João José Cerqueira

Chronic Stress Causes Frontostriatal Reorganization and Affects Decision-Making

Brain Rewiring After Stress Chronic stress, mainly through the release of corticosteroids, affects executive behavior through sequential structural modulation of brain networks. Stress-induced deficits in spatial reference, working memory, and behavioral flexibility are associated with synaptic and dendritic reorganization in both the hippocampus and the medial prefrontal cortex. However, the effects of chronic stress on action selection strategies are unclear. Dias-Ferreira et al. (p. 621) examined whether chronic stress affects the ability of animals to select the appropriate actions based on the consequences of their choice, and found that rats exposed to chronic unpredictable stress rapidly shift toward using habitual strategies. The shift in behavioral strategies observed in chronically stressed animals corresponded to dramatic and divergent changes in connectivity in the associative and sensorimotor corticostriatal circuits underlying these behaviors. Chronic stress alters brain neural circuits and affects the ability of animals to perform actions based on their consequences. The ability to shift between different behavioral strategies is necessary for appropriate decision-making. Here, we show that chronic stress biases decision-making strategies, affecting the ability of stressed animals to perform actions on the basis of their consequences. Using two different operant tasks, we revealed that, in making choices, rats subjected to chronic stress became insensitive to changes in outcome value and resistant to changes in action-outcome contingency. Furthermore, chronic stress caused opposing structural changes in the associative and sensorimotor corticostriatal circuits underlying these different behavioral strategies, with atrophy of medial prefrontal cortex and the associative striatum and hypertrophy of the sensorimotor striatum. These data suggest that the relative advantage of circuits coursing through sensorimotor striatum observed after chronic stress leads to a bias in behavioral strategies toward habit.

The Prefrontal Cortex as a Key Target of the Maladaptive Response to Stress

Research on the detrimental effects of stress in the brain has mainly focused on the hippocampus. Because prefrontal cortex (PFC) dysfunction characterizes many stress-related disorders, we here analyzed the impact of chronic stress in rats on the integrity of the hippocampal–PFC pathway, monitored by behavioral and electrophysiological function and morphological assessment. We show that chronic stress impairs synaptic plasticity by reducing LTP induction in the hippocampal–PFC connection; in addition, it induces selective atrophy within the PFC and severely disrupts working memory and behavioral flexibility, two functions that depend on PFC integrity. We also demonstrate that short periods of stress exposure induce spatial reference memory deficits before affecting PFC-dependent tasks, thus suggesting that the impairment of synaptic plasticity within the hippocampus-to-PFC connection is of relevance to the stress-induced PFC dysfunction. These findings evidence a fundamental role of the PFC in maladaptive responses to stress and identify this area as a target for intervention in stress-related disorders.

The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling.

The mechanisms underlying the initiation/onset of, and the recovery from, depression are still largely unknown; views that neurogenesis in the hippocampus may be important for the pathogenesis and amelioration of depressive symptoms have gained currency over the years although the original evidence has been challenged. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 2 weeks of stress exposure, animals were treated with the antidepressants fluoxetine, imipramine, CP 156,526 or SSR 1494515, alone or combined with methylazoxymethanol, a cytostatic agent used to arrest neurogenesis. We found that antidepressants retain their therapeutic efficacy in reducing both measured indices of depression-like behavior (learned helplessness and anhedonia), even when neurogenesis is blocked. Instead, our experiments suggest re-establishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus and prefrontal cortex, rather than neurogenesis, as the basis for the restoration of behavioral homeostasis by antidepressants.

