The association between brain serotonin transporter binding and impulsivity and aggression in healthy individuals.

The serotonin system plays a critical role in the modulation of impulsive aggression. Although serotonin transporters (SERT) are key in modulating synaptic serotonin levels, few studies have investigated the role of SERT levels in human impulsive aggression. The aim of this study was to investigate whether brain SERT levels are associated with trait impulsive aggression.

GCN5L1 impairs diastolic function in mice exposed to a high fat diet by restricting cardiac pyruvate oxidation.

Left ventricular diastolic dysfunction is a structural and functional condition that precedes the development of heart failure with preserved ejection fraction (HFpEF). The etiology of diastolic dysfunction includes alterations in fuel substrate metabolism that negatively impact cardiac bioenergetics, and may precipitate the eventual transition to heart failure. To date, the molecular mechanisms that regulate early changes in fuel metabolism leading to diastolic dysfunction remain unclear.

Smooth muscle cell CYB5R3 preserves cardiac and vascular function under chronic hypoxic stress.

Chronic hypoxia is a major driver of cardiovascular complications, including heart failure. The nitric oxide (NO) - soluble guanylyl cyclase (sGC) - cyclic guanosine monophosphate (cGMP) pathway is integral to vascular tone maintenance. Specifically, NO binds its receptor sGC within vascular smooth muscle cells (SMC) in its reduced heme (Fe) form to increase intracellular cGMP production, activate protein kinase G (PKG) signaling, and induce vessel relaxation.

Xanthine Oxidase Drives Hemolysis and Vascular Malfunction in Sickle Cell Disease.

Objective: Chronic hemolysis is a hallmark of sickle cell disease (SCD) and a driver of vasculopathy; however, the mechanisms contributing to hemolysis remain incompletely understood. Although XO (xanthine oxidase) activity has been shown to be elevated in SCD, its role remains unknown. XO binds endothelium and generates oxidants as a byproduct of hypoxanthine and xanthine catabolism.

Commercial 4-dimensional echocardiography for murine heart volumetric evaluation after myocardial infarction.

Background: Traditional preclinical echocardiography (ECHO) modalities, including 1-dimensional motion-mode (M-Mode) and 2-dimensional long axis (2D-US), rely on geometric and temporal assumptions about the heart for volumetric measurements. Surgical animal models, such as the mouse coronary artery ligation (CAL) model of myocardial infarction, result in morphologic changes that do not fit these geometric assumptions. New ECHO technology, including 4-dimensional ultrasound (4D-US), improves on these traditional models.

Measuring endogenous changes in serotonergic neurotransmission with [C]Cimbi-36 positron emission tomography in humans.

Developing positron emission tomography (PET) radioligands for the detection of endogenous serotonin release will enable the investigation of serotonergic deficits in many neuropsychiatric disorders. The present study investigates how acute challenges that aim to increase or decrease cerebral serotonin levels affect binding of the serotonin 2A receptor (5-HTR) agonist radioligand [C]Cimbi-36. In a randomized, double-blind, placebo-controlled, three-arm design, 23 healthy volunteers were PET scanned twice with [C]Cimbi-36: at baseline and following double-blind assignment to one of three interventions (1) infusion of the selective serotonin reuptake inhibitor (SSRI) citalopram preceded by oral dosing of the 5-HTR antagonist pindolol, (n = 8) (2) acute tryptophan depletion (ATD) (n = 7) and (3) placebo (n = 8).

Seasonality-resilient individuals downregulate their cerebral 5-HT transporter binding in winter - A longitudinal combined C-DASB and C-SB207145 PET study.

We have recently shown that the emergence and severity of seasonal affective disorder (SAD) symptoms in the winter is associated with an increase in cerebral serotonin (5-HT) transporter (SERT) binding. Intriguingly, we also found that individuals resilient to SAD downregulate their cerebral SERT binding in the winter. In the present paper, we provide an analysis of the SERT- and 5-HT dynamics as indexed by 5-HT receptor (5-HT4R) binding related to successful stress coping.

Self-perceived personality characteristics in seasonal affective disorder and their implications for severity of depression.

The personality traits Neuroticism and Extraversion may be involved in the development of seasonal affective disorder (SAD). However, the impact of personality traits on SAD severity and whether such self-reported traits fluctuate with season is unknown. We investigated the association between Neuroticism, as acquired in a symptom-free phase and depression severity in individuals with SAD and seasonal changes in personality traits in individuals with SAD compared to healthy controls.

Amygdala response to emotional faces in seasonal affective disorder.

Background: Seasonal affective disorder (SAD) is characterized by seasonally recurring depression. Heightened amygdala activation to aversive stimuli is associated with major depressive disorder but its relation to SAD is unclear. We evaluated seasonal variation in amygdala activation in SAD and healthy controls (HC) using a longitudinal design targeting the asymptomatic/symptomatic phases of SAD.

Season-independent cognitive deficits in seasonal affective disorder and their relation to depressive symptoms.

Although cognitive impairments are common in depressed individuals, it is unclear which aspects of cognition are affected and whether they represent state or trait features of depression. We here exploited a naturalistic model, namely the seasonal fluctuations in depressed status in individuals with Seasonal Affective Disorder (SAD), to study depression-related cognition, longitudinally. Twenty-nine medication-free individuals diagnosed with winter-SAD and 30 demographically matched healthy controls with no seasonality symptoms completed the Letter-number Sequencing task (LNS), the Symbol Digit Modalities Test (SDMT) and the Simple Reaction Time (SRT) twice; in summer and in winter.

Brain serotonin 4 receptor binding is inversely associated with verbal memory recall.

Background: We have previously identified an inverse relationship between cerebral serotonin 4 receptor (5-HT R) binding and nonaffective episodic memory in healthy individuals. Here, we investigate in a novel sample if the association is related to affective components of memory, by examining the association between cerebral 5-HT R binding and affective verbal memory recall.

