Models Of Affective Disorders Research Articles

The Genetic Underpinnings of Affective Temperaments: Identifying Novel Risk Variants with a Whole Genome Analytical Approach

One reason behind the failure to understand the neurobiological background of affective disorders and develop more effective treatments is their heterogeneity warranting identification of clinically meaningful endophenotypes. Affective temperaments, considered subclinical manifestations and pathoplastic contributors of affective illnesses may constitute such endophenotypes. 775 general population subjects were phenotyped for affective temperaments using TEMPS-A, and genotyped using Illumina’s CoreExom PsychChip yielding 573141 variants. Primary SNP-based association tests were calculated using linear regression models assuming an additive genetic effect with the first 10 calculated principal components, gender, age, and other affective temperaments as covariates; a Bonferroni-corrected genome-wide significance threshold set at p≤5.0×10−8, and suggestive significance threshold set at p≤1.0x10-5. SNP-level relevances were aggregated to gene-level with the PEGASUS method, with a Bonferroni-corrected significance level set at 2.0×10-6, and suggestive significance thrshold set at p≤4.0×10-4. Functional effects of most significant SNPs as reported in public open databases based on expression quantitative trait loci (eQTL) and 3D-chromatin interactions were explored using FUMA v1.3.5. In SNP-based tests a novel genome-wide significant variant, rs3798978 (p=4.44x10-8) and several other suggestively significant SNPs in ADGRB3 were found for anxious temperament along with suggestively significant SNPs for the other four affective temperaments. In gene-based tests suggestively significant findings emerged for all five temperaments. Functional analysis suggested that several of the identified variants influence gene-expression levels or participate in chromatin interactions in brain areas implicated in affective disorders. In the next step these findings should be investigated in patient samples, and in other models of affective disorders and related phenotypes.DisclosureNo significant relationships.

Dendritic Cells: Neglected Modulators of Peripheral Immune Responses and Neuroinflammation in Mood Disorders?

Affective disorders (AD) including major depressive disorder (MDD) and bipolar disorder (BD) are common mood disorders associated with increased disability and poor health outcomes. Altered immune responses characterized by increased serum levels of pro-inflammatory cytokines and neuroinflammation are common findings in patients with AD and in corresponding animal models. Dendritic cells (DCs) represent a heterogeneous population of myeloid cells that orchestrate innate and adaptive immune responses and self-tolerance. Upon sensing exogenous and endogenous danger signals, mature DCs secrete proinflammatory factors, acquire migratory and antigen presenting capacities and thus contribute to neuroinflammation in trauma, autoimmunity, and neurodegenerative diseases. However, little is known about the involvement of DCs in the pathogenesis of AD. In this review, we summarize the current knowledge on DCs in peripheral immune responses and neuroinflammation in MDD and BD. In addition, we consider the impact of DCs on neuroinflammation and behavior in animal models of AD. Finally, we will discuss therapeutic perspectives targeting DCs and their effector molecules in mood disorders.

P 150 The correlation of attention and neurophysiological characteristics in attention deficit hyperactivity disorder (ADHD)

Scientific background/Introduction Adult ADHD is a frequent psychiatric disorder which begins in childhood and persists into adulthood in up to 60% of the cases. As one pathogenetical mechanism the arousal regulation, which are measurable with EEG under rest, are discussed. The vigilance regulation model of affective disorders and ADHD interprets the hyperactivity and the sensation seeking behaviour as an autoregulatory and partly dysfunctional attempt of the organism to stabilize wakefulness ( Hegerl and Hensch, 2014 ). Different EEG-studies confirm an instable EEG vigilance regulation in ADHD ( Geissler et al., 2014 ) and show correlation with attention deficits ( Sander et al., 2010 ). In the light of this results the correlation of EEG vigilance regulation as neurophysiological tonic arousal and attention deficits (measured by neuropsychological tests) in adult ADHD is investigated. Method Adult ADHD patients and healthy controls were tested with the “Testbatterie zur Aufmerksamkeitsprufung” (subtests alertness, working memory and Go/NoGo). EEG recordings of 15 min under quiet rest with eyes closed were performed. The computer-based Vigilance Algorithm Leipzig (VIGALL) was used to classify 1-s EEG segments into stages on the continuum ranging from full wakefulness to sleep onset. Findings Group comparisons (ADHD vs. healthy controls) and correlational analysis were presented. Discussion The investigated vigilance regulation model in ADHD could establish new insights into the neurophysiology of ADHD in adulthood.

