Modulation of serotonin transporter expression by escitalopram under inflammation.

Selective serotonin reuptake inhibitors (SSRIs) are widely used for depression based on the monoamine deficiency hypothesis. However, the clinical use of these agents is controversial, in part because of their variable clinical efficacy and in part because of their delayed onset of action. Because of the complexities involved in replicating human disease and clinical dosing in animal models, the scientific community has not reached a consensus on the reasons for these phenomena.

Serotonin is a common thread linking different classes of antidepressants.

Depression pathology remains elusive. The monoamine hypothesis has placed much focus on serotonin, but due to the variable clinical efficacy of monoamine reuptake inhibitors, the community is looking for alternative therapies such as ketamine (neurogenesis theory of antidepressant action). There is evidence that different classes of antidepressants may affect serotonin levels; a notion we test here.

Serotonin is a Common Thread Linking Different Classes of Antidepressants.

Depression pathology remains elusive. The monoamine hypothesis has placed much focus on serotonin, but due to the variable clinical efficacy of monoamine reuptake inhibitors, the community is looking for alternative therapies such as ketamine (synaptic plasticity and neurogenesis theory of antidepressant action). There is evidence that different classes of antidepressants may affect serotonin levels; a notion we test here.

Mathematical insights into the role of dopamine signaling in circadian entrainment.

The circadian clock in the mammalian brain comprises interlocked molecular feedback loops that have downstream effects on important physiological functions such as the sleep-wake cycle and hormone regulation. Experiments have shown that the circadian clock also modulates the synthesis and breakdown of the neurotransmitter dopamine. Imbalances in dopamine are linked to a host of neurological conditions including Parkinson's disease, attention-deficit/hyperactivity disorder, and mood disorders, and these conditions are often accompanied by circadian disruptions.

An In Vivo Definition of Brain Histamine Dynamics Reveals Critical Neuromodulatory Roles for This Elusive Messenger.

Histamine is well known for mediating peripheral inflammation; however, this amine is also found in high concentrations in the brain where its roles are much less known. In vivo chemical dynamics are difficult to measure, thus fundamental aspects of histamine's neurochemistry remain undefined. In this work, we undertake the first in-depth characterization of real time in vivo histamine dynamics using fast electrochemical tools.

Voltammetric Approach for Characterizing the Biophysical and Chemical Functionality of Human Induced Pluripotent Stem Cell-Derived Serotonin Neurons.

Depression is quickly becoming one of the world's most pressing public health crises, and there is an urgent need for better diagnostics and therapeutics. Behavioral models in animals and humans have not adequately addressed the diagnosis and treatment of depression, and biomarkers of mental illnesses remain ill-defined. It has been very difficult to identify biomarkers of depression because of measurement challenges.

Comparison of 26-mm Evolut and 23-mm Sapien 3 Valves in TAVR for Small Aortic Annulus.

Background: Patients with small aortic annuli (SAA) are prone to higher post-transcatheter aortic valve replacement (TAVR) transvalvular gradients and development of prosthesis-patient mismatch (PPM). In many patients with SAA, the choice of TAVR valve commonly involves choosing between the 26-mm Medtronic Evolut 2 (ME26) or the 23-mm Edwards Sapien 3 valve (ES23). We compared echocardiographic and clinical outcomes in patients with SAA undergoing TAVR with either valve.

Spiracular fluttering decouples oxygen uptake and water loss: a stochastic PDE model of respiratory water loss in insects.

In insect respiration, oxygen from the air diffuses through a branching system of air-filled tubes to the cells of the body and carbon dioxide produced in cellular respiration diffuses out. The tracheal system has a very large surface area, so water loss is a potential threat and the question of how insects regulate oxygen uptake and water loss has been an important issue in insect physiology for the past century. The tracheal system starts at spiracles on the surface of the body that insects can open and close, and three phases are observed experimentally, open or closed for relatively long periods of time and opening and closing rapidly, which is called fluttering.

One-carbon metabolism during the menstrual cycle and pregnancy.

Many enzymes in one-carbon metabolism (OCM) are up- or down-regulated by the sex hormones which vary diurnally and throughout the menstrual cycle. During pregnancy, estradiol and progesterone levels increase tremendously to modulate physiological changes in the reproductive system. In this work, we extend and improve an existing mathematical model of hepatic OCM to understand the dynamic metabolic changes that happen during the menstrual cycle and pregnancy due to estradiol variation.

Inflammation-Induced Histamine Impairs the Capacity of Escitalopram to Increase Hippocampal Extracellular Serotonin.

Commonly prescribed selective serotonin reuptake inhibitors (SSRIs) inhibit the serotonin transporter to correct a presumed deficit in extracellular serotonin signaling during depression. These agents bring clinical relief to many who take them; however, a significant and growing number of individuals are resistant to SSRIs. There is emerging evidence that inflammation plays a significant role in the clinical variability of SSRIs, though how SSRIs and inflammation intersect with synaptic serotonin modulation remains unknown.

Spiracular fluttering increases oxygen uptake.

Many insects show discontinuous respiration with three phases, open, closed, and fluttering, in which the spiracles open and close rapidly. The relative durations of the three phases and the rate of fluttering during the flutter phase vary for individual insects depending on developmental stage and activity, vary between insects of the same species, and vary even more between different species. We studied how the rate of oxygen uptake during the flutter phase depends on the rate of fluttering.

Fast serotonin voltammetry as a versatile tool for mapping dynamic tissue architecture: I. Responses at carbon fibers describe local tissue physiology.

