Oxytocinergic modulation of stress-associated amygdala-hippocampus pathways in humans is specially mediated by serotonergic mechanisms

Background: The hypothalamic neuropeptide oxytocin (OXT) may exert anxiolytic and stress-reducing actions via modulatory effects on amygdala circuits. Animal models and initial findings in humans suggest that some of these effects are mediated by interactions with other neurotransmitter systems, in particular the serotonin (5-HT) system. Against this background, the present pharmacological resting state fMRI study aimed at determining whether effects of OXT on stress-associated amygdala intrinsic networks are mediated by 5-HT. Methods: We employed a randomized placebo-controlled double-blind parallel-group pharmacological fMRI resting state experiment during which n = 112 healthy male participants underwent a transient decrease in 5-HT signaling via acute tryptophan depletion (ATD+) or the corresponding placebo-control protocols (ATD-) before the administration of intranasal OXT or placebo intranasal spray, respectively. Results: OXT and 5-HT modulation exerted interactive effects on the coupling of the left amygdala with the ipsilateral hippocampus and adjacent midbrain. OXT increased intrinsic coupling in this pathway, while this effect of OXT was significantly attenuated during transiently decreased central serotonergic signaling induced via ATD+. In the absence of OXT or 5-HT modulation this pathway was associated with self-reported stress perception in everyday life, while an OXT-induced modulation of this pathway was following ATD- pre-treatment. Conclusions: Together, the findings provide first evidence that effects of OXT on stress-associated amygdala-hippocampal-midbrain pathways are critically mediated by the 5-HT system in men.

The short chain fatty acid butyrate prevents intracellular replication of Legionella by regulating cysteine levels in macrophages

Macrophages can prevent infections from intracellular pathogens by restricting access to essential nutrients, termed nutritional immunity. With the exception of tryptophan depletion, it is unclear if other amino acids are similarly regulated in infected macrophages. Here, we show that the expression of nutrient transporters in Legionella-infected macrophages is modulated by the short chain fatty acid butyrate. Butyrate prevented the upregulation of the cystine/glutamate exchanger, Slc7a11, in macrophages infected with L. pneumophila, which decreased cellular cysteine levels. Butyrate and the Slc7a11 inhibitor erastin impaired intracellular Legionella replication in macrophages in vitro, with these being restored by exogenous supplementation with cysteine. Butyrate caused increased histone acetylation in infected macrophages, and pan- and class II HDAC inhibitors also restricted intracellular Legionella growth in a cysteine-dependent manner. Intranasal administration of butyrate reduced L. pneumophila lung burdens in mice. Our data suggest that butyrate alters the metabolism of macrophages to promote nutritional immunity by decreasing cysteine levels and that this can be harnessed to treat bacterial lung infections.

Serotonin depletion impairs both Pavlovian and instrumental reversal learning in healthy humans

Serotonin is involved in updating responses to changing environmental circumstances. Optimising behaviour to maximise reward and minimise punishment may require shifting strategies upon encountering new situations. Likewise, autonomic responses to threats are critical for survival yet must be modified as danger shifts from one source to another. Whilst numerous psychiatric disorders are characterised by behavioural and autonomic inflexibility, few studies have examined the contribution of serotonin in humans. We modelled both processes, respectively, in two independent experiments (N = 97). Experiment 1 assessed instrumental (stimulus-response-outcome) reversal learning whereby individuals learned through trial and error which action was most optimal for obtaining reward or avoiding punishment initially, and the contingencies subsequently reversed serially. Experiment 2 examined Pavlovian (stimulus-outcome) reversal learning assessed by the skin conductance response: one innately threatening stimulus predicted receipt of an uncomfortable electric shock and another did not; these contingencies swapped in a reversal phase. Upon depleting the serotonin precursor tryptophan—in a double-blind randomised placebo-controlled design—healthy volunteers showed impairments in updating both actions and autonomic responses to reflect changing contingencies. Reversal deficits in each domain, furthermore, were correlated with the extent of tryptophan depletion. Initial Pavlovian conditioning, moreover, which involved innately threatening stimuli, was potentiated by depletion. These results translate findings in experimental animals to humans and have implications for the neurochemical basis of cognitive inflexibility.

