Sandi C, Richter-Levin G. From high anxiety trait to depression: a neurocognitive hypothesis. Trends Neurosci 32: 312-320

Laboratory of Behavioral Genetics, Brain Mind Institute, Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne CH-1015, Switzerland.
Trends in Neurosciences (Impact Factor: 13.56). 05/2009; 32(6):312-20. DOI: 10.1016/j.tins.2009.02.004
Source: PubMed


Although exposure to substantial stress has a major impact on the development of depression, there is considerable variability in the susceptibility of individuals to the adverse effects of stress. The personality trait of high anxiety has been identified as a vulnerability factor to develop depression. We propose here a new unifying model based on a series of neurocognitive mechanisms (and fed with crucial information provided by research on the fields of emotion, stress and cognition) whereby individuals presenting a high anxiety trait are particularly vulnerable to develop depression when facing stress and adversity. Our model highlights the importance of developing prevention programs addressed to restrain, in high anxious individuals, the triggering of a dysfunctional neurocognitive cascade while coping with stress.

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    • "Consistent with these findings, a high anxiety phenotype has been associated with decreased prefrontal activity, increased amygdala activity (Indovina et al., 2011) and reduced functional (Bishop, 2007; Hahn et al., 2011) and structural connectivity between the two (Kim and Whalen, 2009), features common with a variety of anxiety disorders, including posttraumatic stress disorder (Shin et al., 2005; Killgore et al., 2013; Stevens et al., 2013), panic disorder (Thomas et al., 2001; Killgore et al., 2013) and specific phobia (Ahs et al., 2009; Killgore et al., 2013). Thus, the study of trait anxiety has the potential to provide important insights into the etiology and treatment of anxiety disorders (Sandi and Richter-Levin, 2009; Indovina et al., 2011). Marked individual differences in responsivity to fearful-and anxiety-provoking stimuli have been reported in other animals, including rodents (Duvarci et al., 2009) and monkeys (Nelson et al., 2003). "
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    ABSTRACT: High trait anxiety is a risk factor for the development of anxiety disorders. Like the disorders themselves high trait anxiety has marked phenotypic variation at the level of symptomatology and neural circuits, suggesting that there may be different symptoms and distinct neural circuits associated with risk for these disorders. To address these issues, it is essential to develop reliable animal models of trait anxiety in a non-human primate whose brain bears structural and functional similarity to humans. The present study investigated individual variation in responsivity to fearful and anxiety provoking stimuli in the common marmoset monkey. Seven out of 27 animals failed to display discriminative, conditioned cardiovascular and behavioral responses on an auditory fear discrimination task, similar to that seen in high anxious humans and rodents. Their heightened emotionality to a rubber snake was consistent with the hypothesis that they were high in trait-like anxiety. Evidence for phenotypic variation in the high anxiety group was provided by the finding that discrimination failure was predicted early in conditioning by either hyper-vigilant scanning to the cues or a reduction in blood pressure to the context, i.e., test apparatus. Given that high trait anxiety in humans can be associated with altered prefrontal cognitive functioning and previously we implicated the marmoset anterior orbitofrontal (antOFC) and ventrolateral prefrontal cortex (vlPFC) in negative emotion regulation, we also tested the marmosets on two tests of cognitive flexibility differentially dependent on these two regions. While the high anxious group did not differ overall in their perseverative performance, the two distinct phenotypes were differentially correlated with reduced perseverative responding on the OFC- and vlPFC-dependent flexibility tests. Together, this study provides a new model of trait anxiety in marmosets amenable to analysis of phenotypic variation and neural circuitry.
    Frontiers in Behavioral Neuroscience 04/2014; 8:137. DOI:10.3389/fnbeh.2014.00137 · 3.27 Impact Factor
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    • "Still it is debated whether an HPAaxis hyperactivity is the cause or the consequence in depression (Neigh and Nemeroff, 2006). Nevertheless, it seems clear that an increased stress responsivity can be the cause of increased vulnerability to stress associated diseases (Pardon and Rattray, 2008; Sandi and Richter-Levin, 2009). "