P 131 Association between clinical depressive symptomatology and brain arousal regulation in medicated patients with major depression

Background According to the arousal regulation model of affective disorders, typical depressive symptoms like sensation avoidance and withdrawal in depression can partly be explained as an auto-regulatory attempt to counteract a tonically high brain arousal, which has repeatedly been shown in unmedicated patients with Major Depression (MDD). Brain arousal has so far not been studied in medicated MDD patients and it is unclear to what extent depressive symptomatology is associated with brain arousal regulation. The aim of this study was to compare arousal regulation in medicated MDD patients with healthy controls and to investigate the association between self-rated depressive symptomatology and brain arousal regulation. We hypothesized that despite drug treatment depressed patients would still show a hyperstable brain arousal compared to healthy controls and that depressive symptomatology will be positively associated with the stability of brain arousal regulation. Methods Between 2006 and 2014, 130 currently depressed MDD patients treated with a Selective Serotonine Reuptake Inhibitor (SSRI) and 130 age- and sex-matched healthy controls received a 15 min resting EEG. Depressive symptomatology was assessed with the Beck Depression Inventory (BDI; self-assessment) and sleep quality and duration was measured with the “Allgemeiner Schlaffragebogen” (SF-A). Brain arousal was assessed with the Vigilance Algorithm Leipzig (VIGALL), which classifies 1-s EEG segments as one of seven EEG-vigilance sub-stages. Results No difference in the regulation of brain arousal/wakefulness between medicated MDD patients and healthy controls was found. Also, there was neither a clear association between depression severity nor individual items of the BDI and arousal regulation. Conclusion Our results are in line with a recent longitudinal study, showing a less stable arousal regulation in MDD patients after treatment with SSRI, suggesting a labilizing effect of SSRI on brain arousal regulation. Limitations are the retrospective design and the heterogenity of the group with respect to depression severity.

Genetic predisposition interacts with early-life stress in a mouse model of affective disorders

Genetic predisposition interacts with early-life stress in a mouse model of affective disorders

EPA-0973 – Disturbed regulation of wakefulness as a pathogenetic factor in affective disorders and ADHD

Within the vigilance regulation model the hyperactivity and sensation seeking observed in overtired children, ADHD and mania are interpreted as an autoregulatory attempt to stabilize vigilance (central nervous arousal) by increasing external stimulation. Correspondingly the withdrawal and sensation avoidance in major depression is interpreted as a reaction to a state of tonically high vigilance (1, 2). Using an EEG-based algorithm to classify automatically short EEG-segments into different vigilance stages as observed during the transition from active wakefulness to drowsiness and sleep onset (VIGALL), both patients with ADHD and mania show an unstable vigilance regulation with rapid drops to lower vigilance stages under quiet rest. The contrary was found in unmedicated patients with major depression (2). Studies will be presented supporting the validity of VIGALL (simulataneous EEG-fMRI and EEG/FDG-PET studies, as well as the neurophysiological, clinical and predictive validity of the vigilance regulation model of affective disorders. Among the far reaching consequences of the vigilance model is the question whether psychostimulants have similar beneficial effects in mania as observed in ADHD (3), an aspect which is presently studied in an international, randomized controlled trial (4).

EPA-1260 – Gene-environment interplay in the influence of early life stress on emotionality

The emotional behavior is influenced by several factors, including environment, genetic and the interaction between them, which is the aim of this work. Early life stress has been related to the development of emotional disturbances late in life, nevertheless recent studies have showed a new operational model to this relation, depending on the genetic background. Regarding to depression-like behavior, the most recent manuals for diagnosis of this disease highlights the importance of assess the anhedonia, more than the blue mood, to a correct identification of this pathology. Animal models of affective disorders has been developed aiming to access all range of depressive-like behaviors. A behavioral test to evaluate this lowest tendency to attend pleasure situations is the Sucrose Preference Test (SPT). The neonatal maternal separation procedure was carried out with the Carioca rats, an anxiety disorder Wistar rat model, developed through selective lines matching based in a task of contextual fear conditioning, which gives rise to two different lines: CHF (Carioca High Freezing) and CLF (Carioca Low Freezing). Six CHF and 10 CLF animals were used in this work. We also used Maternal Separated AFR (Animal Facility Rearing) (n=15) and Non-separated AFR groups as controls (CTR group, n=8). The rat pups were separated as a litter (8 to 10 animals per dam) from the dam from post natal day (PND) 1–14, daily, for a three-hour period/day (MS-CHF, MS-CLF and MS-AFR groups); the CTR group did not receive any kind of manipulation in these 14 days, exception for the home cage cleaning once a week, performed for all groups. The weaning was performed at PND21. All the animals were tested in the SPT at PND 60, using a 10% sucrose-solution. The animals were grouped in 4–6 animals and were tested in a free choice protocol for 48 hours. In the first 12 hours, the animals were trained with two bottles of water in the cage. After this, there were two bottles for each cage: one with water and the other with the 10% sucrose solution. The bottles' location was changed often to avoid possible position preference. The total liquid consumption and then thee sucrose consumption ratio were measured. The Kruskal-Wallis test was used to evaluate the differences between the three MS groups. The Dunn's post hoc test showed a difference between the groups in relation to relative sucrose consumption: MS-CHF consumed less sucrose solution than the MS-CLF and MS-AFR groups (KW: 24.02; p

