Effects of mood stabilizers on hippocampus BDNF levels in an animal model of mania

There is an emerging body of data suggesting that mood disorders are associated with decreased brain-derived neurotrophic factor (BDNF). The present study aims to investigate the effects of the mood stabilizers lithium (Li) and valproate (VPT) in an animal model of bipolar disorder. In the first experiment (acute treatment), rats were administered D-amphetamine (AMPH) or saline for 14 days, and then between day 8 and 14, rats were treated with either Li, VPT or saline. In the second experiment (maintenance treatment), rats were pretreated with Li, VPT or saline, and then between day 8 and 14, rats were administered AMPH or saline. In both experiments, locomotor activity was measured using the open-field test and BDNF levels were measured in rat hippocampus by sandwich-ELISA. Li and VPT reversed AMPH-induced behavioral effects in the open-field test in both experiments. In the first experiment, Li increased BDNF levels in rat hippocampus. In the second experiment, AMPH decreased BDNF levels and Li and VPT increased BDNF levels in rat hippocampus. Our results suggest that the present model fulfills adequate face, construct and predictive validity as an animal model of mania.     

An empirically derived approach to the classification and diagnosis of mood disorders

This article describes a system for diagnosing mood disorders that is empiricallyderived and designed for its clinical utility in everyday practice. A ran-domnational sample of psychiatrists and clinical psychologists described a randomlyselected current patient with a measure designed for clinically ex-periencedinformants, the Mood Disorder Diagnostic Questionnaire (MDDQ), and completedadditional research forms. We applied factor analysis to the MDDQ to identifynaturally occurring diagnostic groupings within the patient sample. The analysisyielded three clinically distinct mood disorder dimen-sions or spectra, consistentwith the major mood disturbances included in the DSM and ICD over successiveeditions (major depression, dysthymia, and mania), along with a suicide riskindex. Diagnostic criteria were determined strictly empirically. Initial datausing diagnostic efficiency statistics sup-ported the accuracy of the dimensionsin discriminating DSM-IV diagnoses; regression analyses supported the discriminantvalidity of the MDDQ scales; and correlational analysis demonstrated coherentpatterns of association with family history of mood disorders and functionaloutcomes, supporting va-lidity. Perhaps most importantly, the MDDQ diagnosticscales demonstrated incremental validity in predicting adaptive functioningand psychiatric his-tory over and above DSM-IV diagnosis. The empiricallyderived syndromes can be used to diagnose mood syndromes dimensionally withoutcomplex di-agnostic algorithms or can be combined into diagnostic prototypesthat eliminate the need for ever-expanding categories of mood disorders thatare clini-cally unwieldy.     

Adiponectin and negative mood in healthy premenopausal and postmenopausal women

Negative mood and stress are associated with cardiovascular and metabolic disease. There are likely many physiological mechanisms underlying the poor health outcomes. The relationship of psychological states (negative mood, life stress, and stress-responsive hormones) and adiponectin, an adipokine that promotes insulin sensitivity, was investigated in two separate studies. The two groups of participants included 52 healthy, premenopausal women, and 63 postmenopausal women with a range of stress levels. The relationship between adiponectin and psychological state (perceived stress and negative mood) was examined cross-sectionally in both groups of participants, but also prospectively (1 year later) in the group of postmenopausal women.In premenopausal women, negative mood and nocturnal urinary epinephrine were significantly related to adiponectin, independent of BMI. In postmenopausal women, negative mood was not associated with adiponectin cross-sectionally, but negative mood was a significant predictor for lower levels of adiponectin 1 year later, independent of initial adiponectin concentrations and changes in body mass index. Lastly, having a depressive disorder was related to lower adiponectin. As adiponectin levels are associated with insulin resistance, obesity, and diabetes mellitus, these findings suggest there may be an adiponectin-mediated pathway explaining in part how negative mood affects metabolic health. Mechanistic studies are needed to explore this potential relationship further.     

An evolutionary model for the insect vitellins

Insects can be divided into three groups based on the sizes of the polypeptide constituents of their vitellogenins and vitellins. In order to determine the relationships between these groups, antisera to the vitellins of seven insects from six taxonomic orders were used to assess immunological cross-reactivity. Antigenic relatedness was observed only between vitellins from species within the same family. Amino acid compositional data for vitellins from nine species were used to assess homology by difference matrices. The SΔQ values were similar for both intra-order and inter-order comparisons and strongly suggested relatedness. The SΔ_n comparisons supported the immunological data that indicated that the vitellins were evolving rapidly. For most insect vitellins there are two distinct size classes of polypeptides that seem to be derived from a single asymmetric proteolytic cleavage of a precursor. We propose a model that suggests that the different size polypeptides represent distinct domains and that in the evolution of the vitellogenin genes of the Diptera and Hymenoptera there has been domain elimination.     

