Formyl Peptide Receptor as a Novel Therapeutic Target for Anxiety-Related Disorders

Formyl peptide receptors (FPR) belong to a family of sensors of the immune system that detect microbe-associated molecules and inform various cellular and sensorial mechanisms to the presence of pathogens in the host. Here we demonstrate that Fpr2/3-deficient mice show a distinct profile of behaviour characterised by reduced anxiety in the marble burying and light-dark box paradigms, increased exploratory behaviour in an open-field, together with superior performance on a novel object recognition test. Pharmacological blockade with a formyl peptide receptor antagonist, Boc2, in wild type mice reproduced most of the behavioural changes observed in the Fpr2/3(-/-) mice, including a significant improvement in novel object discrimination and reduced anxiety in a light/dark shuttle test. These effects were associated with reduced FPR signalling in the gut as shown by the significant reduction in the levels of p-p38. Collectively, these findings suggest that homeostatic FPR signalling exerts a modulatory effect on anxiety-like behaviours. These findings thus suggest that therapies targeting FPRs may be a novel approach to ameliorate behavioural abnormalities present in neuropsychiatric disorders at the cognitive-emotional interface

'As above, so below' examining the interplay between emotion and the immune system

While the concept of a palpable relationship between our mental and physical well-being is certainly not new, it is only in the light of modern scientific research that we have begun to realize how deeply connected our emotional and immune states may be. We begin this review with a series of studies demonstrating how four fundamental emotional responses: anger, anxiety, mirth and relaxation are able modulate cytokine production and cellular responses to a variety of immune stimuli. These modulations are shown to be either detrimental or beneficial to a patient's health dependent on the context and duration of the emotion. We also discuss the reverse, highlighting research demonstrating how the loss of key immune cells such as T lymphocytes in clinical and animal studies can negatively impact both emotional well-being and cognition. Additionally, to give a more complete picture of the manifold pathways that link emotion and the immune system, we give a brief overview of the influence the digestive system has upon mental and immunological health. Finally, throughout this review we attempt to highlight the therapeutic potential of this burgeoning field of research in both the diagnosis and treatment of immune and disorders. As well as identifying some of the key obstacles the field must address in order to put this potential into practice

Emotional change-associated T cell mobilization at the early stage of a mouse model of multiple sclerosis

Autoimmune diseases like multiple sclerosis are known to be associated with debilitating emotional disorders that manifest long before the flaring of motor dysfunctions. Given the emerging role of T cells in controlling both emotions and autoimmunity, in this study we explored possible correlation between T cell activation and changes in emotional behavior in a mouse model of multiple sclerosis. Our results showed a significant increase in blood circulating T cells as soon as at day 4 post-immunization. This lymphocytosis remained stable with time and preceded the infiltration of T cell in the CNS. The kinetic of T cell entry in the blood matched the kinetic of changes in behavior measured using the open field test. Treatment with glatiramer acetate, a well-known immunomodulatory drug for multiple sclerosis, suppressed behavioral changes while retaining the T cells in the draining lymph nodes. Together these results provide evidence of a positive correlation between the emigration of T cells in circulation and changes in emotions during chronic inflammatory diseases. The validation of these findings in the clinic might help to better understand the cause of the emotional and psychological burden of patients suffering multiple sclerosis or other autoimmune diseases. Most importantly our study suggests novel therapeutic venues for the treatment of the emotional changes associated with autoimmunity

Immuno-<i>mood</i>ulin:A new anxiogenic factor produced by Annexin-A1 transgenic autoimmune-prone T cells

Patients suffering from autoimmune diseases are more susceptible to mental disorders yet, the existence of specific cellular and molecular mechanisms behind the co-morbidity of these pathologies is far from being fully elucidated. By generating transgenic mice overexpressing Annexin-A1 exclusively in T cells to study its impact in models of autoimmune diseases, we made the unpredicted observation of an increased level of anxiety. Gene microarray of Annexin-A1 CD4+ T cells identified a novel anxiogenic factor, a small protein of approximately 21kDa encoded by the gene 2610019F03Rik which we named Immuno-moodulin. Neutralizing antibodies against Immuno-moodulin reverted the behavioral phenotype of Annexin-A1 transgenic mice and lowered the basal levels of anxiety in wild type mice; moreover, we also found that patients suffering from obsessive compulsive disorders show high levels of Imood in their peripheral mononuclear cells. We thus identify this protein as a novel peripheral determinant that modulates anxiety behavior. Therapies targeting Immuno-moodulin may lead to a new type of treatment for mental disorders through regulation of the functions of the immune system, rather than directly acting on the nervous system

Boc2-treatment reduces anxiety-like behaviour in C57BL/6 mice.

<p>The bar graphs in <b>A</b> show the total number of squares crossed, rears and centre crossings of Boc2-treated mice compared to PBS vehicle-treated during a 5-minute trial in the open field test. The bar graph in B shows the total time (seconds) spent in the lit area and the latency (seconds) to first cross to the dark chamber of Boc2-treated mice compared to PBS vehicle-treated mice during a 5-minute trial. Values are expressed as median ± S.E.M. and representative of four different experiments involving 6 mice per group. * <i>P</i><0.05 and ** <i>P</i><0.01 indicate significant values compared to PBS-vehicle treated mice (Mann–Whitney <i>U</i>-test).</p

Increased level of corticosterone in <i>Fpr2/3</i>^-/- mice.

<p>Levels of corticosterone in the plasma of WT and <i>Fpr2/3</i>^-/-. Values are expressed as ngml⁻¹ and are representative of three experiments with 6 mice.</p

Boc2-treatment increases the recognition of a novel object in C57BL/6 mice.

<p>The bar graphs show the total time (seconds) spent exploring the objects used in the test during the 10-minute acquisition phase (left panel) and the % of time spent on the novel object in the subsequent 5-minute test phase (right panel) of Boc2-treated mice compared to PBS vehicle-treated mice. Values are expressed as median ± S.E.M. and representative of four different experiments involving 6 mice per group. ** <i>P</i><0.01 indicates significant values compared to PBS-vehicle treated mice (Mann–Whitney <i>U</i>-test).</p