Temporally dimorphic recruitment of dopamine neurons into stress response circuitry in Drosophila.

Many studies have pointed to vulnerability to stress and stress-related pathologies at different timepoints during an individual's life span. These sensitive windows are usually during periods of neural development, such as embryogenesis, infancy, and adolescence. It is critical to understand how neural circuitry may change as an individual ages in ways that could affect susceptibility to stress. Here we compare two stages in Drosophila melanogaster: sexual immaturity and sexual maturity. We used the genetic resources available in Drosophila to manipulate pre- and postsynaptic dopamine signaling in sexually immature and mature animals that were then assayed for heart rate and locomotor behavior in response to starvation and oxidative stress. Our results show significant differences in the stress response for sexually immature and mature animals for heart rate, periods of high mobility, mean velocity, and several other parameters of locomotor behavior. Our data show that dopamine neurons are differentially recruited into the stress response circuitry for sexually immature and mature individuals. By observing behaviors that have been previously shown in mammalian models to be affected by stress and altered in models of affective disorders, we provide a genetically tractable model for development and maintenance of the stress response circuitry during sexual maturation.

P-514 - Wakefulness regulation and the prediction of antidepressant treatment in major depression

The vigilance regulation model of affective disorders suggests that tonically high vigilance (i.e. brain arousal) in patients with major depression (MD) induces social withdrawal and sensation avoidance as autoregulatory reactions to decrease external stimulation. A computer based algorithm (VIGALL) has been developed that allows the classification of EEG-vigilance time series. Validation studies revealed a close association of EEG-vigilance stages and autonomous nervous system (ANS) activity and proved the discriminative power of VIGALL by showing that patients with MD reveal a more stable EEG-vigilance regulation compared to healthy controls. Before this background the question raises, whether vigilance regulation patterns could also be used for treatment prediction in MD. The predictive power of three different pre-treatment EEG-vigilance regulation patterns was analyzed in 33 previously unmedicated patients with MD. Results will be presented that show differences of frequency distribution of vigilance regulation patterns in responders and non-responders, defined by a reduction more or less than 30% in Hamilton Depression Rating Scale after two weeks of treatment with an SSRI or mirtazapine. Additionally, differences of ANS activity by means of heart rate variability between responders and non-responders will be shown. The results will be discussed within the light of a possible dysregulation of cortical and autonomous arousal in MD. Also the usage of EEG-vigilance regulation patterns as a biomarker for antidepressant treatment outcome in MD will be adressed.

Copy number variants in two mouse models of affective disorders

Copy number variants in two mouse models of affective disorders

Distinct effects of chronic antidepressant treatment on anxiety and depression-related behavior and stress hormone system regulation in an inbred mouse model for affective disorders

Distinct effects of chronic antidepressant treatment on anxiety and depression-related behavior and stress hormone system regulation in an inbred mouse model for affective disorders

Differential Sensitization of Amygdala Neurons to Afferent Inputs in a Model of Arthritic Pain

