often ineffective and/or linked to unwanted side-effects. On the other hand, availability of successful preventive actions is limited and requires a detailed study of risk factors for neuropsychiatric disease and its specific symptoms. The first part of this thesis aimed to investigate environmental and genetic risk factors for polytoxicomania, i.e. multiple drug (ab)use, as a frequent comorbidity of schizophrenia. In a sample of $\sim$2000 schizophrenia/schizoaffective patients, we addressed the question if the exposure to accumulated environmental risk in early life increases susceptibility to polytoxicomania. Indeed, the accumulation of environmental risk was strongly associated with polytoxicomania throughout life and in particular in pre-adulthood. Moreover, the development of a novel GWAS-PGAS approach led to the identification of 41 common genetic variants potentially conferring risk to preadult polytoxicomania. The objective of the second part of this thesis work was to further investigate brain-directed effects of hypoxia and erythropoietin (EPO) - a central hypoxia-inducible gene - as potential treatment option for neuropsychiatric disorders. Using a hypoxia reporter mouse line (CAG-CreERT2-ODD::R26R-tdTomato), we showed that both inspiratory hypoxia and motor-cognitive challenge, which causes endogenous hypoxia as a result of extensive neuronal activation (termed "functional hypoxia"), increased the number of hypoxic cells in the brain and the expression of hypoxia-inducible genes in the hippocampus. Interestingly, cell types showed variable responsivity to hypoxia: While neurons and endothelial cells were frequently labelled, hypoxia-labelling in microglia was entirely absent. Technical artifacts explaining this phenomenon were excluded by comparing construct mRNA levels across all cell types. Hexokinase 2 (Hk2) was identified as a mediator of cell type-specific hypoxia responsivity. In addition, we report rapid effects of EPO on adult neurodifferentiation in the CA1 (6 hours after injection). Enhanced neuronal differentiation continued under EPO treatment, driving immature neurons (\textit{Tbr1}+, \textit{Tle4}+ and later \textit{Zbtb20}+) towards maturity, and resulted in $\sim$20\% more neurons in the CA1 after 3 weeks of treatment. Simultaneously, the number of microglia in this region declined by an initial wave of apoptosis, followed by attenuated proliferation. This reduction was necessary for the increase in new neurons. Expression data further indicated that the microglial-neuron balance was maintained by signalling of microglial Colony-Stimulating Factor 1 Receptor (CSF1R) and its neuronally expressed ligand Interleukin 34 (IL34).2022-06-0

Human Connection as a Treatment for Addiction

Research supports that social connection is important in both humans and animals. In humans, having a cohesive support/social network system and healthy attachments in childhood predict low risk of later addiction (i.e. substance use disorder), as does perceived support from a religious or other cohesive community. Moreover, personal characteristics such as identifying as religious or spiritual can predict low risk for addiction, but little is known about the intersection of neuroscience and religion/spirituality in this regard. Conversely, adverse childhood experiences (ACEs) have repeatedly been shown to predict later addiction. However, the role of the body’s neuro-hormonal responses, such as the endogenous opioid and oxytocin systems in this process merits further exploration, such as how the production or deprivation of endogenous opioids impact later substance use patterns. Existing research also provides evidence that individuals decrease pursuit of interpersonal connections and social bonds when they use substances that activate opioid receptors. This has been found with both substances of abuse and medications used to treat addiction (e.g., methadone, buprenorphine, naltrexone). Research has also demonstrated that addiction often results in situations of social isolation. However, it remains to be elucidated whether the substances of abuse physiologically meet that need for connection. Importantly, research across numerous fields indicates that intentionally increasing interpersonal connection may be an effective treatment for addiction. However, less is known about how specific characteristics of communities impact the quantity, quality, or effectiveness of care and support for a person with addiction [...]https://dc.etsu.edu/etsu_books/1292/thumbnail.jp

Opioid and stimulant use among a sample of corrections-involved drug users : seeking an understanding of high-risk drug decisions within a system of constraint.

