Advances in multidisciplinary and cross-species approaches to examine the neurobiology of psychiatric disorders.

Current approaches to dissect the molecular neurobiology of complex neuropsychiatric disorders such as schizophrenia and major depression have been rightly criticized for failing to provide benefits to patients. Improving the translational potential of our efforts will require the development and refinement of better disease models that consider a wide variety of contributing factors, such as genetic variation, gene-by-environment interactions, endophenotype or intermediate phenotype assessment, cross species analysis, sex differences, and developmental stages. During a targeted expert meeting of the European College of Neuropsychopharmacology (ECNP) in Istanbul, we addressed the opportunities and pitfalls of current translational animal models of psychiatric disorders and agreed on a series of core guidelines and recommendations that we believe will help guiding further research in this area.

When the serotonin transporter gene meets adversity: the contribution of animal models to understanding epigenetic mechanisms in affective disorders and resilience.

Although converging epidemiological evidence links exposure to stressful life events with increased risk for affective spectrum disorders, there is extraordinary interindividual variability in vulnerability to adversity. The environmentally moderated penetrance of genetic variation is thought to play a major role in determining who will either develop disease or remain resilient. Research on genetic factors in the aetiology of disorders of emotion regulation has, nevertheless, been complicated by a mysterious discrepancy between high heritability estimates and a scarcity of replicable gene-disorder associations.

Methylphenidate normalizes emotional processing in adult patients with attention-deficit/hyperactivity disorder: preliminary findings.

Emotional-motivational dysfunctions may significantly contribute to symptoms of attention-deficit/hyperactivity disorder (ADHD). Hyperactive-impulsive symptoms and sensation seeking could be the result of a search for reinforcers, and cognitive dysfunctions might be due to a low motivational drive. Emotional-motivational dysfunctions could also explain social dysfunctions in ADHD patients because they may lead to misinterpretations of emotional and social clues.

Integrating neurobiological markers of depression.

Context: Although psychiatric disorders are, to date, diagnosed on the basis of behavioral symptoms and course of illness, the interest in neurobiological markers of psychiatric disorders has grown substantially in recent years. However, current classification approaches are mainly based on data from a single biomarker, making it difficult to predict disorders characterized by complex patterns of symptoms.

Objective: To integrate neuroimaging data associated with multiple symptom-related neural processes and demonstrate their utility in the context of depression by deriving a predictive model of brain activation.

Gene-environment interaction influences anxiety-like behavior in ethologically based mouse models.

Ethologically based animal models are widely used; however, results from different laboratories vary significantly which may partly be due to the lack of standardization. Here, we examined the effects of circadian rhythm, lighting condition and mouse strain (BALB/c and C57BL/6, known to differ in measures of avoidance and risk assessment behavior) on two well established behavioral tests in mice: the Elevated Plus Maze (EPM) and the Open Field (OF). Parameters from both paradigms are commonly used as indices of anxiety-like behavior.

Neurovascular coupling in the human visual cortex is modulated by cyclooxygenase-1 (COX-1) gene variant.

Functional hyperemia, the brain's capability to alter microvascular blood flow in response to the metabolic demands of active neurons, is essential for sustained mammalian brain function. Pharmacological studies in mice suggest neurovascular coupling to centrally involve cyclooxygenase-1 (COX-1) metabolites such as prostaglandins. In humans, however, genetic variation of the COX-1 gene impacting the coupling of neural activity to hemodynamic responses (HRs) has not been investigated yet.

Cerebral metabolic responses to 5-HT2A/C receptor activation in mice with genetically modified serotonin transporter (SERT) expression.

Variation in the human serotonin transporter gene (hSERT; 5-HTT) resulting in a life-long alteration in SERT function influences anxiety and the risk of developing affective disorders. The mechanisms underlying the influence of the hSERT gene on these phenotypes remain unclear but may involve altered 5-HT receptor function. Here we characterise the cerebral metabolic response to 5-HT(2A/C) receptor activation in two transgenic mouse models of altered SERT function, SERT knock-out (SERT KO) and hSERT over-expressing (hSERT OE) mice, to test the hypothesis that genetically mediated variability in SERT expression alters 5-HT(2A/C) function.

Differential gene expression in mutant mice overexpressing or deficient in the serotonin transporter: a focus on urocortin 1.