Pain is associated with negative affect such as anxiety and depression. The amygdala plays a key role in emotionality and has been shown to undergo neuroplastic changes in models of affective disorders. Many neurons in the central nucleus of the amygdala (CeA) are driven by nociceptive inputs, but the role of the amygdala in persistent pain states is not known. This study is the first to address nociceptive processing by CeA neurons in a model of prolonged pain. Extracellular single-unit recordings were made from 41 CeA neurons in anesthetized rats. Each neuron's responses to brief mechanical stimulation of joints, muscles, and skin and to cutaneous thermal stimuli were recorded. Background activity, receptive field size, and threshold were mapped, and stimulus-response functions were constructed. These parameters were measured repeatedly before and after induction of arthritis in one knee by intraarticular injections of kaolin and carrageenan. Multireceptive (MR) amygdala neurons (n = 20) with excitatory input from the knee joint responded more strongly to noxious than to innocuous mechanical stimuli of deep tissue (n = 20) and skin (n = 11). After induction of arthritis, 18 of 20 MR neurons developed enhanced responses to mechanical stimuli and expansion of receptive field size. These changes occurred with a biphasic time course (early peak: 1-1.5 h; persistent plateau phase: after 3-4 h). Responses to thermal stimuli did not change (7 of 7 neurons), but background activity (16 of 18 neurons) and electrically evoked orthodromic activity (11 of 12 neurons) increased in the arthritic state. Nociceptive-specific (NS) neurons (n = 13) showed no changes of their responses to mechanical, thermal, and electrical stimulation after induction of arthritis. A third group of neurons did not respond to somesthetic stimuli under control conditions (noSOM neurons; n = 8) but developed prolonged responses to mechanical, but not thermal, stimuli in arthritis (5 of 8 neurons). These data suggest that prolonged pain is accompanied by enhanced responsiveness of a subset of CeA neurons. Their sensitization to mechanical, but not thermal, stimuli argues against a nonspecific state of hyperexcitability. MR neurons could serve to integrate and evaluate information in the context of prolonged pain. Recruitment of noSOM neurons increases the gain of amygdala processing. NS neurons preserve the distinction between nociceptive and nonnociceptive inputs.

Animal models of affective disorders

The classification of affective (mood) disorders according to the Diagnostic and Statistical Manual of Mental disorders, fourth edition, is reviewed. Much is now known on the pathophysiology of affective disorders and recent brain imaging studies have yielded additional information of potential use to research and treatment. A clear genetic influence has been established for many affective disorders and in particular for bipolar disorders. Major depression is amongst the most common of the affective disorders: a recent European study demonstrated a 6-month prevalence rate of 6.9%. Major depression is also the disorder most commonly studied using animal models and consequently many useful animal models of depression have been developed. However there is no direct animal model of clinical depression, instead there are models covering different facets of drug action and disease state. These models can be divided into pharmacological models, based around known drug effects or specific receptor mediated effects on behaviour, symptomatic models, providing information on different features of the symptomatology and time course of depressive episodes, and genetic models. A combination of models will probably yield the most informative data on prospects for new treatments and further understanding of the disease process.

Patient-Centered Goal Planning: A Systemic Psychological Therapy?

This article suggests that using patient-centered goal planning, such as described in other articles in this issue, may be directly beneficial to the patients in terms of reducing anxiety and distress. One theory or model of affective disorder is reviewed, and it is noted that this theory predicts that focusing on patient goals would reduce anxiety. Observational data collected routinely from 82 patients at Rivermead are then analyzed, and it is shown that an initially high level of anxiety reduces coincident with goal planning and without any other specific intervention.

Rat tyrosine hydroxylase gene polymorphisms.

The rat tyrosine hydroxylase gene (TH) from a panel of outbred and inbred rat strains has been analysed by Southern blotting, restriction-endonuclease mapping and direct sequencing of PCR-amplified products for detecting DNA polymorphisms. Five polymorphic sites have been characterized. This information may be used in pharmacogenetic studies to determine the influence of the TH gene in animal models of affective disorders and addictive behaviours.

Blockade of CCK(B) but not CCK(A) receptors before and after the stress of predator exposure prevents lasting increases in anxiety-like behavior: implications for anxiety associated with posttraumatic stress disorder.

Lasting increases in anxiety-like behavior (ALB) in rodents in the elevated plus maze have been reported to follow brief (5 min) exposures to a cat. This study examined the role of CCK(A) and CCK(B) receptors in lasting increases in ALB following exposure to a cat. Block of CCK(B) receptors 30 min before and after cat exposure prevented increases in ALB assessed 1 week later in the elevated plus maze. Blocks of CCK(A) receptors either before or after cat exposure were without effect on increases in ALB measured 1 week later. Changes in activity or exploration could not account for the results. Effects of cat exposure on ALB, startle, and corticosteroid levels have been proposed as a model of affective disorder in posttraumatic stress disorder (PTSD). Implications of these findings for mechanisms of initiation of anxiety in PTSD and posttrauma pharmacological prophylaxis in PTSD are discussed.