A trans-dimensional approach to the behavioral aspects of depression

Depression, a complex mood disorder, displays high comorbidity with anxiety and cognitive disorders. To establish the extent of inter-dependence between these behavioral domains, we here undertook a systematic analysis to establish interactions between mood [assessed with the forced-swimming (FST) and sucrose consumption tests (SCT)], anxiety [elevated-plus maze (EPM) and novelty suppressed feeding (NSF) tests] and cognition (spatial memory and behavioral flexibility tests) in rats exposed to unpredictable chronic-mild-stress (uCMS). Expectedly, uCMS induced depressive-like behavior, a hyperanxious phenotype and cognitive impairment; with the exception of the measure of anxiety in the EPM, these effects were attenuated by antidepressants (imipramine, fluoxetine). Measures of mood by the FST and SCT were strongly correlated, whereas no significant correlations were found between the different measures of anxiety (EPM and NSF); likewise, measures of cognition by spatial memory and behavioral flexibility tests were poorly correlated. Inter-domain analysis revealed significant correlations between mood (FST and SCT) and anxiety-like behavior (NSF, but not EPM). Furthermore, significant correlations were found between cognitive performance (reverse learning task) and mood (FST and SCT) and anxiety-like behavior (NSF). These results demonstrate interactions between different behavioral domains that crosscut the disciplines of psychiatry and neurology.

Morphological Correlates of Corticosteroid-Induced Changes in Prefrontal Cortex-Dependent Behaviors

Imbalances in the corticosteroid milieu have been implicated in several neuropsychiatric disorders, including depression and schizophrenia. Prefrontal cortex (PFC) dysfunction is also a hallmark of these conditions, causing impairments in executive functions such as behavioral flexibility and working memory. Recent studies have suggested that the PFC might be influenced by corticosteroids released during stress. To test this possibility, we assessed spatial working memory and behavioral flexibility in rats submitted to chronic adrenalectomy or treatment with corticosterone (25 mg/kg) or the synthetic glucocorticoid dexamethasone (300 μg/kg); the behavioral analysis was complemented by stereological evaluation of the PFC (prelimbic, infralimbic, and anterior cingulate regions), the adjacent retrosplenial and motor cortices, and the hippocampal formation. Dexamethasone treatment resulted in a pronounced impairment in working memory and behavioral flexibility, effects that correlated with neuronal loss and atrophy of layer II of the infralimbic, prelimbic, and cingulate cortices. Exposure to corticosterone produced milder impairments in behavioral flexibility, but not in working memory, and reduced the volume of layer II of all prefrontal areas. Interestingly, adrenalectomy-induced deleterious effects only became apparent on the reverse learning task and were not associated with structural alterations in the PFC. None of the experimental procedures influenced the morphology of retrosplenial or motor cortices, but stereological measurements confirmed previously observed effects of corticosteroids on hippocampal structure. Our results describe, for the first time, that imbalances in the corticosteroid environment can induce degeneration of specific layers of the PFC; these changes appear to be the morphological correlate of corticosteroid-induced impairment of PFC-dependent behavior(s).

Dissociation of the morphological correlates of stress-induced anxiety and fear.

Chronic stress is a powerful modulator of emotional behaviour. Previous studies have shown that distinct neuronal pathways modulate different emotional behaviours: while the amygdala plays a key role in fear‐conditioned‐to‐cue stimuli, the bed nucleus of stria terminalis (BNST) is implicated in anxiety behaviour and responses to contextual stimuli. In addition, the BNST is directly involved in the regulation of the hypothalamus–pituitary–adrenal (HPA) axis. In the present study, we assessed anxiety (measured in the elevated‐plus maze and acoustic startle apparatus) and fear‐conditioned responses to light stimuli in rats that had been exposed to either chronic unpredictable stress or corticosterone for 28 days; thereafter, stereological estimates of the BNST and amygdaloid complex were performed, followed by three‐dimensional morphometric dendritic analysis. Results show that chronic stress induces hyperanxiety without influencing fear conditioning or locomotion and exploratory activity. Stress‐induced hyperanxiety was correlated with increased volumes of the BNST but not of the amygdala. Dendritic remodelling was found to make a significant contribution to the stress‐induced increase in BNST volume, primarily due to changes in the anteromedial area of the BNST, an area strongly implicated in emotional behaviour and in the neuroendocrine control of the stress response. Importantly, all of the effects of stress were recapitulated by exogenous corticosterone. In conclusion, this study shows that chronic stress impacts on BNST structure and function; its findings pertain to the modulation of emotional behaviour and the maladaptive response to stress.

The stressed prefrontal cortex. Left? Right!