Transcriptome analyses were performed in the anterior raphe area of mutant mice deficient in the serotonin transporter (5-HTT KO) or overexpressing this protein (5-HTT TG), which exhibit opposite changes in anxiety-related behavior. Among genes with altered expression, the gene encoding the neuropeptide urocortin 1 was down-regulated in 5-HTT KO and up-regulated in 5-HTT TG mice. Expression of the gene encoding cocaine-and-amphetamine-related-peptide, which colocalizes with urocortin 1, was also increased in 5-HTT TG mutants.

Ultrastructural characterization of tryptophan hydroxylase 2-specific cortical serotonergic fibers and dorsal raphe neuronal cell bodies after MDMA treatment in rat.

Rationale: 3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a widely used recreational drug known to cause selective long-term serotonergic damage.

Objectives: The aim of this study was to characterize the ultrastructure of serotonergic pericarya and proximal neurites in the dorsal raphe nucleus as well as the ultrastructure of serotonergic axons in the frontal cortex of adolescent Dark Agouti rats 3 days after treatment with 15 mg/kg i.p.

Looking on the bright side of serotonin transporter gene variation.

Converging evidence indicates an association of the short (s), low-expressing variant of the repeat length polymorphism, serotonin transporter-linked polymorphic region (5-HTTLPR), in the human serotonin transporter gene (5-HTT, SERT, SLC6A4) with anxiety-related traits and increased risk for depression in interaction with psychosocial adversity across the life span. However, genetically driven deficient serotonin transporter (5-HTT) function would not have been maintained throughout evolution if it only exerted negative effects without conveying any gain of function. Here, we review recent findings that humans and nonhuman primates carrying the s variant of the 5-HTTLPR outperform subjects carrying the long allele in an array of cognitive tasks and show increased social conformity.

Epistatic interaction of CREB1 and KCNJ6 on rumination and negative emotionality.

G protein-activated K+ channel 2 (GIRK2) and cAMP-response element binding protein (CREB1) are involved in synaptic plasticity and their genes have been implicated depression and memory processing. Excessive rumination is a core cognitive feature of depression which is also present in remission. High scores on the Ruminative Response Scale (RRS) questionnaire are predictive of relapse and recurrence.

Non-linear relationship between 5-HT transporter gene expression and frequency sensitivity of 5-HT signals.

Much evidence suggests that variation in expression of the 5-hydroxytryptamine (5-HT) transporter (5-HTT) is linked to risk of psychiatric illness, but the neurobiological basis of this association is uncertain. In this study, we investigated the impact of variation in 5-HTT expression on subsecond fluctuations in extracellular 5-HT concentrations ([5-HT](o) ). Stimulus-evoked [5-HT](o) was detected using fast-scan cyclic voltammetry at carbon-fibre microelectrodes in the substantia nigra in brain slices from 5-HTT knockout (KO) and 5-HTT over-expressing (OE) mice.

Association between reward-related activation in the ventral striatum and trait reward sensitivity is moderated by dopamine transporter genotype.

The impact of individual differences on human reward processing has been a focus of research in recent years, particularly, as they are associated with a variety of neuropsychiatric diseases including addiction and attention-deficit/hyperactivity disorder. Studies exploring the neural basis of individual differences in reward sensitivity have consistently implicated the ventral striatum (VS) as a core component of the human reward system. However, the mechanisms of dopaminergic neurotransmission underlying ventral striatal activation as well as trait reward sensitivity remain speculative.

Impact of the AHI1 gene on the vulnerability to schizophrenia: a case-control association study.

Background: The Abelson helper integration-1 (AHI1) gene is required for both cerebellar and cortical development in humans. While the accelerated evolution of AHI1 in the human lineage indicates a role in cognitive (dys)function, a linkage scan in large pedigrees identified AHI1 as a positional candidate for schizophrenia. To further investigate the contribution of AHI1 to the susceptibility of schizophrenia, we evaluated the effect of AHI1 variation on the vulnerability to psychosis in two samples from Spain and Germany.

Case-control genome-wide association study of attention-deficit/hyperactivity disorder.

Objective: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. Thus additional genomewide association studies (GWAS) are needed.

Method: We used case-control analyses of 896 cases with DSM-IV ADHD genotyped using the Affymetrix 5.

Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder.

Objective: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of existing studies to boost statistical power.

Method: We used data from four projects: a) the Children's Hospital of Philadelphia (CHOP); b) phase I of the International Multicenter ADHD Genetics project (IMAGE); c) phase II of IMAGE (IMAGE II); and d) the Pfizer-funded study from the University of California, Los Angeles, Washington University, and Massachusetts General Hospital (PUWMa).

Early attentional deficits in an attention-to-prepulse paradigm in ADHD adults.

