CRNS: Model of hippocampal-amygdala interaction: Implications for PTSD

根据NSF 08-514 （CRCNS）的要求，我们提出了一个新的合作项目，以建立海马、杏仁核和腹内侧前额叶皮层在条件反射、消退和情境处理中的相互作用的计算模型。该模型将应用于从创伤后应激障碍（PTSD）患者收集的数据，以期阐明这种疾病的大脑基础。在健康成人和创伤后应激障碍患者中进行平行的实证研究，以产生更多的数据来约束模型，而模型本身将产生新的预测，可能推动进一步的实证研究。因此，我们期待一个持续的过程，在这个过程中，模型被修改，以解释新的数据，同时产生新的预测，以指导进一步的实证研究，这反过来又可能导致新的诊断工具。此外，计算模型将允许我们调查可能存在不同亚型的PTSD，这些亚型涉及不同的脑功能障碍节点，从而导致共同的症状。无法在人类中对该疾病进行对照研究（例如，通过实验诱发的创伤），以及由此产生的对已经患上该疾病的个体的关注，在某种程度上阻碍了对该疾病的病因和影响的研究。尽管动物模型已经取得了一些成功，但计算模型也有潜力来研究各种脑系统的损伤或功能障碍（单独或联合）如何导致PTSD症状。该项目代表了海马体条件反射和情境处理的计算神经科学专家（Myers），创伤后应激障碍的结构、功能和行为异常（Gilbertson, Orr），以及人类和动物焦虑模型中的经典恐惧条件反射（Servatius）之间的新合作。这项研究的结果将使该领域对几个关键的大脑结构在正常学习和记忆以及创伤后应激障碍中的作用有更深入的了解。实证工作将扩大我们对创伤后应激障碍的广义学习缺陷的理解，并允许我们测试模型预测，以及产生新的数据来约束模型。该项目汇集了来自多个学科的研究人员——计算神经科学、实验神经心理学、临床心理学、心理生理学和人类焦虑症的动物模型——并以每个学科的专业知识为基础。高级人员在所涉及的研究方法方面具有丰富的经验，并且具有强大的出版记录以及对教学和指导的承诺。创伤后应激障碍可能影响超过6%的美国人口在其一生中的某个阶段，伴随着医疗负担以及由于失去参与专业和个人活动而产生的社会成本。拟议的工作将增加我们对创伤后应激障碍的理解，并检验它可能不是一种统一的疾病，而是一种病理家族，它们彼此之间有共同的症状集群，也与更广泛的焦虑症有共同的症状。通过更好地了解先前存在的风险因素，以及优化针对可能的PTSD亚型的治疗，这将对预防产生影响。计算建模和试点实证工作将在罗格斯-纽瓦克大学进行，该大学一直被评为全美最多样化的公立大学。迈尔斯每学期培训4-6名本科生实习生，其中许多人是少数族裔，往往是家里第一个上大学的人。她现在的三个本科实习生已经在国家科学会议上展示了他们的研究。迈尔斯本人是计算神经科学领域为数不多的女性研究人员之一。该项目还将资助1名研究生和1-2名本科生，他们将在实验设计、实证检验、数据分析和报告撰写方面发挥关键作用。

DESCRIPTION (provided by applicant): In response to NSF 08-514 (CRCNS), we propose a new collaborative project to develop a computational model of the interaction of hippocampus, amygdala, and ventromedial prefrontal cortex in conditioning, extinction, and contextual processing. The model will be applied to data collected from patients with post-traumatic stress disorder (PTSD), in the hopes of elucidating the brain substrates of this disorder. Parallel empirical studies, in healthy adults and in patients with PTSD, will be conducted to generate further data to constrain the model, while the model itself will generate new predictions that may drive further empirical studies. We thus anticipate an ongoing process in which the model is revised to account for new data while producing new predictions to guide further empirical studies, which in turn may lead to new diagnostic tools. In addition, the computational model will allow us to investigate the possibility that there may be different subtypes of PTSD that involve different nodes of brain dysfunction contributing to a common symptomatology. The inability to conduct controlled studies of the disorder in humans (e.g. via experimentally-induced trauma), and the resulting focus on individuals who have already developed the disorder, have to some extent hindered research into causes vs. effects of the disorder. Although animal models have had some success, there is also a potential here for computational modeling to examine how damage to or dysfunction of various brain systems (alone or in combination) might contribute to PTSD symptomatology. The project represents a new collaboration among experts on computational neuroscience of the hippocampus in conditioning and contextual processing (Myers), on the structural, functional, and behavioral abnormalities in PTSD (Gilbertson, Orr), and on classical fear conditioning in humans and animal models of anxiety (Servatius). Intellectual Merit The outcome of this research will provide the field with a deeper understanding of the role of several critical brain structures in normal learning and memory, as well as in PTSD. The empirical work will expand our understanding of generalized learning deficits in PTSD, and allow us to test model predictions, as well as producing new data to constrain the model. The project brings together researchers from several disciplines - computational neuroscience, experimental neuropsychology, clinical psychology, psychophysiology, and animal models of human anxiety disorders -- and builds on the expertise of each. The senior personnel have significant prior experience in the research methodologies involved and have strong publication records as well as commitments to teaching and mentoring. Broader Impact PTSD may affect over 6% of the US population at some point during their lifetimes, with accompanying health care burdens as well as societal costs due to lost participation in professional and personal activities. The proposed work will increase our understanding of PTSD and examine the idea that it may not be a unified disorder, but a family of pathologies that share clusters of common symptoms with each other and also with the broader spectrum of anxiety disorders. There will be implications for prevention, through better understanding of pre-existing risk factors, and for optimizing treatment that targets possible PTSD subtypes. Computational modeling and pilot empirical work will take place at Rutgers-Newark, which is consistently ranked as the #1 most diverse public university in the nation. Myers trains 4-6 undergraduate interns each semester, many of whom are underrepresented minorities, often the first in their families to go to college. Three of her current undergraduate interns have presented their research at national scientific conferences. Myers herself is one of the few female researchers represented in the field of computational neuroscience. The program will also fund a graduate student and 1-2 undergraduate researchers, who will play key roles in experimental design, empirical testing, data analysis, and report writing.