Cerebral blood flow predicts differential neurotransmitter activity

Application of metabolic magnetic resonance imaging measures such as cerebral blood flow in translational medicine is limited by the unknown link of observed alterations to specific neurophysiological processes. In particular, the sensitivity of cerebral blood flow to activity changes in specific neurotransmitter systems remains unclear. We address this question by probing cerebral blood flow in healthy volunteers using seven established drugs with known dopaminergic, serotonergic, glutamatergic and GABAergic mechanisms of action. We use a novel framework aimed at disentangling the observed effects to contribution from underlying neurotransmitter systems. We find for all evaluated compounds a reliable spatial link of respective cerebral blood flow changes with underlying neurotransmitter receptor densities corresponding to their primary mechanisms of action. The strength of these associations with receptor density is mediated by respective drug affinities. These findings suggest that cerebral blood flow is a sensitive brain-wide in-vivo assay of metabolic demands across a variety of neurotransmitter systems in humans

Could dopamine agonists aid in drug development for anorexia nervosa?

Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage-years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight, and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological, and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction, and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction, and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways

Snca and Bdnf gene expression in the VTA and raphe nuclei of midbrain in chronically victorious and defeated male mice

The study aimed to analyze the mRNA levels of Snca and Bdnf genes in the ventral tegmental area (VTA) and raphe nuclei of the midbrain in male mice that had each won or defeated 20 encounters in daily agonistic interactions. Groups of animals that had the same winning and losing track record followed by a no-fight period for 14 days were also studied. Snca mRNA levels were increased in the raphe nuclei in the losers and in the VTA of the winners. After fighting deprivation Snca mRNA levels were decreased to the control level in both groups. Snca mRNA levels were similar to the control level in the VTA of the losers and in the raphe nuclei of the winners. However Snca gene expression was increased in these areas after no-fight period in the winners and losers in comparison with respective mRNA levels in the undeprived animals. Significant positive correlations were found between the mRNA levels of Snca and Bdnf genes in the raphe nuclei. It was concluded, that social experience affects Snca gene expression depending on brain areas and functional activity of monoaminergic systems in chronically victorious or defeated mice

Serotonin, Inhibition, and Negative Mood

Pavlovian predictions of future aversive outcomes lead to behavioral inhibition, suppression, and withdrawal. There is considerable evidence for the involvement of serotonin in both the learning of these predictions and the inhibitory consequences that ensue, although less for a causal relationship between the two. In the context of a highly simplified model of chains of affectively charged thoughts, we interpret the combined effects of serotonin in terms of pruning a tree of possible decisions, (i.e., eliminating those choices that have low or negative expected outcomes). We show how a drop in behavioral inhibition, putatively resulting from an experimentally or psychiatrically influenced drop in serotonin, could result in unexpectedly large negative prediction errors and a significant aversive shift in reinforcement statistics. We suggest an interpretation of this finding that helps dissolve the apparent contradiction between the fact that inhibition of serotonin reuptake is the first-line treatment of depression, although serotonin itself is most strongly linked with aversive rather than appetitive outcomes and predictions

Acute tryptophan depletion attenuates conscious appraisal of social emotional signals in healthy female volunteers

Rationale: Acute tryptophan depletion (ATD) decreases levels of central serotonin. ATD thus enables the cognitive effects of serotonin to be studied, with implications for the understanding of psychiatric conditions, including depression. Objective: To determine the role of serotonin in conscious (explicit) and unconscious/incidental processing of emotional information. Materials and methods: A randomized, double-blind, cross-over design was used with 15 healthy female participants. Subjective mood was recorded at baseline and after 4 h, when participants performed an explicit emotional face processing task, and a task eliciting unconscious processing of emotionally aversive and neutral images presented subliminally using backward masking. Results: ATD was associated with a robust reduction in plasma tryptophan at 4 h but had no effect on mood or autonomic physiology. ATD was associated with significantly lower attractiveness ratings for happy faces and attenuation of intensity/arousal ratings of angry faces. ATD also reduced overall reaction times on the unconscious perception task, but there was no interaction with emotional content of masked stimuli. ATD did not affect breakthrough perception (accuracy in identification) of masked images. Conclusions: ATD attenuates the attractiveness of positive faces and the negative intensity of threatening faces, suggesting that serotonin contributes specifically to the appraisal of the social salience of both positive and negative salient social emotional cues. We found no evidence that serotonin affects unconscious processing of negative emotional stimuli. These novel findings implicate serotonin in conscious aspects of active social and behavioural engagement and extend knowledge regarding the effects of ATD on emotional perception

