Understanding Reward Dysfunction in Bipolar Affective Disorder through Behavioural, Cognitive and Neurobiological Changes

Bipolar disorder, like many neuropsychiatric conditions, can be studied from a number of perspectives; from observation of behaviour, to study of cognitive dysfunction, through to changes at the molecular and genetic level. A consequence of this way of working is that there is inadequate communication between different levels of analysis, such that insufficient thought is given to whether a theoretical model derived from behavioural work fits with neurobiological data, and vice versa. Such limitations represent a key limiting factor in successful translation. Therefore, this paper takes a dominant theoretical model of bipolar disorder, based on that by Gray (1994) and developed by Alloy et al., (2015) as a basis to propose that the foundational pathology in bipolar is reward hypersensitivity, and to review how recent diverse neurobiological, cognitive and behavioural findings fit with this understanding. Executive Function deficits, partially derived from heritable structural changes are suggested as a foundation through which reward hypersensitivity develops to disorder, and CANA1C polymorphism-induced hyperactivity, further serves to drive the system towards reward seeking goals, through interaction with dopaminergic systems. This action is supplemented by a genetic predisposition for cognitive regulatory dysfunction, leading to improper modulation of emotive and reward networks. Specifically, deficits in top-down limbic modulation leads to behaviours disproportionally driven by limbic and reward circuitry; this pathology strengths over time through use. This therefore eventually results in substantial regional disconnect, reflected in epigenetic changes to neurotransmitters and observable histological changes.

Abnormal brain development of monoamine oxidase mutant zebrafish and impaired social interaction of heterozygous fish

Monoamine oxidase (MAO) deficiency and imbalanced levels of brain monoamines have been associated with developmental delay, neuropsychiatric disorders and aggressive behavior. Animal models are valuable tools to gain mechanistic insight into outcomes associated with MAO deficiency. Here we report a novel genetic model to study the effects of mao-loss-of-function in zebrafish. Quantitative PCR, in situ hybridization and immunocytochemistry were used to study neurotransmitter systems, and expression of relevant genes for brain development in zebrafish mao mutants. Larval and adult fish behavior was evaluated through different tests. A stronger serotonin immunoreactivity was detected in both mao+/- and mao−/- larvae when compared with mao+/+ siblings. Mao−/- larvae were hypoactive, presented decreased reactions to visual and acoustic stimuli. They also had impaired histaminergic and dopaminergic systems, abnormal expression of developmental markers, and they died within 20 days post-fertilization. Mao+/- fish were viable, grew until adulthood and demonstrated anxiety-like behavior and impaired social interactions when compared with adult mao+/+ siblings. Our results indicate that mao−/- and mao+/- mutants could be promising tools to study the roles of MAO in brain development and behavior.

A new experimental design to study inflammation-related versus non-inflammation-related depression in mice

Background Major depressive disorder (MDD) represents a major public health concern, particularly due to its steadily rising prevalence and the poor responsiveness to standard antidepressants notably in patients afflicted with chronic inflammatory conditions, such as obesity. This highlights the need to improve current therapeutic strategies, including by targeting inflammation based on its role in the pathophysiology and treatment responsiveness of MDD. Nevertheless, dissecting the relative contribution of inflammation in the development and treatment of MDD remains a major issue, further complicated by the lack of preclinical depression models suitable to experimentally dissociate inflammation-related vs. inflammation-unrelated depression. Methods While current models usually focus on one particular MDD risk factor, we compared in male C57BL/6J mice the behavioral, inflammatory and neurobiological impact of chronic exposure to high-fat diet (HFD), a procedure known to induce inflammation-related depressive-like behaviors, and unpredictable chronic mild stress (UCMS), a stress-induced depression model notably renowned for its responsivity to antidepressants. Results While both paradigms induced neurovegetative, depressive-like and anxiety-like behaviors, inflammation and downstream neurobiological pathways contributing to inflammation-driven depression were specifically activated in HFD mice, as revealed by increased circulating levels of inflammatory factors, as well as brain expression of microglial activation markers and enzymes from the kynurenine and tetrahydrobiopterin (BH4) pathways. In addition, serotoninergic and dopaminergic systems were differentially impacted, depending on the experimental condition. Conclusions These data validate an experimental design suitable to deeply study the mechanisms underlying inflammation-driven depression comparatively to non-inflammatory depression. This design could help to better understand the pathophysiology of treatment resistant depression.

