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

Serotonin receptors in depression: from A to B [version 1; referees: 3 approved]

The role of serotonin in major depressive disorder (MDD) is the focus of accumulating clinical and preclinical research. The results of these studies reflect the complexity of serotonin signaling through many receptors, in a large number of brain regions, and throughout the lifespan. The role of the serotonin transporter in MDD has been highlighted in gene by environment association studies as well as its role as a critical player in the mechanism of the most effective antidepressant treatments – selective serotonin reuptake inhibitors. While the majority of the 15 known receptors for serotonin have been implicated in depression or depressive-like behavior, the serotonin 1A (5-HT1A) and 1B (5-HT1B) receptors are among the most studied. Human brain imaging and genetic studies point to the involvement of 5-HT1A and 5-HT1B receptors in MDD and the response to antidepressant treatment. In rodents, the availability of tissue-specific and inducible knockout mouse lines has made possible the identification of the involvement of 5-HT1A and 5-HT1B receptors throughout development and in a cell-type specific manner. This, and other preclinical pharmacology work, shows that autoreceptor and heteroreceptor populations of these receptors have divergent roles in modulating depression-related behavior as well as responses to antidepressants and also have different functions during early postnatal development compared to during adulthood

Combining Small-Volume Metabolomic and Transcriptomic Approaches for Assessing Brain Chemistry

The integration of disparate data types provides a more complete picture of complex biological systems. Here we combine small-volume metabolomic and transcriptomic platforms to determine subtle chemical changes and to link metabolites and genes to biochemical pathways. Capillary electrophoresis–mass spectrometry (CE–MS) and whole-genome gene expression arrays, aided by integrative pathway analysis, were utilized to survey metabolomic/transcriptomic hippocampal neurochemistry. We measured changes in individual hippocampi from the mast cell mutant mouse strain, C57BL/6 <i>Kit</i>^{<i>W‑sh/W‑sh</i>}. These mice have a naturally occurring mutation in the white spotting locus that causes reduced c-Kit receptor expression and an inability of mast cells to differentiate from their hematopoietic progenitors. Compared with their littermates, the mast cell-deficient mice have profound deficits in spatial learning, memory, and neurogenesis. A total of 18 distinct metabolites were identified in the hippocampus that discriminated between the C57BL/6 <i>Kit</i>^{<i>W‑sh/W‑sh</i>} and control mice. The combined analysis of metabolite and gene expression changes revealed a number of altered pathways. Importantly, results from both platforms indicated that multiple pathways are impacted, including amino acid metabolism, increasing the confidence in each approach. Because the CE–MS and expression profiling are both amenable to small-volume analysis, this integrated analysis is applicable to a range of volume-limited biological systems

Synaptic mechanism underlying serotonin modulation of transition to cocaine addiction

Compulsive drug use despite adverse consequences defines addiction. While mesolimbic dopamine signaling is sufficient to drive compulsion, psychostimulants such as cocaine also boost extracellular serotonin (5-HT) by inhibiting reuptake. We used SERT Met172 knockin (SertKI) mice carrying a transporter that no longer binds cocaine to abolish 5-HT transients during drug self-administration (SA). SertKI mice showed an enhanced transition to compulsion. On the other hand, pharmacologically elevating 5-HT reversed the inherently high rate of compulsion transition with optogenetic dopamine self-stimulation. The bidirectional effect on behavior was explained by presynaptic depression of orbitofrontal cortex to dorsal striatum synapses induced by 5-HT via 5-HT(1B) receptors. Consequently, in projection-specific 5-HT(1B) receptor knockout mice the fraction of individuals compulsively self-administering cocaine was elevated