Mathematical modeling of limbic system dynamics, pathophysiology, and response to stress
Abstract
The severe psychological trauma often experienced by warfighters can lead to changes that persist long after deployment. Among the most insidious mental disorders affecting the returning soldier is post-traumatic stress disorder (PTSD). It causes intrusive recollections, hyperarousal, anxiety and insomnia that prevent patients from leading a functional life. In the United States, roughly 20% of veterans from recent wars suffer from PTSD, underlying the scope of the issue and bringing a sense of urgency in finding solutions. Under normal conditions, several neuroendocrine, emotional and cognitive systems cooperatively manage stress, from eliciting Òfight or flightÓ responses to long term learning. Central to these processes is the hypothalamic-pituitary-adrenal (HPA) axis that integrates the many physical and psychological inputs received by the brain and that controls the bodyÕs response to stress through the secretion of glucocorticoid hormones. Once in circulation, glucocorticoids feedback into the HPA axis, returning the system to homeostasis. Sudden, severe or repeated trauma may overwhelm this process, leading to the emergence of stress related disorders. Some regions of the brain that participate in stress regulation intersect with memory circuits, providing an avenue for stress to affect cognitive processes. In this proposal we will develop models to study the synergy between the HPA axis and several neuroanatomical regions that control its behavior under stress. Activation of the HPA axis is regulated by diverse ÒafferentÓ inputs from the hippocampus, the amygdala, the locus coeruleus and the suprachiasmatic nucleus. Despite recent progress in biochemically characterizing each of them, a more complete picture of their interplay is lacking. The presence of various components leads to inherent complexities such as feedback loops, multiple time scales, competing pathways. At times, experimental results can appear contradictory due to different measurement protocols. Against this backdrop, computational and mathematical modeling emerge as vital tools for eval- uating putative mechanisms, to inform experimental design and interpret clinical observations. To date, there have been few mathematical models of the HPA axis, and even fewer of stress response upstream of the HPA axis. On the other hand, rapid advancements in neuroimaging, epigenetics, gene targeting and other laboratory methods make this topic ripe for much needed quantitative analysis. For example, transgenic mice have been used to dissect HPA axis response, hormone secretion, and behavior under a variety of knock-out or over-expression conditions. Our goal is to integrate psychiatry with mathematical modeling to help interpret findings and provide a framework to test future hypotheses. Topic 1: We will couple the HPA axis to the suprachiasmatic nucleus and introduce a 24-hour, circadian rhythm to study time-dependent aspects of stress response. We will also incorporate circadian-dependent sensitivity of target tissues. Topic 2: We will characterize stress initiation and termination by coupling the HPA axis to the endocannabinoid (eCB) system that controls neurotransmitter release in the brain. Stress response will be modeled as a gateway process on the synaptic input to the hypothalamus. Long- and short-term glucocorticoid feedback and possible habituation will be analyzed. Topic 3: Stress response depends on two types of hippocampal mineralocorticoid/glucocorticoid receptors (MR/GR), their abundances and different operational timescales. We will couple the HPA axis to stress-induced activation of hippocampal MR/GR receptors. Topic 4: Our models will be validated with experimental observations We will identify findings from differential gene expression...
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Sep 11, 2018
- Source ID
- W911NF1810345
Entities
People
- Maria-rita D Orsogna
Organizations
- Army Contracting Command
- California State University, Northridge
- United States Army