The relationship between mood and preferences among natural landscapes: An evolutionary perspective

The evolutionary approach to aesthetics contends that psychological responses to stimuli evolved because they contributed to survival and reproduction. Thus, psychological reactions to stimuli can be thought of as motivators of appropriate environment-contingent behavior. We explored this idea by examining the relationship between mood and landscape preference across individuals. We predicted that subjects who reported positive moods (e.g., cheerful, energetic, optimistic) would be motivated to explore, and thus, would prefer landscapes rich in “Prospect” (vast expanses and overviews), while subjects who experienced mood dysphoria (e.g., tense, depressed, fatigued) would be motivated to reduce stress, and thus, prefer landscapes rich in “Refuge” (enclosed, protected spaces). While not all of the predictions were confirmed, in general, landscape preferences were found to relate to mood in the manner predicted. These results suggest that mood can affect aesthetic judgment, and that this effect might be the result of a psychological mechanism evolved to facilitate adaptive behavior.     

Gender differences in diurnal variations of subjective activation and mood

This article evaluates the influence of gender on diurnal and postlunch period variations in subjective activation and mood. This topic is not often addressed in the literature; particularly, little attention has been paid to how biological rhythms might bias research results. We studied 40 university student volunteers (20 men, 20 women) aged 18 to 23 years old (X = 20.23, SD = 1.03); they responded to questions on eight unipolar visual analog scales every hour from 08:00 to 21:00. Gender differences were observed in both diurnal and postlunch variations for scales of positive activation (alertness, vigor); sleepiness, however, was only sensitive to diurnal variation, and weariness was sensitive only to a postlunch effect. Women displayed a morning- type pattern, with their optimal moment (11:00) coming 2h earlier than for men, and their activation ratings ranged more widely. The only mood scale that showed differences related to gender was that of happiness, for which women had a higher diurnal mean, a diurnal peak 2h earlier, and a less-intense postlunch effect. Endogenous control of rhythmic pattern appears to be less intense in women, probably due to the coexistence of circamensual rhythmicity, although environmental or sociocultural influences may play a modulating role. Chronopsychological gender differences in affective states should be studied further given the implication they have for the prevention and treatment of mood disorders. (Chronobiology International, 18(3), 491-502, 2001)     

The evolutionary origins of mood and its disorders

The term 'mood' in its scientific usage refers to relatively enduring affective states that arise when negative or positive experience in one context or time period alters the individual's threshold for responding to potentially negative or positive events in subsequent contexts or time periods. The capacity for mood appears to be phylogenetically widespread and the mechanisms underlying it are highly conserved in diverse animals, suggesting it has an important adaptive function. In this review, we discuss how moods can be classified across species, and what the selective advantages of the capacity for mood are. Core moods can be localised within a two-dimensional continuous space, where one axis represents sensitivity to punishment or threat, and the other, sensitivity to reward. Depressed mood and anxious mood represent two different quadrants of this space. The adaptive function of mood is to integrate information about the recent state of the environment and current physical condition of the organism to fine-tune its decisions about the allocation of behavioural effort. Many empirical observations from both humans and non-human animals are consistent with this model. We discuss the implications of this adaptive approach to mood systems for mood disorders in humans.     

An evolutionary space-time model with varying among-site dependencies

It is now widely accepted that sites in a protein do not undergo independent evolutionary processes. The underlying assumption is that proteins are composed of conserved and variable linear domains, and thus rates at neighboring sites are correlated. In this paper, we comprehensively examine the performance of an autocorrelation model of evolutionary rates in protein sequences. We further develop a model in which the level of correlation between rates at adjacent sites is not equal at all sites of the protein. High correlation is expected, for example, in linear functional domains. On the other hand, when we consider nonlinear functional regions (e.g., active sites), low correlation is expected because the interaction between distant sites imposes independence of rates in the linear sequence. Our model is based on a hidden Markov model, which accounts for autocorrelation at certain regions of the protein and rate independence at others. We study the differences between the novel model and models which assume either independence or a fixed level of dependence throughout the protein. Using a diverse set of protein data sets we show that the novel model better fits most data sets. We further analyze the potassium-channel protein family and illustrate the relationship between the dependence of rates at adjacent sites and the tertiary structure of the protein.     