Harnessing temperament to elucidate the complexities of serotonin function

This review highlights the utility of using concepts of consistent behavioural patterns (CBPs) (temperament in healthy individuals; and psychopathology of mental illness) in conjunction with situational contextuality. We also point to multiple roles of central serotonin (5-hydroxytryptamine, 5-HT) as a biomarker of CBPs. We use empirical demonstrations of the complex and trait-dependent effects of manipulating 5-HT via acute dietary tryptophan depletion (ATD) to highlight the relevance of these constructs in the neurochemical control of behaviour. Neurochemical and temperament trait interactions, for example, 5-HT and empathy, psychopathy, neuroticism, impulsivity, and hyperthymia are postulated to underlie this complexity.

Parasite and host defense mechanisms: whenToxoplasma subjugates the brain

Brain is an immune-privileged organ for infection with the neurotropic protozoan parasite, Toxoplasma gondii. T. gondii escapes the immune system by establishing a dormant and lifelong bradyzoite cyst during chronic and latent phases within the brain and musculature of immunocompetent individuals. During acute stage T. gondii stimulates the host defense to display depressive behaviors over a background of sickness. Infection with T. gondii is initiated with its proliferative tachyzoite that acts on peripheral immune cells to produce the pro-inflammatory cytokines, most of them induce the behavioral signs of sickness. For instance, interleukin-(IL) 1β, tumor necrosis factor-α and IL-6 are triggering most of sickness symptoms. Whereas, the cardinal inflammatory cytokine interferon-γ activates, indoleamine 2,3 dioxygenase (IDO), an enzyme mainly synthesized by phagocytic cells like macrophages and microglia. IDO activation causes tryptophan depletion and precipitates the depressive symptoms. On other hand, brain encysting with the bradyzoite is characterized by immunosuppression in form of reduced pro-inflammatory and heightened anti-inflammatory responses as evidenced by increased phagocytic activity and release of IL-10 and TGF-β. To conclude, T. gondii has multiple strategies to harness the host’s immune mechanisms and behavior by the virtue of dual effects of tachyzoite-induced immune invasion intertwined with bradyzoite-induced immune evasion.

Pro-Inflammatory Cytokines: Potential Links between the Endocannabinoid System and the Kynurenine Pathway in Depression

Substance use/abuse is one of the main causes of depressive symptoms. Cannabis and synthetic cannabinoids in particular gained significant popularity in the past years. There is an increasing amount of clinical data associating such compounds with the inflammatory component of depression, indicated by the up-regulation of pro-inflammatory cytokines. Pro-inflammatory cytokines are also well-known to regulate the enzymes of the kynurenine pathway (KP), which is responsible for metabolizing tryptophan, a precursor in serotonin synthesis. Enhanced pro-inflammatory cytokine levels may over-activate the KP, leading to tryptophan depletion and reduced serotonin levels, which can subsequently precipitate depressive symptoms. Therefore, such mechanism might represent a possible link between the endocannabinoid system (ECS) and the KP in depression, via the inflammatory and dysregulated serotonergic component of the disorder. This review will summarize the data regarding those natural and synthetic cannabinoids that increase pro-inflammatory cytokines. Furthermore, the data on such cytokines associated with KP activation will be further reviewed accordingly. The interaction of the ECS and the KP has been postulated and demonstrated in some studies previously. This review will further contribute to this yet less explored connection and propose the KP to be the missing link between cannabinoid-induced inflammation and depressive symptoms.

