Mast cells affect brain physiology and behavior

Mast cells are immune cells that are found in the brain. Behavioral and endocrine states increase the number and activation of brain mast cells, independent of the animal's immune status. Activation causes the release of many neuro-active mediators into the brain parenchyma. However, the function or impact of mast cells in the brain has not been studied. The recruitment of mast cells to the brain, and their subsequent activation following a stressor suggests that they may have a role in regulating the stress response through interactions with neural systems. The goal of this thesis is to examine the functional role of brain mast cells using a mouse model. Mast cells are present in the mouse brain parenchyma, meninges and choroid plexus from birth throughout adulthood. A mast cell deficient (KitW-sh /W-sh) mouse is a strong model to study the effects of mast cells on brain physiology and behavior. The homozygote mutant lacks all brain mast cells resulting in reductions of mast cell-derived mediators. Interestingly, mast cell deficient mice have increased levels of anxiety-like behavior and stress-induced defecation compared to heterozygote (mast cell competent) littermate controls. Since mast cells are activated by stressors via corticotrophin releasing factor, it is surprising that no differences in the hypothalamic-pituitary-adrenal axis reactivity are seen between mast cell deficient mice and littermate controls. Instead, the effects of mast cells on anxiety behavior and physiology may be mediated through mast cell contribution of serotonin to the hippocampus, a brain region where many mast cells reside. In vitro, application of a mast cell activator to hippocampal slices causes a rise in serotonin levels in the hippocampus of control, but not mast cell deficient mice. Given the known effects of hippocampal serotonin as a trophic factor and transmitter, hippocampal function is likely affected by the absence of mast cells. There are deficits in hippocampal neurogenesis, but not subventricular zone neurogenesis (a brain region with no mast cells), in mast cell deficient mice. This deficit can be reversed by increasing serotonin signaling with SSRI treatment or by enriched housing conditions. Mast cell deficient mice also have deficits in hippocampal dependent spatial learning and memory which can be reversed by enriched housing. Overall these results show that mast cells affect neural systems and behavior in the absence of an immune stimulus. These studies link an immune cell to the brain and behavior, and suggest a beneficial role for the recruitment of mast cells and subsequent neuroimmune interactions