Identification of Biomolecular Pathways Associated With the Central Nervous System Based Symptoms of Gulf War Illness

The clinical profile of GWI is characterized by the presence the central nervous systems (CNS) symptoms which include memory impairment, anxiety, widespread pain and motor problems. Now, even twenty years later, veterans with GWI continue to suffer from these persistent symptoms. Currently, there is no treatment available for treating GWI, which is largely due to the complexity of the clinical presentation of this illness and the heterogeneity of GW exposures. The main goals of this thesis were to develop and characterize GW agent exposure mouse models that recapitulate the CNS symptoms of GWI and to identify the underlying aberrant biological pathways. Three major objectives were undertaken to accomplish these goals: (1) Two mouse models of GW-agent exposure were developed using combination of the anti-nerve gas treatment pyridostigmine bromide (PB), pesticides (permethrin), an insect repellent (N,N-Diethyl-meta-toluamide) and stress. Neurobehavioral studies show that combined exposure to GW agents produced anxiety and sensorimotor deficits in one mouse model and anxiety and cognitive impairment in the other. Neuropathological studies showed a presence of astrogliosis in both models. (2) Exploratory proteomic studies suggested that lipid-metabolism and immune/inflammation were associated with GW-agent exposure. (3) As lipid dysfunction is upstream of the inflammatory pathways, a lipidomics approach was used to identify the GW-agent exposure dependent lipid profiles. Lipid profiles of mouse models of GW-agent exposure were compared with those of other neurological conditions to identify profiles that were unique to GW-agent exposure. Lipid profiles were interrogated to identify lipid-metabolism pathways that may be amenable to therapeutic targeting. Studies described in this thesis provide novel insight into the pathobiology of GWI and suggest that pathways involved in phosphatidylcholine metabolism might be of therapeutic value in treating the CNS symptoms of GWI