In the United States, high-risk drug use remains a significant social problem. Opioids and stimulants are two drug classes that have contributed to substantial recent increases in drug-related arrests, overdose, and mortality. Kentucky has been particularly devastated by high rates of opioid and stimulant use. Opioid and stimulant effects, while highly rewarding, can result in adverse consequences. Still, some people choose to use these drugs, and choose to continue using even after experiencing adverse consequences, such as incarceration. The aim of this study was to explore high-risk drug use among a sample of corrections-involved adults in Kentucky and to identify endogenous and exogenous factors with the potential to have influenced drug-related decision-making prior and subsequent to incarceration. Attention was paid to understanding concomitant opioid and stimulant use and heroin use. Survey data collected as part of an ongoing corrections-based substance use treatment program outcomes study were examined. The final sample (N=1,563) included adults released into Kentucky counties between 2012-2017. Non-parametric statistical tests and multinomial logistic regression were used to identify factors associated with opioid, stimulant, and concomitant use; binary logistic regression was used to identify factors associated with heroin use. Results indicate that opioid and stimulant use was endemic in this sample, though rates of use subsequent to incarceration were lower than pre-incarceration rates. During the 30-day period prior to incarceration, 29.0% of participants reported concomitant use, 28.5% reported opioid use, and 18.0% reported stimulant use. During the one-year post-release period, 11.9% of participants reported concomitant use, 12.5% reported opioid use, and 8.3% reported stimulant use. During this post-release period, 10.7% reported heroin use. Concomitant and heroin use positively correlated with many factors with the potential to adversely influence cognition and constrain choice. Similar relationships between many of these factors and outcomes involving other drug or no drug use were not observed. Behavioral economics, a molar view of choice and behavior, was used to conceptualize how factors in the lives of participants had the potential to influence and constrain decision-making in respect to high-risk drugs. Findings are discussed in light of how they may inform future research, policy, and practice

Specifying and Targeting Cognitive-Affective Dysfunctions in Antisocial Individuals

Antisocial behavior includes a wide range of behaviors that violate social norms, from criminal acts to substance misuse. The adverse consequences of antisocial behavior produce a great physical and emotional burden on perpetrators, victims, and family members. This burden is not addressed adequately, with incarceration being the most common intervention for antisocial behavior. When individuals who chronically engage in antisocial behavior are offered therapeutic treatments, the majority neither complete nor benefit from them. One reason existing treatments do not fully address antisocial behavior is because they do not consider or target cognitive-affective dysfunctions driving such behavior, and mechanistic research, to date, does not adequately characterize these cognitive-affective dysfunctions. The present dissertation consists of three studies that refine accounts of cognitive-affective dysfunctions contributing to antisocial behavior and demonstrate how targeting identified dysfunctions can improve cognition and behavior in chronically antisocial individuals. More specifically, Study 1 examines how reward features impact perception, executive functioning, and risk-based decision-making in antisocial individuals. Study 2 examines how reward information is integrated during effort-based decision-making in antisocial individuals, and how negative affect impacts this integration. Finally, Study 3 tests a novel cognitive remediation training package designed to address cognitive-affective dysfunctions in antisocial individuals. Across the three studies in this dissertation, findings highlight that cognitive-affective dysfunctions related to antisocial behavior reflect difficulty integrating information in specific affectively charged circumstances, and call for a less pessimistic view about treatment for antisocial behavior, and the burden it produces, when these dysfunctions are considered

Neuropsychology and neuroimaging in diffuse brain damage : a study of visual event perception

The aims of this project were (1) to investigate two forms of event perception: perception of movement and perception of sudden appearance, (2) to develop event perception procedures which could be applied to testing clinical populations, and (3) to relate event perception to abnormalities shown by neuroimaging. In addition issues relevant to each of the particular clinical populations involved were addressed. Event perception tasks used stimuli consisting of a background of randomly selected dots of light. In one task a dot was added to the display (appearance), in the other a dot started to move (movement onset). Four laboratory experiments were conducted examining the ability to detect and locate these events under varying conditions in healthy controls. Results indicated that neuronal coding strategies were different for appearances and movement onset. Laboratory tasks were adapted for clinical application and administered to groups of patients with different neurological conditions. Five studies were conducted to assess sensitivity and specificity of the Event Perception tasks in clinical settings. The groups studied were chronic solvent abusers, detoxified alcoholics, patients suffering from optic neuritis, and patients with traumatic brain injury. Event Perception tasks were found to be differentially sensitive to neurological conditions and showed dissociations and double dissociations both within and between neurological conditions. Relationships with Magnetic Resonance Imaging (MRI) and Single Photon Emission Computed Tomography (SPECT) were investigated in patients with head injury. Patterns of brain damage differed significantly for patients with impaired performance on the movement task. It is concluded that Event Perception tasks are of value in the assessment of neurological patients: They allow assessment of functions which are not usually evaluated in neuropsychological examinations, facilitate detection of subtle deficits and deficits which may present at an early stage, and offer greater specificity and sensitivity than many traditional neuropsychological test procedures. Event Perception tasks are easy to administer and do not suffer from training effects on repeated administration to the same degree as many traditional measures. It is also argued that tests with a theoretical basis are better suited to clinical research in neuropsychology than many traditional tasks because they potentially allow a more precise explanation and assessment of the abnormal processes under investigation