An evolutionary analytical model of a complementary circular code

The subset X0=[AAC,AAT,ACC,ATC,ATT,CAG,CTC,CTG, GAA,GAC,GAG,GAT,GCC,GGC,GGT,GTA,GTC,GTT,TAC,TTC] of 20 trinucleotides has a preferential occurrence in the frame 0 (reading frame established by the ATG start trinucleotide) of protein (coding) genes of both prokaryotes and eukaryotes. This subset X0 is a complementary maximal circular code with two permutated maximal circular codes X1 and X2 in the frames 1 and 2 respectively (frame 0 shifted by one and two nucleotides respectively in the 5'-3' direction). X0 is called a C3 code (Arquès and Michel, 1997, J. Biosyst 44, 107-134). A quantitative study of these three subsets X0, X1 and X2 in the three frames 0, 1 and 2 of eukaryotic protein genes shows that their occurrence frequencies are constant functions of the trinucleotide positions in the sequences. The frequencies of X0, X1 and X2 in the frame 0 of eukaryotic protein genes are 48.5%, 29% and 22.5% respectively. These properties are not observed in the 5' and 3' regions of eukaryotes where X0, X1 and X2 occur with variable frequencies around the random value (1/3). Several frequency asymmetries unexpectedly observed, e.g. the frequency difference between X1 and X2 in the frame 0, are related to a new property of the C3 code X0 involving substitutions. An evolutionary analytical model at three parameters (p, q, t) based on an independent mixing of the 20 codons (trinucleotides in the frame 0) of X0 with equiprobability (1/20) followed by t approximately 4 substitutions per codon according to the proportions p approximately 0.1, q approximately 0.1 and r = 1 - p - q approximately 0.8 in the three codon sites respectively, retrieves the frequencies of X0, X1 and X2 observed in the three frames of protein genes and explains these asymmetries. The complex behaviour of these analytical curves is totally unexpected and a priori difficult to imagine. Finally, the evolutionary analytical method developed could be applied to the phylogenetic tree reconstruction and the DNA sequence alignment.     

Time perception,depression and sadness

This study examined changes in time perception as a function of depressive symptoms, assessed for each participant with the Beck Depression Inventory (BDI). The participants performed a temporal bisection task in which they had to categorize a signal duration of between 400 and 1600 ms as either as short or long. The data showed that the bisection function was shifted toward the right, and that the point of subjective equality was higher in the depressive than in the non-depressive participants. Furthermore, the higher the depression score was, the shorter the signal duration was judged to be. In contrast, the sensitivity to time was similar in these two groups of participants. These results thus indicate that the probe durations were underestimated by the depressive participants. The sadness scores assessed by the Brief Mood Inventory Scale (BMIS) also suggest that the emotional state of sadness in the depressive participants goes some way to explaining their temporal performance. Statistical analyses and modeling of data support the idea according to which these results may be explained by a slowing down of the internal clock in the depressive participants.     

Hemoglobin function in the vertebrates: An evolutionary model

Comparative data on quaternary structure, cooperativity, Bohr effect and regulation by organic phosphates are reviewed for vertebrate hemoglobins. A phylogeny of hemoglobin function in the vertebrates is deduced. It is proposed that from the monomeric hemoglobin of the common ancestor of vertebrates, a deoxy dimer, as seen in the lamprey, could have originated with a single amino acid substitution. The deoxy dimer has a Bohr effect, cooperativity and a reduced oxygen affinity compared to the monomer. One, or two, additional amino acid substitutions could have resulted in the origin of a tetrameric deoxy hemoglobin which dissociated to dimers on oxygenation. Gene duplication, giving incipient alpha and beta genes, probably preceded the origin of a tetrameric oxyhemoglobin. The origin of an organic phosphate binding site on the tetrameric hemoglobin of an early fish required only one, or two, amino acid substitutions. ATP was the first organic phosphate regulator of hemoglobin function. The binding of ATP by hemoglobin may have caused the original elevation in the concentration of ATP in the red blood cells by relieving end product inhibition of ATP synthesis. The switch from regulation of hemoglobin function by ATP to regulation by DPG may have been a consequence of the curtailment of oxidative phosphorylation in the red blood cell. The basic mechanisms by which ATP and DPG concentrations can respond to strss on the oxygen transport system were present before the origin of an organic phosphate binding site on hemoglobin. A switch from ATP regulation to IP5 regulation occurred in the common ancestor of birds.     

