Author:
Naughton Sean X.,Yang Eun-Jeong,Iqbal Umar,Trageser Kyle,Charytonowicz Daniel,Masieri Sibilla,Estill Molly,Wu Henry,Raval Urdhva,Lyu Weiting,Wu Qing-li,Shen Li,Simon James,Sebra Robert,Pasinetti Giulio Maria
Abstract
AbstractGulf War Illness (GWI) is a chronic multisymptom disorder that affects approximately 25–32% of Gulf War veterans and is characterized by a number of symptoms such as cognitive impairment, psychiatric disturbances, chronic fatigue and gastrointestinal distress, among others. While the exact etiology of GWI is unknown, it is believed to have been caused by toxic exposures encountered during deployment in combination with other factors such as stress. In the present study we sought to evaluate the hypothesis that exposure to the toxin permethrin could prime neuroinflammatory stress response and elicit psychiatric symptoms associated with GWI. Specifically, we developed a mouse model of GWI, to evaluate the effects of chronic permethrin exposure followed by unpredictable stress. We found that subjecting mice to 14 days of chronic permethrin exposure followed by 7 days of unpredictable stress resulted in the development of depression-like behavior. This behavioral change coincided with distinct alterations in the microglia phenotype, indicating microglial activation in the hippocampus. We revealed that blocking microglial activation through Gi inhibitory DREADD receptors in microglia effectively prevented the behavioral change associated with permethrin and stress exposure. To elucidate the transcriptional networks impacted within distinct microglia populations linked to depression-like behavior in mice exposed to both permethrin and stress, we conducted a single-cell RNA sequencing analysis using 21,566 single nuclei collected from the hippocampus of mice. For bioinformatics, UniCell Deconvolve was a pre-trained, interpretable, deep learning model used to deconvolve cell type fractions and predict cell identity across spatial datasets. Our bioinformatics analysis identified significant alterations in permethrin exposure followed by stress-associated microglia population, notably pathways related to neuronal development, neuronal communication, and neuronal morphogenesis, all of which are associated with neural synaptic plasticity. Additionally, we observed permethrin exposure followed by stress-mediated changes in signal transduction, including modulation of chemical synaptic transmission, regulation of neurotransmitter receptors, and regulation of postsynaptic neurotransmitter receptor activity, a known contributor to the pathophysiology of depression in a subset of the hippocampal pyramidal neurons in CA3 subregions. Our findings tentatively suggest that permethrin may prime microglia towards a state of inflammatory activation that can be triggered by psychological stressors, resulting in depression-like behavior and alterations of neural plasticity. These findings underscore the significance of synergistic interactions between multi-causal factors associated with GWI.
Funder
Department of Defense
Office of Patient Care Services, Department of Veterans Affairs
Publisher
Springer Science and Business Media LLC
Reference63 articles.
1. Inoue C, Shawler E, Jordan CH, Moore MJ, Jackson CA. Veteran and Military Mental Health Issues. StatPearls. Treasure Island (FL) ineligible companies. Disclosure: Evan Shawler declares no relevant financial relationships with ineligible companies. Disclosure: Christopher Jordan declares no relevant financial relationships with ineligible companies. Disclosure: Marlyn Moore declares no relevant financial relationships with ineligible companies. Disclosure: Christopher Jackson declares no relevant financial relationships with ineligible companies.2024.
2. Black DW, Carney CP, Forman-Hoffman VL, Letuchy E, Peloso P, Woolson RF, et al. Depression in veterans of the first Gulf War and comparable military controls. Ann Clin Psychiatry. 2004;16(2):53–61.
3. Carlson EB, Palmieri PA, Vogt D, Macia K, Lindley SE. Development and cross-validation of a veterans mental health risk factor screen. PLoS ONE. 2023;18(2):e0272599.
4. Kuhn E, Drescher K, Ruzek J, Rosen C. Aggressive and unsafe driving in male veterans receiving residential treatment for PTSD. J Trauma Stress. 2010;23(3):399–402.
5. Engdahl BE, James LM, Miller RD, Leuthold AC, Lewis SM, Carpenter AF, et al. Brain function in Gulf War Illness (GWI) and Associated Mental Health Comorbidities. J Neurol Neuromedicine. 2018;3(4):24–34.