Modeling Neuroimmune Interactions in Human Subjects and Animal Models to Predict Subtype-Specific Multidrug Treatments for Gulf War Illness.

Gulf War Illness (GWI) is a persistent chronic neuroinflammatory illness exacerbated by external stressors and characterized by fatigue, musculoskeletal pain, cognitive, and neurological problems linked to underlying immunological dysfunction for which there is no known treatment. As the immune system and the brain communicate through several signaling pathways, including the hypothalamic-pituitary-adrenal (HPA) axis, it underlies many of the behavioral and physiological responses to stressors via blood-borne mediators, such as cytokines, chemokines, and hormones. Signaling by these molecules is mediated by the semipermeable blood-brain barrier (BBB) made up of a monocellular layer forming an integral part of the neuroimmune axis. BBB permeability can be altered and even diminished by both external factors (e.g., chemical agents) and internal conditions (e.g., acute or chronic stress, or cross-signaling from the hypothalamic-pituitary-gonadal (HPG) axis). Such a complex network of regulatory interactions that possess feed-forward and feedback connections can have multiple response dynamics that may include several stable homeostatic states beyond normal health. Here we compare immune and hormone measures in the blood of human clinical samples and mouse models of Gulf War Illness (GWI) subtyped by exposure to traumatic stress for subtyping this complex illness. We do this via constructing a detailed logic model of HPA-HPG-Immune regulatory behavior that also considers signaling pathways across the BBB to neuronal-glial interactions within the brain. We apply conditional interactions to model the effects of changes in BBB permeability. Several stable states are identified in the system beyond typical health. Following alignment of the human and mouse blood profiles in the context of the model, mouse brain sample measures were used to infer the neuroinflammatory state in human GWI and perform treatment simulations using a genetic algorithm to optimize the Monte Carlo simulations of the putative treatment strategies aimed at returning the ill system back to health. We identify several ideal multi-intervention strategies and potential drug candidates that may be used to treat chronic neuroinflammation in GWI.

Compatibility drives female preference and reproductive success in the monogamous California mouse (Peromyscus californicus) more strongly than male testosterone measures.

Female assessment of male attractiveness and how preferred qualities impact reproductive success is central to the study of mate choice. Male attractiveness may depend on traits beneficial to the reproductive success (RS) of any female, termed 'universal quality', and/or on behavioral and biological interactions between potential mates that reflect 'compatibility'. The steroid hormone testosterone (T) often underlies male attractiveness in rodents and is associated with enhanced paternal care in the monogamous and biparental California mouse (Peromyscus californicus). We hypothesized that (1) T-characteristics are universally attractive to female California mice and that (2) if reproductive success is higher for females mated with preferred males, then females mated with males preferred by other females will also have higher reproductive success. Alternatively, we speculated that pair compatibility, based on emergent pair qualities, is important for a species with coordinated offspring care. We assessed individual T-characteristics in three ways: (1) T-response to GnRH challenges (2) baseline T-level and (3) T-response to a female. Testosterone-response did not predict female preference, but females spent more time investigating males with higher baseline T (accounting for only 9.6% of the variation in investigation time). None of the T-measures was associated with RS. Females paired with males they preferred produced litters more quickly and had higher RS than females paired with their non-preferred males. Naïve females who did not undergo preference tests had equivalent RS regardless of whether their mate was preferred or non-preferred by another female. These data suggest that higher male T elicits investigation, but female preference in the California mouse is more strongly linked with compatibility because individual preference was a better predictor of RS than any T measure.