Adults with attention-deficit/hyperactivity disorder (ADHD) were examined for early and late attentional processes as a function of controlled attention. The test paradigm was the attentional modulation of prepulse inhibition (PPI; early controlled attentional processing) and prepulse facilitation (PPF; late controlled attentional processing). In 49 patients and 49 controls, the authors measured acoustic startle responses to 96-dB startle pulses preceded 120, 240 (for PPI), 2,000, and 4,500 (for PPF) ms by a 68-dB prepulse noise.

On the role of serotonin and effort in voluntary attention: evidence of genetic variation in N1 modulation.

Ascending serotonergic projections from the raphe nuclei to frontal brain areas and the dense distribution of receptor and transporter sites in prefrontal and sensory regions support the idea that serotonin exerts influence on cognitive functioning. Indeed, growing evidence suggests serotonin to be an important factor in learning and memory; however, its precise role in executive processes particularly in voluntary attention is less clear. Event-related EEG studies showed the N1 potential to predict top-down attention allocation and implicated the auditory N1 in central serotonergic activity.

Dopamine transporter (SLC6A3) genotype impacts neurophysiological correlates of cognitive response control in an adult sample of patients with ADHD.

Studies provide ample evidence for a dysfunction in dopaminergic neurotransmission in Attention-Deficit/Hyperactivity Disorder (ADHD). In that respect, a common variable number of tandem repeats (VNTR) polymorphism in the 3' untranslated region (UTR) of the dopamine transporter gene (SLC6A3) has been repeatedly associated with the disorder. Here, we examined the influence of the common 9- and 10-repeat alleles of SLC6A3 on prefrontal brain functioning and cognitive response control in a large sample of adult ADHD patients (n=161) and healthy controls (n=109).

Brain-specific conditional and time-specific inducible Tph2 knockout mice possess normal serotonergic gene expression in the absence of serotonin during adult life.

Several lines of evidence implicate a dysregulation of tryptophan hydroxylase (TPH)-dependent serotonin (5-HT) synthesis in emotional behaviour and stress, and point to its relevance for the etiology and pathogenesis of various neuropsychiatric disorders. We therefore studied different animal models featuring reduced Tph2 expression to investigate the consequences of impaired brain 5-HT synthesis on neuronal development. Specifically, brain-specific conditional and time-specific inducible Tph2 knockout (KO) models were generated and investigated for altered serotonergic neuron-specific gene expression.

A functional NOS1 promoter polymorphism interacts with adverse environment on functional and dysfunctional impulsivity.

Rationale: Neuronal nitric oxide synthase (NOS1) knockout results in increased impulsive aggression in mice under adverse housing conditions. In line with this, we have previously shown that a functional promoter polymorphism of NOS1, termed NOS1 ex1f-VNTR, is associated with impulsivity-related traits and related disorders.

Objective: This study aims to examine whether adverse environment interacts with the risk allele on impulsivity-related measures.

Functional amygdala-hippocampus connectivity during anticipation of aversive events is associated with Gray's trait "sensitivity to punishment".

Background: The reinforcement sensitivity theory postulates a behavioral inhibition system that modulates reaction to stimuli indicating aversive events. Gray's dimension of anxiety, reflecting human trait sensitivity to aversive events, determines the extent to which stimuli activate the behavioral inhibition system. Although structural brain imaging has previously identified the amygdala and the hippocampus as two major components related to the behavioral inhibition system, the functional dynamics of the responses in these structures remain unclear.

The expression of the transcription factor FEV in adult human brain and its association with affective disorders.

A wide range of physiological processes and neuronal functioning is modulated by the serotonergic system. Serotonin (5-HT) plays an important role during early brain development. Moreover, dysfunction of the 5-HT system is implicated in psychiatric disorders, especially in affective disorders.

Increased vulnerability to psychosocial stress in heterozygous serotonin transporter knockout mice.

Epidemiological evidence links exposure to stressful life events with increased risk for mental illness. However, there is significant individual variability in vulnerability to environmental risk factors, and genetic variation is thought to play a major role in determining who will become ill. Several studies have shown, for example, that individuals carrying the S (short) allele of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) have an increased risk for major depression following exposure to stress in adulthood.

Social status and day-to-day behaviour of male serotonin transporter knockout mice.

Humans differing in the amount of serotonin transporter (5-HTT) are known to be differentially prone to neuropsychiatric disorders. Genetically modified mice eliciting abrogated transporter function display a number of corresponding phenotypic changes in behavioural tests. However, a characterisation of the effects of serotonergic malfunction on the day-to-day life is still missing.