The prevalence of mild cognitive impairment in Gulf War veterans: a follow-up study

Gulf 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.

show abstract

Regional distribution of cellular of molecular pathways in a mouse model of Gulf War illness by Single-Cell RNA Sequencing Analysis

Naughton,

Yang,

Iqbal

et al. 2024

Preprint

View full text Add to dashboard Cite

Gulf War Illness (GWI) is a chronic multisymptom disorder that affects approximately 25–32% of Gulf War veterans, and the combination of permethrin exposure with stress may have collectively and synergistically contributed to its development. However, the exact underlying pathogenic mechanisms within the brain that links permethrin and stress to the development of GWI remains unclear. In the current study, we investigate the effects and the associated molecular mechanisms within the microglia-neuron interplay in a mouse model of GWI, focusing on how exposure to permethrin may act as a priming agent when followed by stress. Subjecting mice to 14 days of chronic permethrin exposure followed by 7 days of 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 hippocampa. 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 the CA3 subregions. These studies tentatively suggest that permethrin may prime toward a depression-like behavior that can be triggered by psychological stress in mice through microglial activation, resulting in alterations of neural plasticity. This new evidence underscores the significance of the synergistic role of multi-causal factors associated with GWI.

show abstract

The prevalence of mild cognitive impairment in Gulf War veterans: a follow-up study

Cited by 3 publications

References 107 publications

TMS-derived short afferent inhibition discriminates cognitive status in older adults without dementia

TMS-derived short afferent inhibition discriminates cognitive status in older adults without dementia

Permethrin exposure primes neuroinflammatory stress response to drive depression-like behavior through microglial activation in a mouse model of Gulf War Illness

Regional distribution of cellular of molecular pathways in a mouse model of Gulf War illness by Single-Cell RNA Sequencing Analysis

Contact Info

Product

Resources

About