Methods: Twenty-four healthy volunteers were scanned with the 5-HT R radioligand [C]SB207145 and positron emission tomography, and were tested with the Verbal Affective Memory Test-24.

State-dependent alterations in inhibitory control and emotional face identification in seasonal affective disorder.

Background: Depressed individuals often exhibit impaired inhibition to negative input and identification of positive stimuli, but it is unclear whether this is a state or trait feature. We here exploited a naturalistic model, namely individuals with seasonal affective disorder (SAD), to study this feature longitudinally.

Aim: The goal of this study was to examine seasonal changes in inhibitory control and identification of emotional faces in individuals with SAD.

Bright-light intervention induces a dose-dependent increase in striatal response to risk in healthy volunteers.

Bright-light interventions have successfully been used to reduce depression symptoms in patients with seasonal affective disorder, a depressive disorder most frequently occurring during seasons with reduced daylight availability. Yet, little is known about how light exposure impacts human brain function, for instance on risk taking, a process affected in depressive disorders. Here we examined the modulatory effects of bright-light exposure on brain activity during a risk-taking task.

Seasonal difference in brain serotonin transporter binding predicts symptom severity in patients with seasonal affective disorder.

Cross-sectional neuroimaging studies in non-depressed individuals have demonstrated an inverse relationship between daylight minutes and cerebral serotonin transporter; this relationship is modified by serotonin-transporter-linked polymorphic region short allele carrier status. We here present data from the first longitudinal investigation of seasonal serotonin transporter fluctuations in both patients with seasonal affective disorder and in healthy individuals. Eighty (11)C-DASB positron emission tomography scans were conducted to quantify cerebral serotonin transporter binding; 23 healthy controls with low seasonality scores and 17 patients diagnosed with seasonal affective disorder were scanned in both summer and winter to investigate differences in cerebral serotonin transporter binding across groups and across seasons.

Brain serotonin 4 receptor binding is associated with the cortisol awakening response.

Serotonin signalling is considered critical for an appropriate and dynamic adaptation to stress. Previously, we have shown that prefrontal serotonin transporter (SERT) binding is positively associated with the cortisol awakening response (CAR) (Frokjaer et al., 2013), which is an index of hypothalamic-pituitary-adrenal (HPA)-axis output dynamics.

Serotonin 2A receptor agonist binding in the human brain with [(11)C]Cimbi-36: Test-retest reproducibility and head-to-head comparison with the antagonist [(18)F]altanserin.

Introduction: [(11)C]Cimbi-36 is a recently developed serotonin 2A (5-HT2A) receptor agonist positron emission tomography (PET) radioligand that has been successfully applied for human neuroimaging. Here, we investigate the test-retest variability of cerebral [(11)C]Cimbi-36 PET and compare [(11)C]Cimbi-36 and the 5-HT2A receptor antagonist [(18)F]altanserin.

Methods: Sixteen healthy volunteers (mean age 23.

High trait aggression in men is associated with low 5-HT levels, as indexed by 5-HT4 receptor binding.

Impulsive aggression has commonly been associated with a dysfunction of the serotonin (5-HT) system: many, but not all, studies point to an inverse relationship between 5-HT and aggression. As cerebral 5-HT4 receptor (5-HT4R) binding has recently been recognized as a proxy for stable brain levels of 5-HT, we here test the hypothesis in healthy men and women that brain 5-HT levels, as indexed by cerebral 5-HT4R, are inversely correlated with trait aggression and impulsivity. Sixty-one individuals (47 men) underwent positron emission tomography scanning with the radioligand [(11)C]SB207145 for quantification of brain 5-HT4R binding.

Threat-related amygdala functional connectivity is associated with 5-HTTLPR genotype and neuroticism.

Communication between the amygdala and other brain regions critically regulates sensitivity to threat, which has been associated with risk for mood and affective disorders. The extent to which these neural pathways are genetically determined or correlate with risk-related personality measures is not fully understood. Using functional magnetic resonance imaging, we evaluated independent and interactive effects of the 5-HTTLPR genotype and neuroticism on amygdala functional connectivity during an emotional faces paradigm in 76 healthy individuals.

Serotonin 2A receptor agonist binding in the human brain with [¹¹C]Cimbi-36.

[(11)C]Cimbi-36 was recently developed as a selective serotonin 2A (5-HT(2A)) receptor agonist radioligand for positron emission tomography (PET) brain imaging. Such an agonist PET radioligand may provide a novel, and more functional, measure of the serotonergic system and agonist binding is more likely than antagonist binding to reflect 5-HT levels in vivo. Here, we show data from a first-in-human clinical trial with [(11)C]Cimbi-36.

Three-week bright-light intervention has dose-related effects on threat-related corticolimbic reactivity and functional coupling.

Background: Bright-light intervention is reported to successfully treat depression, in particular seasonal affective disorder, but the neural pathways and molecular mechanisms mediating its effects are unclear. An amygdala-prefrontal cortex corticolimbic circuit regulates responses to salient environmental stimuli (e.g.

5-HTTLPR status predictive of neocortical 5-HT4 binding assessed with [(11)C]SB207145 PET in humans.

Serotonin (5-HT) is a neuromodulator affecting myriad aspects of personality and behavior and has been implicated in the pathophysiology of affective disorders including depression and anxiety. The 5-HTTLPR is a common genetic polymorphism within the promoter region of the gene coding for the serotonin transporter such that the S allele is associated with reduced transcriptional efficacy compared to the L allele, potentially contributing to increased serotonin levels. In humans, this genetic variant has been linked to inter-individual variability in risk for affective disorders, related aspects of personality and brain function including response to threat.