An evolutionary explanation of the aggregation model of species coexistence

In ecology, the 'aggregation model of coexistence' provides a powerful concept to explain the unexpectedly high species richness of insects on ephemeral resources like dung pats, fruits, etc. It suggests that females aggregate their eggs across resource patches, which leads to an increased intraspecific competition within occupied patches and a relatively large number of patches that remain unoccupied. This provides competitor-free patches for heterospecifics, facilitating species coexistence. At first glance, deliberately causing competition among the females' own offspring and leaving resources to heterospecific competitors seems altruistic and incompatible with individual fitness maximization, raising the question of how natural selection operates in favour of egg aggregation on ephemeral resource patches. Allee effects that lead to fitness maxima at intermediate egg densities have been suggested, but not yet detected. Using drosophilid flies on decaying fruits as a study system, we demonstrate a hump-shaped relationship between egg density and individual survival probability, with maximum survivorship at intermediate densities. This pattern clearly selects for egg aggregation and resolves the possible conflict between the ecological concept of species coexistence on ephemeral resources and evolutionary theory.     

An evolutionary hybrid cellular automaton model of solid tumour growth

We propose a cellular automaton model of solid tumour growth, in which each cell is equipped with a micro-environment response network. This network is modelled using a feed-forward artificial neural network, that takes environmental variables as an input and from these determines the cellular behaviour as the output. The response of the network is determined by connection weights and thresholds in the network, which are subject to mutations when the cells divide. As both available space and nutrients are limited resources for the tumour, this gives rise to clonal evolution where only the fittest cells survive. Using this approach we have investigated the impact of the tissue oxygen concentration on the growth and evolutionary dynamics of the tumour. The results show that the oxygen concentration affects the selection pressure, cell population diversity and morphology of the tumour. A low oxygen concentration in the tissue gives rise to a tumour with a fingered morphology that contains aggressive phenotypes with a small apoptotic potential, while a high oxygen concentration in the tissue gives rise to a tumour with a round morphology containing less evolved phenotypes. The tissue oxygen concentration thus affects the tumour at both the morphological level and on the phenotype level.     

An evolutionary model for maximum likelihood alignment of DNA sequences

Summary Most algorithms for the alignment of biological sequences are not derived from an evolutionary model. Consequently, these alignment algorithms lack a strong statistical basis. A maximum likelihood method for the alignment of two DNA sequences is presented. This method is based upon a statistical model of DNA sequence evolution for which we have obtained explicit transition probabilities. The evolutionary model can also be used as the basis of procedures that estimate the evolutionary parameters relevant to a pair of unaligned DNA sequences. A parameter-estimation approach which takes into account all possible alignments between two sequences is introduced; the danger of estimating evolutionary parameters from a single alignment is discussed.     

An evolutionary model of influenza A with drift and shift

Influenza A virus evolves through two types of evolutionary mechanisms - drift and shift. These two evolutionary mechanisms allow the pathogen to infect us repeatedly, as well as occasionally create pandemics with large morbidity and mortality. Here we introduce a novel model that incorporates both evolutionary mechanisms. This necessitates the modelling of three types of strains - seasonal human strains, bird-to-human transmittable H5N1 strains and evolved pandemic H5N1 strain. We define reproduction and invasion reproduction numbers and use them to establish the presence of dominant and coexistence equilibria. We find that the amino acid substitution structure of human influenza can destabilize the human influenza equilibrium and sustained oscillations are possible. We find that for low levels of infection in domestic birds, these oscillations persist, inducing oscillations in the number of humans infected with the avian flu strain. The oscillations have a period of 365 days, similar to the one that can be observed in the cumulative number of human H5N1 cases reported by the World Health Organization (WHO). Furthermore, we establish some partial global results on the competition of the strains.     

An evolutionary model of influenza A with drift and shift

Influenza A virus evolves through two types of evolutionary mechanisms – drift and shift. These two evolutionary mechanisms allow the pathogen to infect us repeatedly, as well as occasionally create pandemics with large morbidity and mortality. Here we introduce a novel model that incorporates both evolutionary mechanisms. This necessitates the modelling of three types of strains – seasonal human strains, bird-to-human transmittable H5N1 strains and evolved pandemic H5N1 strain. We define reproduction and invasion reproduction numbers and use them to establish the presence of dominant and coexistence equilibria. We find that the amino acid substitution structure of human influenza can destabilize the human influenza equilibrium and sustained oscillations are possible. We find that for low levels of infection in domestic birds, these oscillations persist, inducing oscillations in the number of humans infected with the avian flu strain. The oscillations have a period of 365 days, similar to the one that can be observed in the cumulative number of human H5N1 cases reported by the World Health Organization (WHO). Furthermore, we establish some partial global results on the competition of the strains.     