Effect of early and late pharmacological correction with GABA derivatives on cognitive disorders in offspring of rats with experimental preeclampsia

BACKGROUND: Preeclampsia is a serious complication of pregnancy which augments the risk of cognitive disorders in the offspring at different stages of life. Presently, there are no methods with proven effectiveness for correction of post-hypoxic disorders in children of mothers with preeclampsia. AIM: To assess the cognitive functions of the offspring of rats with experimental preeclampsia (EP) through early (40th to 70th day of life) and late (24th to 25th month of life) pharmacological correction with gamma aminobutyric acid (GABA) derivatives: Succicard, Salifen, Phenibut, and the drug of comparisonPantogam. MATERIALS AND METHODS: EP was modeled by replacing drinking water with 1.8% sodium chloride solution in rats from the first day of pregnancy to delivery. In the offspring, short-term and long-term memory was studied at the age of 34, 1819, and 2526 months in the Novel object recognition test and Barnes Maze test. The functioning of the GABAergic and dopaminergic systems (which play an essential role in the development of memory) was evaluated by cases of convulsions after administering corazol at a dose of 20 mg/kg intraperitoneally (model of corazol kindling) and by haloperidol-induced catalepsy (haloperidol at a dose of 0.3 mg/kg intraperitoneally), respectively. RESULTS: Early and late pharmacological correction with GABA derivativessuccicard, Salifen, Phenibut, and comparison drug, Pantogamneutralized the negative effect of EP on the function of GABAergic and dopaminergic systems in the offspring of the experimental groups. Therapy with Succicard in puberty and long-term periods of life contributed to the improvement of short-term and long-term memory in the offspring of rats with EP. Thus, it could be reasonable enough to develop a drug against cognitive disorders in children of mothers with preeclampsia. CONCLUSION: In the offspring of rats with EP, short-term and long-term disorders of memory in the functioning of the GABAergic and dopaminergic systems were noted in the early and late stages of the individual development. Pharmacological correction with GABA derivatives improves cognitive processes and the functioning of neurotransmitter systems in the offspring of rats with complicated pregnancy. The highest effectiveness was demonstrated by succicard, and was comparable with or superior to the Pantogam (standard drug).

Dopamine D1 and D2 Receptors Are Important for Learning About Neutral-Valence Relationships in Sensory Preconditioning

Dopamine neurotransmission has been ascribed multiple functions with respect to both motivational and associative processes in reward-based learning, though these have proven difficult to tease apart. In order to better describe the role of dopamine in associative learning, this series of experiments examined the potential of dopamine D1- and D2-receptor antagonism (or combined antagonism) to influence the ability of rats to learn neutral valence stimulus-stimulus associations. Using a sensory preconditioning task, rats were first exposed to pairings of two neutral stimuli (S2-S1). Subsequently, S1 was paired with a mild foot-shock and resulting fear to both S1 (directly conditioned) and S2 (preconditioned) was examined. Initial experiments demonstrated the validity of the procedure in that measures of sensory preconditioning were shown to be contingent on pairings of the two sensory stimuli. Subsequent experiments indicated that systemic administration of dopamine D1- or D2-receptor antagonists attenuated learning when administered prior to S2-S1 pairings. However, the administration of a more generic D1R/D2R antagonist was without effect. These effects remained constant regardless of the affective valence of the conditioning environment and did not differ between male and female rats. The results are discussed in the context of recent suggestions that dopaminergic systems encode more than a simple reward prediction error, and provide potential avenues for future investigation.

Neural correlates of extrinsic and intrinsic outcome processing during learning in individuals with TBI: a Pilot Investigation

Objective: Outcome processing, the ability to learn from feedback, is an important component of adaptive behavior and rehabilitation. Evidence from healthy adults implicates the striatum and dopamine in outcome processing. Animal research shows that damage to dopaminergic pathways in the brain can lead to a disruption of dopamine tone and transmission. Such evidence thus suggests that persons with TBI experience deficits in outcome processing. However, no research has directly investigated outcome processing and associated neural mechanisms in TBI. Here, we examine outcome processing in individuals with TBI during learning. Given that TBI negatively impacts striatal and dopaminergic systems, we hypothesize that individuals with TBI exhibit deficits in learning from outcomes. Methods: To test this hypothesis, individuals with moderate-to-severe TBI and healthy adults were presented with a declarative paired-associate word learning task. Outcomes indicating performance accuracy were presented immediately during task performance and in the form of either monetary or performance-based feedback. Two types of feedback provided the opportunity to test whether extrinsic and intrinsic motivational aspects of outcome presentation play a role during learning and outcome processing. Results: Our results show that individuals with TBI exhibited impaired learning from feedback compared to healthy participants. Additionally, individuals with TBI exhibited increased activation in the striatum during outcome processing. Conclusions: The results of this study suggest that outcome processing and learning from immediate outcomes is impaired in individuals with TBI and might be related to inefficient use of neural resources during task performance as reflected by increased activation of the striatum.

