Chronic Adolescent CDPPB Treatment Alters Short-Term, but not Long-Term, Glutamatergic Receptor Expression.

Dysfunction of the glutamatergic system is believed to underlie many neurodevelopmental disorders including autism, Rett syndrome and schizophrenia. Metabotropic glutamate receptor (mGluR5) positive allosteric modulators (PAM) potentiate glutamatergic signaling, particularly indirectly via the NMDA receptor. Preclinical studies report mGluR5 PAMs can improve schizophrenia-relevant behaviours.

Platform for systems medicine research and diagnostic applications in psychotic disorders-The METSY project.

Psychotic disorders are associated with metabolic abnormalities including alterations in glucose and lipid metabolism. A major challenge in the treatment of psychosis is to identify patients with vulnerable metabolic profiles who may be at risk of developing cardiometabolic co-morbidities. It is established that both central and peripheral metabolic organs use lipids to control energy balance and regulate peripheral insulin sensitivity.

Listeria monocytogenes in Different Specimens from Healthy Red Deer and Wild Boars.

In the past, Listeria monocytogenes has been isolated from game feces and meat. However, less information is available on the occurrence of L. monocytogenes in other specimens originating from game animals.

mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia.

Rationale: An imbalance of excitatory and inhibitory neurotransmission underlies the glutamate hypothesis of schizophrenia. Agonists of group II metabotropic glutamate receptors, mGluR2/3, have been proposed as novel therapeutic agents to correct this imbalance. However, the influence of mGluR2/3 activity on excitatory and inhibitory neurotransmitter receptors has not been explored.

Neuregulin 1 Prevents Phencyclidine-Induced Behavioral Impairments and Disruptions to GABAergic Signaling in Mice.

Background: Substantial evidence from human post-mortem and genetic studies has linked the neurotrophic factor neuregulin 1 (NRG1) to the pathophysiology of schizophrenia. Genetic animal models and in vitro experiments have suggested that altered NRG1 signaling, rather than protein changes, contributes to the symptomatology of schizophrenia. However, little is known about the effect of NRG1 on schizophrenia-relevant behavior and neurotransmission (particularly GABAergic and glutamatergic) in adult animals.

Neuregulin 1 expression and electrophysiological abnormalities in the Neuregulin 1 transmembrane domain heterozygous mutant mouse.

Background: The Neuregulin 1 transmembrane domain heterozygous mutant (Nrg1 TM HET) mouse is used to investigate the role of Nrg1 in brain function and schizophrenia-like behavioural phenotypes. However, the molecular alterations in brain Nrg1 expression that underpin the behavioural observations have been assumed, but not directly determined. Here we comprehensively characterise mRNA Nrg1 transcripts throughout development of the Nrg1 TM HET mouse.

Metabotropic glutamate receptor mGluR2/3 and mGluR5 binding in the anterior cingulate cortex in psychotic and nonpsychotic depression, bipolar disorder and schizophrenia: implications for novel mGluR-based therapeutics.

Background: Metabotropic glutamate receptors 2/3 (mGluR2/3) and 5 (mGluR5) are novel therapeutic targets for major depression (MD), bipolar disorder (BD) and schizophrenia. We aimed to determine whether mGluR2/3 and mGluR5 binding in the anterior cingulate cortex (ACC), a brain region essential for the regulation of mood, cognition and emotion, were differentially altered in these pathologies.

Methods: Using postmortem human brains derived from 2 cohorts, [(3)H]LY341495 binding to mGluR2/3 and [(3)H]MPEP binding to mGluR5 were measured by receptor autoradiography in the ACC.

Negativity towards negative results: a discussion of the disconnect between scientific worth and scientific culture.

Science is often romanticised as a flawless system of knowledge building, where scientists work together to systematically find answers. In reality, this is not always the case. Dissemination of results are straightforward when the findings are positive, but what happens when you obtain results that support the null hypothesis, or do not fit with the current scientific thinking? In this Editorial, we discuss the issues surrounding publication bias and the difficulty in communicating negative results.

Metabotropic glutamate receptor 5 binding and protein expression in schizophrenia and following antipsychotic drug treatment.

Metabotropic glutamate receptor 5 (mGluR5) has been identified as a potential therapeutic target for schizophrenia, primarily due to its ability to indirectly modulate glutamatergic signalling through the NMDA receptor (NMDAR). Despite its potential, molecular studies characterising mGluR5 in schizophrenia are limited. We therefore aimed to determine if the mGluR5 binding site or protein levels were altered in schizophrenia or by current antipsychotics.