Socially driven changes in neural and behavioural plasticity in zebrafish

Tese de doutoramento, Biologia (Etologia), Universidade de Lisboa, Faculdade de Ciências, 2015Social competence, the ability of individuals to regulate the expression of their social behaviour in order to optimize their social relationships in a group, is especially benefic for individuals living in complex social environments, and implies the ability to perceive social cues and produce appropriate behavioural output responses (Social Plasticity). Numerous examples of social competence can be found in nature, where individuals extract social information from the environment, and change their behavioural response based on the collected information. At the neuronal level, two major plasticity mechanisms have been proposed to underlie social plasticity, structural reorganization and biochemical switching of the neuronal networks underlying behaviour. The neural substrate for behavioural plasticity has been identified as the social decision-making (SDM) network, such that the same neural circuitry may underlie the expression of different behaviours depending on social context. The goal of this work is to study the proximate mechanism underlying behavioural flexibility in the context of experience-dependent behavioural shifts, in an integrative framework. For this purpose we exposed male zebrafish to two types of social interactions: (1) real-opponent interactions, from which a Winner and Loser emerged; and (2) Mirror-elicited interactions, that produced individuals that did not experience a change in social status, despite expressing similar levels of aggressive behaviour to those participating in real-opponent fights. In a first set of experiments, we studied the influence of neuromodulators on social plasticity mechanisms, by characterizing the endocrine response to social challenges, as well as the social modulation of brain monoamines and nonapeptides. Next we tested the SDM network hypothesis by contrasting changes in functional localization vs. connectivity across this network. Finally we characterized changes in expression of key genes for different neuroplasticity mechanisms in response to changes in social status. Our research suggests different social plasticity mechanisms underlying Winners and Losers both at physiological and molecular levels, for Mirror-fighters, where the experience of winning or losing was decoupled for the fighting experience, few changes were detected. This, by itself suggests a pivotal role of social perception in triggering shifts between socially driven behavioural states

Sensory Contact Model: Protocol, Control, Applications

Among the models that become more and more popular in behavioral neuroscience are biosocial models, which allow studying the consequences of chronic social conflicts and social stress in animals. The sensory contact model appears to represent one of such models. Repeated experience of aggression or social defeats in daily agonistic interactions in male mice of different strains leads to the formation of opposing kinds of social behavior: one attributable to winners (aggressors) and another attributable to losers (defeated males, victims of aggression). A large variety of behavioral pathologies which develop in male mice in these conditions (anxious depression, catalepsy, social withdrawal, pronounced aggression, anxiety, hyperactivity, cognitive disturbances, anhedonia etc.), which are accompanied by somatic changes (reduced gonad function, psychogenic immune deficiency etc), suggest that this approach could be used for different aims of biomedical studies. Putative mechanisms of release and maintenance of aggressive and submissive behaviors in male mice under the sensory contact model, criteria of correct application, basic experimental setups and problem of the control, methodical capabilities and potentials of the sensory contact model applications are discussed in this paper

Aluminum-induced testosterone decrease results in physiological and behavioral changes in male mice

Recently, there has been much controversy on the role of testosterone on social and aggression behaviors. This work aimed to determine the effect of testosterone decrease, induced by aluminum exposure on the level of aggression. Male Swiss-Webster strain mice were classified into three groups. The first (control group) received distilled water, while the second and third groups were administrated 300 and 600 mg/kg aluminum chloride, respectively, by oral route for 20 days. Thereafter, they were subjected to “standard opponent” test. A significant decrease in testosterone levels in the treated groups was obtained at both the low and high doses of aluminum. Expectedly, significant decreases were observed in the social contacts, threat, attack and number of fights of both treated groups in a dose dependant manner. All blood parameters revealed a dose dependent significant decrease as well. A significant decrease in both serotonin and dopamine levels was simultaneously obtained with the decrease of testosterone level especially at the high dose of aluminum. In contrast, at the high dose, acetylcholine recorded significantly high value. In conclusion, aluminum-induced testosterone decrease resulted in a significant decline in aggression, several blood parameters and levels of neurotransmitters.Keywords: Aluminum, Swiss-Webster mice, standard opponent test, social behavior, testosteron

Molecular implications of prolonged aggression experience: Th, Dat1, Snca and Bdnf gene expression in the ventral tegmental area of the victorious male mice

Th, Dat1, Snca and Bdnf were the genes whose mRNA levels in the ventral tegmental area of the midbrain were measured in male mice that were victorious in 20 daily agonistic interactions and in a group of such victorious mice that had later not been allowed to fight for 14 days. This experiment demonstrated increased Th, Dat1 and Snca but not Bdnf mRNA levels in the former group as compared to the controls. In the latter group, the expression of the Th and Dat1 genes was still enhanced, while the level of Snca mRNA did not differ from that in the controls. These findings suggest that positive fighting experience enhances the expression of the genes concerned with dopaminergic systems and this enhanced expression is preserved for a long time afterwards. Significant positive correlations were found between the level of aggression and Th and Snca mRNA levels in the winners

Neuropharmocological Alterations of the Aggressive Behavior of Crayfish

Serotonergic-related compounds often facilitate aggression in various animals, including crayfish. However to date, studies have seldom shown the mechanism by which serotonergicrelated compounds alter aggressive behavior. It is assumed that serotonin changes the neurochemistry of those injected. In our study, we have attempted to report an observable mechanism by examining the communication system of crayfish. Crayfish use urine to communicate aggressive status, thus we analyzed the frequency of urine release from those injected with serotonergic-related compounds. For each trial, two size-matched crayfish, within 5% body weight, were allowed to interact after injection with serotonin, an agonist, an antagonist, or vehicle control. The concentration of all drugs was 3mM at a delivery dosage of 0.1ml/g. Aggressive interactions were recorded under black light to illuminate a fluorescein dye that was added to all injections. Urine release and aggressive behaviors were then analyzed