Connectivity adaptations in dopaminergic systems define the brain maturity of investors

Investment decisions rely on perceptions from external stimuli along with the integration of inner brain-body signals, all of which are shaped by experience. As experience is capable of molding both the structure and function of the human brain, we have used a novel neuroimaging connectomic-genetic approach to investigate the influence of investment work experience on brain anatomy. We found that senior investors display higher gray matter volume and increased structural brain connectivity in dopamine-related pathways, as well as a set of genes functionally associated with adrenaline and noradrenaline biosynthesis (SLC6A3, TH and SLC18A2), which is seemingly involved in reward processing and bodily stress responses during financial trading. These results suggest the key role of catecholamines in the way senior investors harness their emotions while raising bodily awareness as they grow in investment maturity.

Comparative Analysis of Neurotoxicity of Six Phthalates in Zebrafish Embryos

The effects and underlying mechanisms of phthalates on neurotoxicity remain unclear as compared with the potentials of these substances as endocrine disruptors. The locomotor activities of zebrafish embryos were investigated upon exposure to six phthalates: dimethyl phthalate (DMP), diethyl phthalate (DEP), benzyl butyl phthalate (BBzP), di-2-ethylhexyl phthalate (DEHP), di-n-octyl phthalate (DnOP), and diisononyl phthalate (DiNP). Moreover, changes in fluorescence intensity in the green fluorescent protein (GFP) transgenic (Tg) lines Tg(HuC:eGFP), Tg(sox10:eGFP), and Tg(mbp:GFP) were measured after exposure to six phthalates, and changes in the expression profiles of genes involved in the cholinergic (ache) and dopaminergic systems (dat, th, and drd1b) were assessed. Exposure to BBzP, DEHP, and DiNP affected larval behaviors, whereas exposure to DMP, DEP, and DnOP revealed no alterations. A reduced expression of Tg(HuC:eGFP) was observed upon exposure to BBzP, DEHP, and DiNP. The expression of Tg(sox10:eGFP) and Tg(mbp:GFP) was reduced only in response to BBzP and DiNP, respectively. Further, exposure to DiNP upregulated ache and drd1b. The upregulation of ache and downregulation of drd1b was observed in DEHP-exposed groups. Exposure to BBzP suppressed th expression. These observations indicate that exposure to phthalates impaired embryogenesis of the neurological system and neurochemicals in zebrafish embryos, although the detailed mechanisms varied among the individual phthalates. Further mechanistic studies are needed to better understand the causality between phthalate exposure and neurotoxicity.

Restoration of Noradrenergic Function in Parkinson’s Disease Model Mice

Dysfunction of the central noradrenergic and dopaminergic systems is the primary neurobiological characteristic of Parkinson’s disease (PD). Importantly, neuronal loss in the locus coeruleus (LC) that occurs in early stages of PD may accelerate progressive loss of dopaminergic neurons. Therefore, restoring the activity and function of the deficient noradrenergic system may be an important therapeutic strategy for early PD. In the present study, the lentiviral constructions of transcription factors Phox2a/2b, Hand2 and Gata3, either alone or in combination, were microinjected into the LC region of the PD model VMAT2 Lo mice at 12 and 18 month age. Biochemical analysis showed that microinjection of lentiviral expression cassettes into the LC significantly increased mRNA levels of Phox2a, and Phox2b, which were accompanied by parallel increases of mRNA and proteins of dopamine β-hydroxylase (DBH) and tyrosine hydroxylase (TH) in the LC. Furthermore, there was considerable enhancement of DBH protein levels in the frontal cortex and hippocampus, as well as enhanced TH protein levels in the striatum and substantia nigra. Moreover, these manipulations profoundly increased norepinephrine and dopamine concentrations in the striatum, which was followed by a remarkable improvement of the spatial memory and locomotor behavior. These results reveal that over-expression of these transcription factors in the LC improves noradrenergic and dopaminergic activities and functions in this rodent model of PD. It provides the necessary groundwork for the development of gene therapies of PD, and expands our understanding of the link between the LC-norepinephrine and dopamine systems during the progression of PD.

Biological predictors of suicidal behaviour in mood disorders

Predicting suicide is difficult due to its low base rate and the multicausal nature of suicidal behaviour. Retrospective and cross-sectional studies have identified a number of biologic abnormalities associated with suicide and non-fatal suicide attempt. Non-fatal suicidal behaviour shows a big range in terms of degree of intent and medical damage or lethality. High intent more lethal suicide attempts are associated with greater risk of suicide and different demographics and biology compared with impulsive low lethality attempts. Prospective studies of suicide provide estimates of the predictive utility of biologic measures. Here, we review prospective studies of suicidal behaviour and serotonergic, noradrenergic, dopaminergic systems, inflammation, polyunsaturated fatty acids, and the hypothalamic–pituitary–adrenocortical (HPA) axis function in mood disorders. The most promising biologic predictors are low cerebrospinal fluid (CSF), 5-hydroxyindoleacetic acid (5-HIAA), and HPA axis dysfunction, as demonstrated by dexamethasone non-suppression where each are associated with a 4.5-fold greater risk of suicide.