Exaggerated Increases in Microglia Proliferation, Brain Inflammatory Response and Sickness Behaviour upon Lipopolysaccharide Stimulation in Non-Obese Diabetic Mice.

Unlabelled: The non-obese diabetic (NOD) mouse, an established model for autoimmune diabetes, shows an exaggerated reaction of pancreas macrophages to inflammatory stimuli. NOD mice also display anxiety when immune-stimulated. Chronic mild brain inflammation and a pro-inflammatory microglial activation is critical in psychiatric behaviour.

The gene expression profile of CD11c+ CD8α- dendritic cells in the pre-diabetic pancreas of the NOD mouse.

Two major dendritic cell (DC) subsets have been described in the pancreas of mice: The CD11c+ CD8α- DCs (strong CD4+ T cell proliferation inducers) and the CD8α+ CD103+ DCs (T cell apoptosis inducers). Here we analyzed the larger subset of CD11c+ CD8α- DCs isolated from the pancreas of pre-diabetic NOD mice for genome-wide gene expression (validated by Q-PCR) to elucidate abnormalities in underlying gene expression networks. CD11c+ CD8α- DCs were isolated from 5 week old NOD and control C57BL/6 pancreas.

Inhibition of stress-induced hepatic tryptophan 2,3-dioxygenase exhibits antidepressant activity in an animal model of depressive behaviour.

The role of hepatic tryptophan 2,3 dioxygenase (TDO) was assessed in the provocation of stress-induced depression-related behaviour in the rat. TDO drives tryptophan metabolism via the kynurenine pathway (KP) and leads to the production of neuroactive metabolites including kynurenine. A single 2 h period of restraint stress in adult male Sprague-Dawley rats provoked an increase in circulating concentrations of the glucocorticoid corticosterone and induction of hepatic TDO expression and activity.

Autoimmunity, inflammation, and psychosis: a search for peripheral markers.

Accumulating evidence supports the view that deregulation of the immune system represents an important vulnerability factor for psychosis. In a subgroup of psychotic patients, the high comorbidity with autoimmune and chronic inflammatory conditions suggests a common underlying immune abnormality leading to both conditions. The reviewed data of affective and nonaffective psychosis show that if immune biomarkers exist for such immune abnormality, they may be found in raised macrophage/monocyte inflammatory activation patterns (monocytosis, high-inflammatory gene expression, raised glucocorticoid receptor β/glucocorticoid receptor α ratio, and high levels of proinflammatory and anti-inflammatory monocyte/macrophage derived cytokines in serum/plasma), reduced T cell numbers/proliferation, and TH1 skewing.

Noradrenaline acting on astrocytic β₂-adrenoceptors induces neurite outgrowth in primary cortical neurons.

The neurotransmitter noradrenaline (NA) has anti-inflammatory properties and promotes expression of neurotrophic factors in the central nervous system (CNS) via activation of glial adrenoceptors. Here we examined the ability of conditioned media (CM) from NA-treated glial cells to impact upon neuronal complexity. Primary rat cortical neurons were treated either directly with NA (1-10 μM), or treated with CM from NA-stimulated primary mixed glial cells.

Evidence for a dysregulated immune system in the etiology of psychiatric disorders.

There is extensive bi-directional communication between the brain and the immune system in both health and disease. In recent years, the role of an altered immune system in the etiology of major psychiatric disorders has become more apparent. Studies have demonstrated that some patients with major psychiatric disorders exhibit characteristic signs of immune dysregulation and that this may be a common pathophysiological mechanism that underlies the development and progression of these disorders.

Poly I:C-induced activation of the immune response is accompanied by depression and anxiety-like behaviours, kynurenine pathway activation and reduced BDNF expression.

In this study we characterised the ability of the viral mimetic poly I:C to induce a neuroinflammatory response and induce symptoms of depression and anxiety in rats. Furthermore, the ability of poly I:C to deplete central tryptophan and serotonin via induction of indolamine 2,3 dioxygenase (IDO), and also the ability of poly I:C to impact upon expression of the neurotrophin BDNF and its receptor TrkB were examined as potential mechanisms to link inflammation to depression. Poly I:C induced a neuroinflammatory response characterised by increased expression of IL-1β, IL-6, TNF-α and CD11b in frontal cortex and hippocampus.

The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes.

This review describes a key role for mononuclear phagocytes in the pathogenesis of major psychiatric disorders. There is accumulating evidence for activation of microglia (histopathology and PET scans) and circulating monocytes (enhanced gene expression of immune genes, an overproduction of monocyte/macrophage-related cytokines) in patients with bipolar disorder, major depressive disorder, and schizophrenia. These data are strengthened by observations in animal models, such as the MIA models, the chronic stress models, and the NOD mouse model.

Distinct alterations in colonic morphology and physiology in two rat models of enhanced stress-induced anxiety and depression-like behaviour.

Stress and anxiety are important causal and exacerbating factors in functional gastro-intestinal (GI) disorders such as irritable bowel syndrome. Stress affects GI motility, faecal transit and visceral pain sensitivity. Additionally, permeability and function of the gut epithelium, which acts as a barrier between the external environment and the body's internal milieu is altered by stress.

Sonic hedgehog promotes the generation of myelin proteins by transplanted oligosphere-derived cells.

The generation of large numbers of functionally relevant cells for transplantation remains central to the use of cell replacement as a therapeutic strategy for neurodegenerative diseases. In this study we have analyzed the effect of sonic hedgehog (Shh) pretreatment on the myelinating potential of transplanted oligosphere-derived cells. The retina was chosen as a model for assessing this myelinating capability because 1) there is a lack of endogenous myelin in the normal rodent retina and 2) the retinal ganglion cell (RGC) axons are receptive to myelination, once myelinating cells have access to the retinal nerve fiber layer.

Differentiation of oligodendrocytes in neurospheres derived from embryonic rat brain using growth and differentiation factors.

Studies on the isolation and propagation of multipotent neural precursors as neurospheres suggest their potential use in the reconstitution of neurons and oligodendrocytes in neurodegenerative diseases. To ensure that an adequate number of functionally relevant cells are present after transplantation, in vitro manipulation of cell fate before transplantation may be necessary to control the terminal phenotype of these cells. Using growth factors known to have a role in oligodendrocyte development such as sonic hedgehog, platelet-derived growth factor (PDGF), and basic fibroblast growth factor (FGF-2), we have tried to increase the number of oligodendroglia derived from E18 cortical neurospheres.