Pain is a multidimensional experience emerging from the flow of information between multiple brain regions. A growing body of evidence suggests that pathological pain causes plastic changes of ...various brain regions. Here, we hypothesized that the induction of neuropathic pain alters distributed patterns of the resting-state brain activity in animal models, and capturing the altered pattern would enable identification of neuropathic pain at the individual level. We acquired micro-positron emission tomography with (18)Ffluorodeoxyglucose (FDG micro-PET) images in awake rats with spinal nerve ligation (SNL) and without (sham) (SNL group, n=13; sham group, n=10). Multivariate pattern analysis (MVPA) with linear support vector machine (SVM) successfully identified the brain with SNL (92.31% sensitivity, 90.00% specificity, and 91.30% total accuracy). Predictive brain regions with increased metabolism were mainly located in prefrontal-limbic-brainstem areas including the anterior olfactory nucleus (AON), insular cortex (IC), piriform cortex (PC), septal area (SA), basal forebrain/preoptic area (BF/POA), amygdala (AMY), hypothalamus (HT), rostral ventromedial medulla (RVM) and the ventral midbrain (VMB). In contrast, predictive regions with decreased metabolism were observed in widespread cortical areas including secondary somatosensory cortex (S2), occipital cortex (OC), temporal cortex (TC), retrosplenial cortex (RSC), and the cerebellum (CBL). We also applied the univariate approach and obtained reduced prediction performance compared to MVPA. Our results suggest that developing neuroimaging-based diagnostic tools for pathological pain can be achieved by considering patterns of the resting-state brain activity.
: Neuroinflammation is a primary feature of Alzheimer's disease (AD), for which an increasing number of drugs have been specifically developed. The present study aimed to define the therapeutic ...impact of a specific subpopulation of T cells that can suppress excessive inflammation in various immune and inflammatory disorders, namely, CD4
CD25
Foxp3
regulatory T cells (Tregs).
: To generate Aβ antigen-specific Tregs (Aβ
Tregs), Aβ 1-42 peptide was applied
and subsequent
splenocyte culture. After isolating Tregs by magnetic bead based purification method, Aβ
Tregs were adoptively transferred into 3xTg-AD mice via tail vein injection. Therapeutic efficacy was confirmed with behavior test, Western blot, quantitative real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry staining (IHC).
suppression assay was performed to evaluate the suppressive activity of Aβ
Tregs using flow cytometry. Thy1.1
Treg trafficking and distribution was analyzed to explore the infused Tregs migration into specific organs in an antigen-driven manner in AD mice. We further assessed cerebral glucose metabolism using
F-FDG-PET, an imaging approach for AD biological definition. Subsequently, we evaluated the migration of Aβ
Tregs toward Aβ activated microglia using live cell imaging, chemotaxis, antibody blocking and migration assay.
: We showed that Aβ-stimulated Tregs inhibited microglial proinflammatory activity and modulated the microglial phenotype via bystander suppression. Single adoptive transfer of Aβ
Tregs was enough to induce amelioration of cognitive impairments, Aβ accumulation, hyper-phosphorylation of tau, and neuroinflammation during AD pathology. Moreover, Aβ-specific Tregs effectively inhibited inflammation in primary microglia induced by Aβ exposure. It may indicate bystander suppression in which Aβ-specific Tregs promote immune tolerance by secreting cytokines to modulate immune responses during neurodegeneration.
: The administration of Aβ antigen-specific regulatory T cells may represent a new cellular therapeutic strategy for AD that acts by modulating the inflammatory status in AD.