The endocrine stress response is linked to one specific locus on chromosome 3 in a mouse model based on extremes in trait anxiety.

Background: The hypothalamic-pituitary-adrenal (HPA) axis is essential to control physiological stress responses in mammals. Its dysfunction is related to several mental disorders, including anxiety and depression. The aim of this study was to identify genetic loci underlying the endocrine regulation of the HPA axis.

Metabolic parameters and emotionality are little affected in G-protein coupled receptor 12 (Gpr12) mutant mice.

Background: G-protein coupled receptors (GPR) bear the potential to serve as yet unidentified drug targets for psychiatric and metabolic disorders. GPR12 is of major interest given its putative role in metabolic function and its unique brain distribution, which suggests a role in emotionality and affect. We tested Gpr12 deficient mice in a series of metabolic and behavioural tests and subjected them to a well-established high-fat diet feeding protocol.

The (15)N isotope effect as a means for correlating phenotypic alterations and affected pathways in a trait anxiety mouse model.

Stable isotope labeling techniques hold great potential for accurate quantitative proteomics comparisons by MS. To investigate the effect of stable isotopes in vivo, we metabolically labeled high anxiety-related behavior (HAB) mice with the heavy nitrogen isotope (15)N. (15)N-labeled HAB mice exhibited behavioral alterations compared to unlabeled ((14)N) HAB mice in their depression-like phenotype.

Proteomic and metabolomic profiling of a trait anxiety mouse model implicate affected pathways.

Depression and anxiety disorders affect a great number of people worldwide. Whereas singular factors have been associated with the pathogenesis of psychiatric disorders, growing evidence emphasizes the significance of dysfunctional neural circuits and signaling pathways. Hence, a systems biology approach is required to get a better understanding of psychiatric phenotypes such as depression and anxiety.

Proteomics and metabolomics analysis of a trait anxiety mouse model reveals divergent mitochondrial pathways.

Background: Although anxiety disorders are the most prevalent psychiatric disorders, no molecular biomarkers exist for their premorbid diagnosis, accurate patient subcategorization, or treatment efficacy prediction. To unravel the neurobiological underpinnings and identify candidate biomarkers and affected pathways for anxiety disorders, we interrogated the mouse model of high anxiety-related behavior (HAB), normal anxiety-related behavior (NAB), and low anxiety-related behavior (LAB) employing a quantitative proteomics and metabolomics discovery approach.

Methods: We compared the cingulate cortex synaptosome proteomes of HAB and LAB mice by in vivo (15)N metabolic labeling and mass spectrometry and quantified the cingulate cortex metabolomes of HAB/NAB/LAB mice.

Density of metabotropic glutamate receptors 2 and 3 (mGluR2/3) in the dorsolateral prefrontal cortex does not differ with schizophrenia diagnosis but decreases with age.

Metabotropic glutamate receptors 2 and 3 (mGluR2/3) have been shown as efficient targets for antipsychotic intervention. We therefore investigated the receptor density of mGluR2/3 in the dorsolateral prefrontal cortex (dlPFC; Brodman area 46) of schizophrenia/schizoaffective patients (n=37) and matched controls (n=37) using receptor autoradiography. No difference in mGluR2/3 density was identified in relation to schizophrenia diagnosis.

Stable isotope metabolic labeling with a novel N-enriched bacteria diet for improved proteomic analyses of mouse models for psychopathologies.

The identification of differentially regulated proteins in animal models of psychiatric diseases is essential for a comprehensive analysis of associated psychopathological processes. Mass spectrometry is the most relevant method for analyzing differences in protein expression of tissue and body fluid proteomes. However, standardization of sample handling and sample-to-sample variability are problematic.

A hypomorphic vasopressin allele prevents anxiety-related behavior.

Background: To investigate neurobiological correlates of trait anxiety, CD1 mice were selectively bred for extremes in anxiety-related behavior, with high (HAB) and low (LAB) anxiety-related behavior mice additionally differing in behavioral tests reflecting depression-like behavior.

Methodology/ Principal Findings: In this study, microarray analysis, in situ hybridization, quantitative real-time PCR and immunohistochemistry revealed decreased expression of the vasopressin gene (Avp) in the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei of adult LAB mice compared to HAB, NAB (normal anxiety-related behavior) and HABxLAB F1 intercross controls, without detecting differences in receptor expression or density. By sequencing the regions 2.

