Simultaneous and Spectroscopic Redox Molecular Imaging of Multiple Free Radical Intermediates Using Dynamic Nuclear Polarization-Magnetic Resonance Imaging

Redox reactions that generate free radical intermediates are essential to metabolic processes. However, their intermediates can produce reactive oxygen species, which may promote diseases related to oxidative stress. We report here the use of dynamic nuclear polarization-magnetic resonance imaging (DNP-MRI) to conduct redox molecular imaging. Using DNP-MRI, we obtained simultaneous images of free radical intermediates generated from the coenzyme Q₁₀ (CoQ₁₀), flavin mononucleotide (FMN), and flavin adenine dinucleotide (FAD) involved in the mitochondrial electron transport chain as well as the radicals derived from vitamins E and K₁. Each of these free radicals was imaged in real time in a phantom comprising a mixture of free radicals localized in either lipophilic or aqueous environments. Changing the frequency of electron spin resonance (ESR) irradiation also allowed each of the radical species to be distinguished in the spectroscopic images. This study is the first to report the spectroscopic DNP-MRI imaging of free radical intermediates that are derived from endogenous species involved in metabolic processes

Minocycline Modulates Human Social Decision-Making: Possible Impact of Microglia on Personality-Oriented Social Behaviors

<div><h3>Background</h3><p>Microglia, one of the glial cells, play important roles in various brain pathologies including psychiatric disorders. In addition, microglia have recently been proved to monitor synaptic reactions via direct-touching even in normal brain. Human microglia may modulate various social/mental functions, while microglial social/mental roles remain unresolved especially in healthy humans. There is no known drug with the specific effect of modulating microglia. Therefore, using minocycline, a tetracycline antibiotic and the most famous microglial inhibitor, is one of the best alternative approaches to clarify microglial functions on human social/mental activities.</p> <h3>Methodology/Principal Findings</h3><p>We conducted a double-blind randomized trial of trust game, a monetary decision-making experiment, with ninety-nine human adult males who decided how much to trust an anonymous partner after a four-day administration of minocycline. Our previous pilot trial indicated a positive effect of minocycline, while the underlying mechanisms were not clarified. Therefore, in this trial with larger samples, we additionally measured the effects of anxiety and personality. The monetary score in trust game was significantly lower in the minocycline group. Interestingly, participants’ ways of decision-making were significantly shifted; cooperativeness, one component of personality, proved to be the main modulating factor of decision-making in the placebo group, on the other hand, the minocycline group was mainly modulated by state anxiety and trustworthiness.</p> <h3>Conclusions/Significance</h3><p>Our results suggest that minocycline led to more situation-oriented decision-making, possibly by suppressing the effects of personality traits, and furthermore that personality and social behaviors might be modulated by microglia. Early-life events may activate human microglia, establish a certain neuro-synaptic connection, and this formation may determine each human’s personality and personality- oriented social behaviors in later life. To explore these mechanisms, further translational research is needed.</p> <h3>Trial Registration</h3><p>UMIN clinical trial center <a href="http://tinyurl.com/7yvmpxb">UMIN000004803</a></p> </div

Behavior in Trust Game, and Effects of Minocycline on Personality, Anxiety and Trust.

<p>We performed t-test on the behavior (monetary score) in trust game, and the average scores are shown in the Table. The effects of minocycline on personality, anxiety and trust were evaluated with the seven subscales of TCI, the two subscales of STAI, and GTS. We performed ANOVA with a repeated measure; the scores of the subscales as the dependent variable, and drug condition (Minocycline vs. Control), repeated measure of the subscales’ scores (<i>Before</i> vs. <i>After</i> treatment) and their interaction as independent variables. As four participants (three for control, one for minocycline group) failed to complete the questions of STAI and GTS, 95 sets of data were analyzed. Significant and/or marginal effects are shown in the Table. Results were expressed as means (S.D.).</p

Trust Game Structure.

<p>Trust Game Structure.</p

Multiple Regression Analysis on Behavior in Trust Game.

<p>Note: *p<.05,</p>**<p>p<.01.</p><p>We performed a multiple linear regression analysis of the amount of money offered in trust game as the dependent variable, and subscales of TCI, STAI and GTS as independent variables by conditions. Remarkable effects are shown in the Table.</p

Possible Impact of Microglia on Personality and Social Behaviors.

<p>Early-life environmental experiences such as psychological stress and traumatic events may activate human microglia, establish a certain neuro-synaptic-microglial connection, which is memorized unconsciously as a primer for an extended period, and this formation in the human brain determines each human’s personality and personality- oriented social behaviors in later life. In sum, neuronal networks with active microglia may induce noisy-decision-making, which is equivalent to personality- oriented behaviors (A). On the other hand, decision-making with neuronal dominant networks may induce straightforward behaviors, which are less affected by personality (B). In the present study, the control group’s personality- oriented behaviors could be formulated by microglial priming effects (A), and the minocycline group’s situation- oriented behaviors may be induced by suppressing microglial contribution to social behaviors (B).</p

Flow Diagram of This Study.

<p>Flow Diagram of This Study.</p