Coping and Personality as Predictors of Post-Traumatic Intrusions, Numbing, Avoidance and General Distress: A Study of Victims of the Perth Flood

Trauma symptoms, coping and personality were assessed in 44 victims of the Perth flood. The sample was characterized by high levels of intrusions, numbness, arousal and general emotional distress. General levels of symptomatology were predicted by two coping strategies: emotion-focused coping and thought suppression. Overall trauma symptoms and emotion-focused coping were associated with the personality trait of neuroticism. These data are consistent with the Wells and Matthews (1994a) model of affective disorders and stress. The model proposes that certain types of emotion-focused coping tend to lead to greater access to negative self-beliefs, and that thought suppression tends to prime subsequent intruding thoughts. A second personality trait, private self-consciousness, was associated with relatively greater levels of numbing symptoms, and relatively lower levels of arousal symptoms. This patterning of symptoms may result from use of ruminative coping strategies. Hence, intrusions of trauma-related material are not simply a function of automatic activation of a fear network, but are also influenced by the person's voluntary efforts to deal with the aftermath of the event.

Inescapable footshocks induce progressive and long-lasting behavioural changes in male rats

Long-term behavioural consequences of exposure to a brief (15 min) session of inescapable footshocks (10×6 s, 1 mA) were investigated in male rats. The time course of the effects of inescapable footshocks was assessed by studying the behaviour of groups of rats at different post-stress intervals. Footshocked rats (S) did not differ from control (C) rats (exposed to the shock box for 15 min) in their behavioural response to an open field whether tested 1 h or 4 h post-stress. However, one day after shocks, S rats showed less locomotion and rearing, and more immobility and attention as compared to C rats. At 7 days or 14 days post-stress, S rats exhibited decreased locomotion, rearing, sniffing, and grooming, and increased immobility, attention, and defecation relative to C rats. In a second experiment, we investigated whether footshocks affect the behavioural response to a sudden drop in background noise during exposure to a novel environment. At 21 days post-stress, S rats showed a markedly enhanced immobility response to this stimulus as compared to C rats. In order to investigate whether rats could be exposed repeatedly to the open field without affecting the differences in behaviour between the two treatment groups, C and S rats were tested in an open field for the first time at 7 days post-stress, which yielded the typical effects of footshocks. When these rats were exposed to a second open-field test one week later, the behavioural responses of C and S rats were not different. However, the typical long-lasting effects of footshocks were still present when the same rats were exposed to a noise test at 21 days post-stress. Qualitatively similar effects were found when the reverse experiment was conducted (first noise test at 14 days, and the second noise test at 21 days, and finally an open-field test at 28 days post-stress). The present results demonstrate that exposure of rats to a short session of inescapable footshocks induces a gradually developing and long-lasting change in behavioural responses to novel environmental stimuli. It is suggested that footshock-induced long-lasting behavioural changes may serve as a model of affective disorders in man.

Stroke as a model of affective disorder : Robert G. Robinson University of Iowa, College of Medicine, Iowa City, IA 52242

Stroke as a model of affective disorder : Robert G. Robinson University of Iowa, College of Medicine, Iowa City, IA 52242

Monoamine Receptors in an Animal Model of Affective Disorder

After a relatively mild course of uncontrollable shocks, two distinct groups of rats can be defined in terms of their performance in learning to escape from a controllable stressor. Response-deficient (RD) rats do not learn to terminate the controllable stressor, whereas nondeficient (ND) rats learn this response as readily as do untreated control rats. The current studies were designed to determine the neurochemical correlates of the behavioral differences between these groups of rats. The major findings concerned postsynaptic beta-adrenergic effects in the hippocampus of RD rats. These included an up-regulation of beta-adrenergic receptors and, in parallel experiments, an increase in the sensitivity of adenylyl cyclase to stimulation by norepinephrine. There was no difference in brain levels of catecholamines between the three groups of rats. A statistically significant increase in levels of 5-hydroxytryptamine was noted in the hippocampus and hypothalamus of RD rats as compared to levels in ND rats, but no significant differences were measured between groups of rats in terms of S1 or S2 serotonergic receptor binding. These results implicate both beta-adrenergic and serotonergic mechanisms in the behavioral deficit caused by uncontrollable shock.