Impaired extinction of learned fear in rats selectively bred for high anxiety--evidence of altered neuronal processing in prefrontal-amygdala pathways.

The impaired extinction of acquired fear is a core symptom of anxiety disorders, such as post-traumatic stress disorder, phobias or panic disorder, and is known to be particularly resistant to existing pharmacotherapy. We provide here evidence that a similar relationship between trait anxiety and resistance to extinction of fear memory can be mimicked in a psychopathologic animal model. Wistar rat lines selectively bred for high (HAB) or low (LAB) anxiety-related behaviour were tested in a classical cued fear conditioning task utilizing freezing responses as a measure of fear.

The vasopressin system--from antidiuresis to psychopathology.

Vasopressin is a neuropeptide with multiple functions. In addition to its predominantly antidiuretic action after peripheral secretion from the posterior pituitary, it seems to fulfill--together with its receptor subtype--all requirements for a neuropeptide system critically involved in higher brain functions, including cognitive abilities and emotionality. Following somatodendritic and axonal release in distinct brain areas, vasopressin acts as a neuromodulator and neurotransmitter in multiple and varying modes of interneuronal communication.

Diabetes insipidus and, partially, low anxiety-related behaviour are linked to a SNP-associated vasopressin deficit in LAB mice.

Following secretion from the posterior pituitary, the neuropeptide vasopressin (AVP) stimulates the kidney to retain water, and when released centrally it can contribute to anxiety- and depression-like behaviours. We hypothesized that CD1 mice bred for low trait anxiety (LAB) suffer from a deficit in AVP. Both osmotically stimulated peripheral secretion and intra-paraventricular nucleus (PVN) release of AVP were found decreased in LAB animals compared with normal anxiety (NAB) or high anxiety (HAB) controls.

Candidate genes of anxiety-related behavior in HAB/LAB rats and mice: focus on vasopressin and glyoxalase-I.

Two animal models of trait anxiety, HAB/LAB rats and mice, are described, representing inborn extremes in anxiety-related behavior. The comprehensive phenotypical characterization included basal behavioral features, stress-coping strategies and neuroendocrine responses upon stressor exposure with HAB animals being hyper-anxious, preferring passive coping, emitting more stressor-induced ultrasonic vocalization calls and showing typical peculiarities of the hypothalamic-pituitary-adrenocortical axis and line-specific patterns of Fos expression in the brain indicative of differential neuronal activation. In most cases, unselected Wistar rats and CD1 mice, respectively, displayed intermediate behaviors.

Airjet and FG-7142-induced Fos expression differs in rats selectively bred for high and low anxiety-related behavior.

We reported recently that two rat lines bred for either high (HAB) or low (LAB) anxiety-related behavior display differential Fos expression in restricted parts of the fear/anxiety circuitry when exposed to mild anxiety evoked in exploratory anxiety tests. Since different forms of anxiety are thought to activate different parts of the anxiety circuitry, we investigated now whether (1) an aversive stimulus which elicits escape behavior (airjet) and (2) the anxiogenic/panicogenic drug FG-7142 would reveal further differences in Fos expression as a marker of neuronal activation between HAB and LAB rats. Both airjet exposure and FG-7142 induced Fos expression in both lines in various anxiety-related brain areas.

Genetic predisposition to anxiety-related behavior determines coping style, neuroendocrine responses, and neuronal activation during social defeat.

Genetic background may influence an individual's susceptibility to, and subsequent coping strategy for, an acute stressor. When exposed to social defeat (SD), rats bred for high (HAB) or low (LAB) trait anxiety, which also differ in depression-like behavior, showed highly divergent passive and active coping behaviors, respectively. HABs spent more time freezing and emitted more ultrasound vocalization calls during SD than LABs, which spent more time rearing and grooming.

Impaired repression at a vasopressin promoter polymorphism underlies overexpression of vasopressin in a rat model of trait anxiety.

Two inbred rat lines have been developed that show either high (HAB) or low (LAB) anxiety-related behavior. The behavioral phenotype correlates with arginine vasopressin (AVP) expression at the level of the hypothalamic paraventricular nucleus (PVN), but not supraoptic nucleus, with HAB animals overexpressing the neuropeptide in both magnocellular and parvocellular subdivisions of the PVN. We detected a number of single nucleotide polymorphisms (SNPs) in the AVP locus that differ between the HAB and LAB animals, two of which were embedded in cis-regulatory elements.