It is important to monitor serotonin neurochemistry in the context of brain disorders. Specifically, a better understanding of biophysical alterations and associated biochemical functionality within subregions of the brain will enable better of understanding of diseases such as depression. Fast voltammetric tools at carbon fiber microelectrodes provide an opportunity to make direct evoked and ambient serotonin measurements in vivo in mice.

Corrigendum: Hippocampal Serotonin Dynamics in Male and Female Mice: Determining Effects of Acute Escitalopram Using Fast Scan Cyclic Voltammetry.

[This corrects the article DOI: 10.3389/fnins.2019.

Hippocampal Serotonin Dynamics in Male and Female Mice: Determining Effects of Acute Escitalopram Using Fast Scan Cyclic Voltammetry.

Depression is a highly prevalent psychiatric disorder, impacting females at a rate roughly twice that of males. This disparity has become the focus of many studies which are working to determine if there are environmental or biological underpinnings to depression pathology. The biology of depression is not well understood, but experts agree that a key neurotransmitter of interest is serotonin.

Systems biology of robustness and homeostatic mechanisms.

All organisms are subject to large amounts of genetic and environmental variation and have evolved mechanisms that allow them to function well in spite of these challenges. This property is generally referred to as robustness. We start with the premise that phenotypes arise from dynamical systems and are therefore system properties.

Sex differences in hepatic one-carbon metabolism.

Background: There are large differences between men and women of child-bearing age in the expression level of 5 key enzymes in one-carbon metabolism almost certainly caused by the sex hormones. These male-female differences in one-carbon metabolism are greatly accentuated during pregnancy. Thus, understanding the origin and consequences of sex differences in one-carbon metabolism is important for precision medicine.

Systems Biology of Phenotypic Robustness and Plasticity.

Gene regulatory networks, cellular biochemistry, tissue function, and whole body physiology are imbued with myriad overlapping and interacting homeostatic mechanisms that ensure that many phenotypes are robust to genetic and environmental variation. Animals also often have plastic responses to environmental variables, which means that many different phenotypes can correspond to a single genotype. Since natural selection acts on phenotypes, this raises the question of how selection can act on the genome if genotypes are decoupled from phenotypes by robustness and plasticity mechanisms.

A voltammetric and mathematical analysis of histaminergic modulation of serotonin in the mouse hypothalamus.

Histamine and serotonin are neuromodulators which facilitate numerous, diverse neurological functions. Being co-localized in many brain regions, these two neurotransmitters are thought to modulate one another's chemistry and are often implicated in the etiology of disease. Thus, it is desirable to interpret the in vivo chemistry underlying neurotransmission of these two molecules to better define their roles in health and disease.

Mathematical modeling of perifusion cell culture experiments on GnRH signaling.

The effects of pulsatile GnRH stimulation on anterior pituitary cells are studied using perifusion cell cultures, where constantly moving culture medium over the immobilized cells allows intermittent GnRH delivery. The LH content of the outgoing medium serves as a readout of the GnRH signaling pathway activation in the cells. The challenge lies in relating the LH content of the medium leaving the chamber to the cellular processes producing LH secretion.

Mathematical analysis of the regulation of competing methyltransferases.

Background: Methyltransferase (MT) reactions, in which methyl groups are attached to substrates, are fundamental to many aspects of cell biology and human physiology. The universal methyl donor for these reactions is S-adenosylmethionine (SAM) and this presents the cell with an important regulatory problem. If the flux along one pathway is changed then the SAM concentration will change affecting all the other MT pathways, so it is difficult for the cell to regulate the pathways independently.

Using mathematical models to understand metabolism, genes, and disease.

Mathematical models are a useful tool for investigating a large number of questions in metabolism, genetics, and gene-environment interactions. A model based on the underlying biology and biochemistry is a platform for in silico biological experimentation that can reveal the causal chain of events that connect variation in one quantity to variation in another. We discuss how we construct such models, how we have used them to investigate homeostatic mechanisms, gene-environment interactions, and genotype-phenotype mapping, and how they can be used in precision and personalized medicine.

Escape from homeostasis.

Many physiological systems, from gene networks to biochemistry to whole organism physiology, exhibit homeostatic mechanisms that keep certain variables within a fairly narrow range. Because homeostatic mechanisms buffer traits against environmental and genetic variation they allow the accumulation of cryptic genetic variation. Homeostatic mechanisms are never perfect and can be destabilized by mutations in genes that alter the kinetics of the underlying mechanism.

Mathematical modeling of the effects of glutathione on arsenic methylation.

Background: Arsenic is a major environmental toxin that is detoxified in the liver by biochemical mechanisms that are still under study. In the traditional metabolic pathway, arsenic undergoes two methylation reactions, each followed by a reduction, after which it is exported and released in the urine. Recent experiments show that glutathione plays an important role in arsenic detoxification and an alternative biochemical pathway has been proposed in which arsenic is first conjugated by glutathione after which the conjugates are methylated.

Targeted metabolomics and mathematical modeling demonstrate that vitamin B-6 restriction alters one-carbon metabolism in cultured HepG2 cells.

Low vitamin B-6 nutritional status is associated with increased risk for cardiovascular disease and certain cancers. Pyridoxal 5'-phosphate (PLP) serves as a coenzyme in many cellular processes, including several reactions in one-carbon (1C) metabolism and the transsulfuration pathway of homocysteine catabolism. To assess the effect of vitamin B-6 deficiency on these processes and associated pathways, we conducted quantitative analysis of 1C metabolites including tetrahydrofolate species in HepG2 cells cultured in various concentrations of pyridoxal.