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    ABSTRACT: Stress and an altered stress response have been associated with many multifactorial diseases, such as psychiatric disorders or neurodegenerative diseases. As currently mouse mutants for each single gene are generated and phenotyped in a large-scale manner, it seems advisable also to test these mutants for alterations in their stress responses. Here we present the determinants of a robust and reliable non-invasive test for stress-responsivity in mice. Stress is applied through restraining the mice in tubes and recording behavior in the Open Field 20 min after cessation of the stress. Two hours, but not 15 or 50 min of restraint lead to a robust and reproducible increase in distance traveled and number of rearings during the first 5 min in the Open Field in C57BL/6 mice. This behavioral response is blocked by the corticosterone synthesis inhibitor metyrapone, but not by RU486 treatment, indicating that it depends on corticosteroid secretion, but is not mediated via the glucocorticoid receptor type II. We assumed that with a stress duration of 15 min one could detect hyper-responsivity, and with a stress duration of 2 h hypo-responsivity in mutant mouse lines. This was validated with two mutant lines known to show opposing effects on corticosterone secretion after stress exposure, corticotropin-releasing hormone (CRH) over-expressing mice and CRH receptor 1 knockout (KO) mice. Both lines showed the expected phenotype, i.e., increased stress responsivity in the CRH over-expressing mouse line (after 15 min restraint stress) and decreased stress responsivity in the CRHR1-KO mouse line (after 2 h of restraint stress). It is possible to repeat the acute stress test several times without the stressed animal adapting to it, and the behavioral response can be robustly evoked at different ages, in both sexes and in different mouse strains. Thus, locomotor and rearing behavior in the Open Field after an acute stress challenge can be used as reliable, non-invasive indicators of stress responsivity and corticosterone secretion in mice.
    Frontiers in Behavioral Neuroscience 04/2014; 8:125. DOI:10.3389/fnbeh.2014.00125 · 3.27 Impact Factor
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    • "The amygdala has been implicated in the processing of salience, particularly in response to fear stimuli [15], [16]. Enhanced amygdala reactivity can be detected in individuals with high state and trait anxiety levels exposed to emotionally arousing stimuli (for a review, see [17]) and has emerged as a hallmark in a variety of anxiety disorders, including post-traumatic stress disorder (PTSD) and social phobia [18], [19]. Importantly, neuroimaging studies in PTSD patients indicate that increased amygdala activation is not only observed following exposure to disorder-relevant stimuli [20]–[22], but also at rest [23] and during the completion of non-emotional tasks [24], [25]. "
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    ABSTRACT: Stress during childhood and adolescence is a risk factor for psychopathology. Alterations in γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain, have been found following stress exposure and fear experiences and are often implicated in anxiety and mood disorders. Abnormal amygdala functioning has also been detected following stress exposure and is also implicated in anxiety and social disorders. However, the amygdala is not a unitary structure; it includes several nuclei with different functions and little is known on the potential differences the impact of early life stress may have on this system within different amygdaloid nuclei. We aimed here to evaluate potential regional differences in the expression of GABAergic-related markers across several amygdaloid nuclei in adult rats subjected to a peripuberty stress protocol that leads to enhanced basal amygdala activity and psychopathological behaviors. More specifically, we investigated the protein expression levels of glutamic acid decarboxylase (GAD; the principal synthesizing enzyme of GABA) and of GABA-A receptor subunits α2 and α3. We found reduced GAD and GABA-A α3, but not α2, subunit protein levels throughout all the amygdala nuclei examined (lateral, basolateral, basomedial, medial and central) and increased anxiety-like behaviors and reduced sociability in peripubertally stressed animals. Our results identify an enduring inhibition of the GABAergic system across the amygdala following exposure to early adversity. They also highlight the suitability of the peripuberty stress model to investigate the link between treatments targeting the dysfunctional GABAergic system in specific amygdala nuclei and recovery of specific stress-induced behavioral dysfunctions.
    PLoS ONE 04/2014; 9(4):e94666. DOI:10.1371/journal.pone.0094666 · 3.23 Impact Factor
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