ENVIRONMENT AFFECTS DOPAMINERGIC NEUROIMMUNE PROCESSES

中枢神经系统（CNS）和免疫系统之间存在广泛的通信，涉及共享的递质和调节剂。因此，对革兰氏阴性菌细胞壁成分脂多糖（LPS）（一种普遍存在的环境污染物）的抑制会导致神经和免疫改变，包括脑多巴胺（DA）浓度的长期降低和炎症反应的引发。同样，多氯联苯（PCBs）是一种广泛分布的环境毒物，暴露于多氯联苯会引起神经和免疫毒性作用，包括脑DA浓度降低和免疫功能改变，如中性粒细胞呼吸爆发活性增加。为了进一步了解多氯联苯对中枢神经系统和免疫功能的影响，我们将评估多氯联苯和LPS单独或联合暴露后小鼠的神经和免疫功能。对环境物质混合物的分析对风险评估至关重要。由于这两种物质在环境中广泛分布，因此有可能同时暴露于这两种物质。由于神经系统和免疫系统之间存在极端的交叉对话，我们将(i)通过实验改变每个系统的活动，并确定最初未受干扰的系统（通过纹状体DA消耗和LPS挑战）的神经和免疫后果；（ii）确定暴露于多氯联苯（单独或与LPS联合）的神经和免疫后果。我们假设，与单独暴露于多氯联苯或LPS相比，多氯联苯混合物和LPS联合暴露会导致纹状体DA的更大消耗和炎症反应的增强。过去的许多研究都涉及多氯联苯的神经毒性和免疫毒性作用，但没有研究涉及包括多巴胺能神经元在内的调节神经内分泌免疫回路的影响。纹状体DA将在药理学上减少，并将评估这种减少对中枢和外周细胞因子产生和外周免疫反应性的影响。接下来，将评估中央还原对中央和外周细胞因子产生和外周免疫反应性的作用。接下来，我们将研究中央和外周LPS和PCB混合单独或联合给药对脑多巴胺、细胞因子和外周免疫反应性的作用。该研究的成功完成将有助于揭示脑多巴胺对外周免疫反应的作用，以及与单独暴露于多氯联苯或LPS相比，多氯联苯和LPS联合暴露如何改变神经毒性和炎症/免疫反应。

DESCRIPTION Extensive communication exists between the central nervous system (CNS) and the immune system, involving shared transmitters and modulators. Thus, composure to the gram-negative bacteria cell wall component lipopolysaccharide (LPS), a ubiquitous environmental contaminant, results in neural and immune alterations including long-lasting reductions in brain dopamine (DA) concentrations and an elicitation of an inflammatory response. Similarly, exposure to polychlorinated biphenyls (PCBs), a widely distributed environmental toxicant, causes neuro- and immunotoxic effects including a reduction in brain DA concentrations and alterations in immune functions such as increased respiratory burst activity of neutrophils. In order to further understanding of the PCBs alter CNS and immune functions we will assess neural and immune function in mice following exposure to PCBs and LPS alone or in combination. Analysis of mixtures of environmental agents are critical for risk assessments. Since both agents are widely distributed in the environment there is likelihood for a combined exposure to the two. Because of the extreme cross-talk between the nervous and immune systems we will (i) experimentally alter the activity of each system and determine the neurological and immunological consequences to the initially unperturbed system (by striatal DA depletion and LPS challenge) and (ii) determine the neurological and immunological consequences of exposure to PCBs, either alone or in combination with LPS. We hypothesize that combined exposure to PCB mixture and LPS causes a greater depletion in striatal DA and in augmented inflammatory response compared to exposure to PCBs or LPS alone. Many past studies have addressed the neurotoxic and immunotoxic effects of PCBs, but none addressed effects on the regulatory neuro endocrine immune circuit including the involvement of dopaminergic neurons. Striatal DA will be reduced pharmacologically and the effect of the reduction on central and peripheral cytokine production and on peripheral immune reactivity will be assessed. Next, the role of central reduction on central and peripheral cytokine production and on peripheral immune reactivity will be assessed. Next, the role of central and peripheral LPS and PCB mixture administration separately or in combination on brain dopamine, cytokines, and peripheral immune reactivity will be examined. Successful completion of the proposed research will help reveal the role of brain dopamine on peripheral immune reactivity and how combined exposure to PCBs and LPS alter the neurotoxic and inflammatory/immune responses compared to an exposure to PCBs or LPS alone.