Perseverative behavior under uncertainty is enhanced by tryptophan depletion but diminished with subclinical obsessive–compulsive symptoms

Serotonin is critically involved in flexible decision-making, yet the preponderance of evidence comes from non-human studies. Many insights about the serotonin's function have come from the technique of dietary acute tryptophan depletion (ATD). However, it is unclear whether ATD modulates choice behavior during probabilistic reversal learning (PRL), a widely used model of behavioral flexibility with significant translational and clinical value. To determine whether ATD affects latent choice tendencies, we applied computational models of reinforcement learning to PRL data from healthy human volunteers (n = 62; 29 females) who had received either ATD or placebo in a randomized, double-blind, placebo-controlled procedure. A secondary objective was to ascertain how model parameters related to clinically relevant self-report questionnaires. ATD did not affect the updating ("learning rates") or deployment ("reinforcement sensitivity") of value representations driving choice. However, ATD increased "stimulus stickiness", the tendency to choose a previously chosen visual stimulus again, regardless of reinforcement--a pattern seen in stimulant use disorder (SUD). Greater subclinical obsessive-compulsive symptoms were associated with lower stimulus stickiness, a pattern seen in clinically diagnosed obsessive-compulsive disorder (OCD). Low reinforcement sensitivity was instead related to intolerance of uncertainty and symptoms of depression and anxiety. Individuals with higher trait impulsivity showed lower reward and higher punishment learning rates, which parallels findings in SUD. Collectively, these results point to a role for serotonin in compulsive tendencies. They underscore the utility of computational modelling in illuminating the microstructure of behavior, which could point towards new markers of vulnerability to psychopathology.

Acute tryptophan depletion in healthy subjects increases preferences for negative reciprocity

Reciprocity motivates to reward those who are kind (= positive reciprocity) and to punish those who are unkind (= negative reciprocity). The neurotransmitter serotonin (5-HT) modulates human behavior in numerous social situations, such as retaliation in response to perceived unfairness. In a placebo-controlled study, we used acute tryptophan depletion (ATD) to investigate the influence of available serotonin on choice behavior and reciprocity in the Hawk-Dove game. This game illustrates a conflict situation and incorporates two potential strategies: the cooperative Dove strategy and the uncooperative, more aggressive Hawk strategy. After strategic choices, we elicited the subjects’ expectations (= beliefs) regarding the opponent’s choices and controlled for risk preferences and current mood. We defined strategy choices as negative reciprocity when the participants opted for Hawk in response to an expected Hawk. We hypothesized that the ATD-induced reduction of 5-HT availability would increase participants’ preferences for negative reciprocity. Generalized estimating equations reveal no significant main effect of ATD on assessed belief, mood, or risk attitude. But assessment of ATD’s marginal effects over beliefs suggests that ATD significantly increases the tendency for negative reciprocity, whereas positive reciprocity (Dove in response to an expected Dove) is unaffected. We could therefore demonstrate that 5-HT availability mediates (negative) reciprocal behavior in social decision-making.

c-Myc plays a key role in IFN-γ induced persistence of Chlamydia trachomatis

SummaryChlamydia trachomatis (Ctr) can persist over long periods of time within their host cell and thereby establish chronic infections. One of the major inducers of chlamydial persistence is interferon-gamma (IFN-γ) released by immune cells as a mechanism of immune defence. IFN-γ activates the catabolic depletion of L-tryptophan (Trp) via indoleamine 2,3-dioxygenase (IDO), resulting in persistent Chlamydia. Here we show that IFN-γ depletes c-Myc, the key regulator of host cell metabolism, in a STAT1-dependent manner. Expression of c-Myc rescued Chlamydia from IFN-γ-induced persistence in cultured cell lines, but also in human fallopian tube organoids. L-tryptophan concentrations control c-Myc levels via the PI3K-GSK3ß axis. Unbiased metabolic analysis revealed that Chlamydia infection reprograms the host cell tricarboxylic acid (TCA) cycle to support pyrimidine biosynthesis. Addition of TCA cycle intermediates or pyrimidine/purine nucleosides to infected cells rescued Chlamydia from IFN-γ-induced persistence. Thus, our results challenge the longstanding hypothesis of L-tryptophan depletion through IDO as the major mechanism of IFN-γ-induced metabolic immune defence and significantly extends the understanding of the role IFN-γ as a broad modulator of host cell metabolism.