An inclusive fitness model for the evolutionary advantage of sibmating

Summary We construct an inclusive fitness model of the relative selective advantage of sibmating and outbreeding behaviour, under the assumption that inbred offspring pay a fitness penalty. We are particularly interested in the question of whether such inbreeding depression is enough to generate a stable phenotypic polymorphism, with both kinds of breeding observed. The model predicts that, under diploidy, such a polymorphism is never found, but under haplodiploidy, it exists for a narrow range of parameter values. The inclusive fitness argument is technically interesting because care must be taken with reproductive values. We also present a corrected version of a one-locus genetic model for sibmating and find that the inclusive fitness and genetic models give identical results when selection is weak.     

Experimental mood manipulation does not induce change in preference for natural landscapes

According to evolutionary theory, emotions are psychological mechanisms that have evolved to enhance fitness in specific situations by motivating appropriate (adaptive) behavior. Taking this perspective, a previous study examined the relationship between mood and preference for natural environments. It reported that participants’ anxiety level was associated with a preference for landscapes offering what Appleton called "refuge," while participants’ anger and cheerfulness were both associated with a preference for landscapes offering what Appleton called "prospect." We attempted to replicate these results and to improve on the study by experimentally manipulating mood. Using a between-subjects design, 80 participants were instructed to self-induce one of four moods: anger, sadness, anxiety, or joy. After the mood induction, they viewed fourteen landscape photographs and recorded the seven most preferred. It was hypothesized that subjects experiencing anger or joy would prefer landscapes rich in "prospect" features, whereas participants experiencing sadness or anxiety would prefer landscapes rich in "refuge" features. In contrast to the previous study, the predictions were not supported: artificially induced moods may not provide ecological validity as a test of the "mood as motivator" model; alternatively, the first study may have reported an alpha error. To see whether the model has practical value, we recommend a study of landscape preference using participants with clinically significant levels of mood dysphoria. Bernadette Klopp received her B.A. (Honours) in Psychology from the University of Queensland. Her areas of research interest focus on environment and aesthetics, environmental psychology, and the evolution of art as a form of social communication. Bernadette is currently employed by the Commonwealth Rehabilitation Service of Queensland, but she hopes to pursue further graduate study. Linda Mealey, Ph.D., is just finishing a three-year stint as Senior Lecturer at the School of Psychology, University of Queensland, before returning to her Associate Professor position at the College of St. Benedict in central Minnesota. She is Vice-President/President-Elect of the International Society for Human Ethology, a Councilor of the Human Behavior and Evolution Society, and a member of the editorial board of Politics and the Life Sciences.     

Evening types demonstrate reduced SSRI treatment efficacy

Selective serotonin reuptake inhibitors (SSRIs) have a profound effect on the circadian system's response to environmental light, which may impact treatment outcomes for patients depending on their habitual light exposure patterns. Here, we investigated the relationship between time-of-day preference, depressive symptoms and self-reported antidepressant treatment response. Evening types reported having taken a higher number of antidepressant medications in the previous 5 years and lower SSRI efficacy than morning types. While undergoing SSRI treatment, evening types also reported more depressive symptoms and suicidality. It is concluded that time-of-day preference may prove informative in predicting SSRI treatment responses.     

An evolutionary model for protein-coding regions with conserved RNA structure

Here we present a model of nucleotide substitution in protein-coding regions that also encode the formation of conserved RNA structures. In such regions, apparent evolutionary context dependencies exist, both between nucleotides occupying the same codon and between nucleotides forming a base pair in the RNA structure. The overlap of these fundamental dependencies is sufficient to cause "contagious" context dependencies which cascade across many nucleotide sites. Such large-scale dependencies challenge the use of traditional phylogenetic models in evolutionary inference because they explicitly assume evolutionary independence between short nucleotide tuples. In our model we address this by replacing context dependencies within codons by annotation-specific heterogeneity in the substitution process. Through a general procedure, we fragment the alignment into sets of short nucleotide tuples based on both the protein coding and the structural annotation. These individual tuples are assumed to evolve independently, and the different tuple sets are assigned different annotation-specific substitution models shared between their members. This allows us to build a composite model of the substitution process from components of traditional phylogenetic models. We applied this to a data set of full-genome sequences from the hepatitis C virus where five RNA structures are mapped within the coding region. This allowed us to partition the effects of selection on different structural elements and to test various hypotheses concerning the relation of these effects. Of particular interest, we found evidence of a functional role of loop and bulge regions, as these were shown to evolve according to a different and more constrained selective regime than the nonpairing regions outside the RNA structures. Other potential applications of the model include comparative RNA structure prediction in coding regions and RNA virus phylogenetics.