The prefrontal cortex (PFC) plays an important role in the integration of cognitive and affective behavior and regulating autonomic and neuroendocrine functions. This region of the brain, which may be considered analogous to the RAM memory of a computer, is important for translating stressful experience into adaptive behavior. The PFC responds to stress and modulates the response to stress through regulation of the hypothalamic paraventricular nucleus (PVN) which, in turn, controls sympathoadrenal and hypothalamic-pituitary-adrenal (HPA) activity. Interestingly, the latter convey the signals that link the CNS with the immune system. The present review highlights findings that contribute to elucidate the involvement of the PFC in the control of behavioral and neuroendocrine responses to chronic stress. It also considers the implications of these regulatory links for disorders of the nervous and immune systems.

Stress-induced changes in human decision-making are reversible

Appropriate decision-making relies on the ability to shift between different behavioral strategies according to the context in which decisions are made. A cohort of subjects exposed to prolonged stress, and respective gender- and age-matched controls, performed an instrumental behavioral task to assess their decision-making strategies. The stressed cohort was reevaluated after a 6-week stress-free period. The behavioral analysis was complemented by a functional magnetic resonance imaging (fMRI) study to detect the patterns of activation in corticostriatal networks ruling goal-directed and habitual actions. Using structural MRI, the volumes of the main cortical and subcortical regions implicated in instrumental behavior were determined. Here we show that chronic stress biases decision-making strategies in humans toward habits, as choices of stressed subjects become insensitive to changes in outcome value. Using functional imaging techniques, we demonstrate that prolonged exposure to stress in humans causes an imbalanced activation of the networks that govern decision processes, shifting activation from the associative to the sensorimotor circuits. These functional changes are paralleled by atrophy of the medial prefrontal cortex and the caudate, and by an increase in the volume of the putamina. Importantly, a longitudinal assessment of the stressed individuals showed that both the structural and functional changes triggered by stress are reversible and that decisions become again goal-directed.

The impact of age on emotional and cognitive behaviours triggered by experimental neuropathy in rats

ABSTRACT Chronic pain syndromes encompass several clinical entities that frequently affect the individuals’ emotional and cognitive behaviours which, in turn, can also alter pain perception. Additionally, both pain perception and motivational‐affective behaviours change with increasing age. In order to evaluate the influence of age upon the interaction between chronic pain and affective/cognitive behaviours, 3‐, 10‐ and 22‐month‐old rats with 1 month neuropathy (spared nerve injury, SNI model) were compared with age‐matched sham‐operated controls in the open field (OF; locomotor and exploratory behaviours), elevated plus‐maze (EPM; anxiety‐like behaviour), forced swimming (FST; depressive‐like behaviour), working memory water maze (WM; spatial short‐term memory), Morris water maze (MWM; spatial reference memory) and spatial reversal (behavioural flexibility) tests. Locomotor and exploratory activities decreased steadily with age and were further reduced by SNI. Aging was associated with increased anxiety‐like behaviour, which was potentiated by SNI in both 3‐ and 22‐month‐old rats. The performance in the FST was affected by SNI but only in mid‐aged animals. Cognitive performances in the MWM and spatial reversal tests deteriorated with age; however, the SNI lesion was only detrimental in the reversal task to mid‐aged animals. Our data demonstrate that the influence of neuropathic pain on affective and cognitive behaviours is age dependent and varies with the behavioural domain that is tested. Importantly, mid‐aged animals seem to be more susceptible to depression and cognitive deterioration associated to chronic pain than young and old groups.

Stress and glucocorticoid footprints in the brain—The path from depression to Alzheimer's disease

Increasingly, stress is recognized as a trigger of depressive episodes and recent evidence suggests a causal role of stress in the onset and progression of Alzheimers disease (AD) pathology. Besides aging, sex is an important determinant of prevalence rates for both AD and mood disorders. In light of a recent meta-analysis indicating that depressed subjects have a higher likelihood of developing AD, a key message in this article will be that both depression and AD are stress-related disorders and may represent a continuum that should receive more attention in future neurobiological studies. Accordingly, this review considers some of the cellular mechanisms that may be involved in regulating this transition threshold. In addition, it highlights the importance of addressing the question of how aging and sex interplay with stress to influence mood and cognition, with a bias towards consideration of neuroplastic events in particular brain regions, as the basis of AD and depressive disorders.