Mathematical modeling of limbic system dynamics, pathophysiology, and response to stress

Severe psychological trauma, as experienced by warfighters, can lead to long-lasting changes, per- sisting long after deployment is completed. For example, post-traumatic stress disorder (PTSD) 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. PTSD emerges as the body?s stress response system fails to effectively cope with a traumatic event. Under normal conditions, several neuroendocrine, emotional and cognitive systems cooperatively manage stress, from eliciting ?fight or flight? 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 body?s 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 finely-tuned cycle, leading to the emergence of stress related disorders, such as PTSD. Some anatomical regions of the brain that participate in stress regulation also intersect with memory circuits, providing an avenue for stress to affect cognitive processes. In this proposal we will systematically develop models to study how the HPA axis responds to up- stream input with the aim of giving a more complete mathematical description of stress response. Examples of neuroanatomical regions that influence the HPA axis are so called afferent areas such as the hippocampus, the amygdala, the locus coeruleus and the suprachiasmatic nucleus. Despite recent progress in biochemically characterizing the above subsystems, a holistic picture is lacking due to the many complexities involved, such as feedback loops, timing, competing events and multiple time scales. Experimental results can also be contradictory due to different setups, timings or dosages utilized. Mathematical modeling can be of great help as putative mechanisms or intervention strategies can be evaluated for consistency, informing experimental design and the interpretation of results. To date, to the best of our knowledge, there is no mathematical description of stress response upstream of the HPA axis; on the other hand, rapid advancements in gene targeting and other laboratory methods make this topic ripe for much needed quantitative analysis. Our goal is to effectively integrate psychiatry with mathematical modeling to help interpret findings and test hypothesis in a systematic manner. Topic 1: We will study the time dependent aspects of stress response by coupling the HPA axis to the suprachiasmatic nucleus and by introducing a 24-hour, circadian rhythm. Stress, dysregulated glucocorticoid secretion, loss of circadian rhythmicity and memory deficts are interdependent phenomena; we will consider stress timing, duration, noise, circadian-dependent sensitivity of target tissues and, in the case of repeated exposure, periodicity. 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. Endocannabinoid-mediated stress response will be modeled as a gateway process on the synaptic input to the hypothalamus. Long- and short-term glucocorticoid feedback mechanisms, and pos- sible habituation will be analyzed. Interactions between the HPA axis and the eCB system are key in memory retrieval. Topic 3: We will couple the HPA axis to stress-induced activation of glucocorticoid receptors in the hippocampus. Stress response depends on receptor abundance, on the competition between different classes of hippocampal MR/GR receptors, and on the different time scales over which they exert their action. The hippocampus is one of the main centers for memory formation and storage in the brain; receptor activation under stress is directly linked to cognitive performance. We will develop our models to be consistent with experimental observations; adapt them to represent current medical and/or psychological protocols; propose alternate intervention methods. This is collaborative work between UCLA and CSUN, a minority serving institution.