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Exposure to chronic stress leads to an array of anatomical, functional, and metabolic changes in the brain that play a key role in triggering psychiatric disorders such as depression. The hippocampus is particularly well known as a target of maladaptive responses to stress. To capture stress-induced changes in metabolic and functional connectivity in the hippocampus, stress-resistant (low-responders) or -susceptible (high-responders) rats exposed to a chronic unpredictable stress paradigm (categorized according to their hormonal and behavioral responses) were assessed by multimodal neuroimaging; the latter was achieved by using localized ¹H MR spectroscopy and resting-state functional MRI (fMRI) at 11,7T data from stressed (n = 25) but also control (n = 15) male Wistar rats. Susceptible animals displayed increased GABA-glutamine (+19%) and glutamate-glutamine (+17%) ratios and decreased levels of macromolecules (-11%); these changes were positively correlated with plasma corticosterone levels. In addition, the neurotransmitter levels showed differential associations with functional connectivity between the hippocampus and the amygdala, the piriform cortex and thalamus between stress-resistant and -susceptible animals. Our observations are consistent with previously reported stress-induced metabolomic changes that suggest overall neurotransmitter dysfunction in the hippocampus. Their association with the fMRI data in this study reveals how local adjustments in neurochemistry relate to changes in the neurocircuitry of the hippocampus, with implications for its stress-associated dysfunctions. [ABSTRACT FROM AUTHOR]

Exposure to chronic stress can have broad effects on health ranging from increased predisposition for neuropsychiatric disorders to deregulation of immune responses. The chronic unpredictable stress (CUS) protocol has been widely used to study the impact of stress exposure in several animal models and consists in the random, intermittent, and unpredictable exposure to a variety of stressors during severalweeks. CUS has consistently been shown to induce behavioral and immunological alterations typical of the chronic stressresponse. Unfortunately C57BL/6 mice, one of the most widely used mouse strains, due to the great variety of genetically modified lines, seem to be resistant to the commonly used 4-week-long CUS protocol. The definition of an alternative CUS protocol allowing the use of C57BL/6 mice in chronic stress experiments is a need. Here, we show that by extending the CUS protocol to 8weeks is possible to induce a chronic stress-response in C57BL/6 mice, as revealed by abrogated body weight gain, increased adrenals weight, and an overactive hypothalamic-pituitary-adrenal axis with increased levels of serum corticosterone. Moreover, we also observed stress-associated behavioral alterations, including the potentiation of anxious-like and depressive-like behaviors and a reduction of exploratory behavior, as well as subtle stress-related changes in the cell population of the thymus and of the spleen.The present protocol for C57BL/6 mice consistently triggers the spectrum of CUS-induced changes observed in rats and, thus, will be highly useful to researchers that need to use this particular mouse strain as an animal model of neuropsychiatric disorders and/or immune deregulation related to CUS. [ABSTRACT FROM AUTHOR]

Chronic stress has been widely reported to have deleterious impact in multiple biological systems. Specifically, structural and functional remodeling of several brain regions following prolonged stress exposure have been described; importantly, some of these changes are eventually reversible. Recently, we showed the impact of stress on resting state networks (RSNs), but nothing is known about the plasticity of RSNs after recovery from stress. Herein, we examined the "plasticity" of RSNs, both at functional and structural levels, by comparing the same individuals before and after recovery from the exposure to chronic stress; results were also contrasted with a control group. Here we show that the stressed individuals after recovery displayed a decreased resting functional connectivity in the default mode network (DMN), ventral attention network (VAN), and sensorimotor network (SMN) when compared to themselves immediately after stress; however, this functional plastic recovery was only partial as when compared with the control group, as there were still areas of increased connectivity in dorsal attention network (DAN), SMN and primary visual network (VN) in participants recovered from stress. Data also shows that participants after recovery from stress displayed increased deactivations in DMN, SMN, and auditory network (AN), to levels similar to those of controls, showing a normalization of the deactivation pattern in RSNs after recovery from stress. In contrast, structural changes (volumetry) of the brain areas involving these networks are absent after the recovery period. These results reveal plastic phenomena in specific RSNs and a functional remodeling of the activation-deactivation pattern following recovery from chronic-stress, which is not accompanied by significant structural plasticity. [ABSTRACT FROM AUTHOR]

Exposure to a novel environment triggers the response of several brain areas that regulate emotional behaviors. Here, we studied theta oscillations within the hippocampus (HPC)-amygdala (AMY)-medial prefrontal cortex (mPFC) network in exploration of a novel environment and subsequent familiarization through repeated exposures to that same environment; in addition, we assessed how concomitant stress exposure could disrupt this activity and impair both behavioral processes. Local field potentials (LFP) were simultaneously recorded from dorsal and ventral hippocampus (dHPC and vHPC, respectively), basolateral amygdala (BLA) and mPFC in freely behaving rats while they were exposed to a novel environment, then repeatedly re-exposed over the course of 3 weeks to that same environment and, finally, on re-exposure to a novel unfamiliar environment. A longitudinal analysis of theta activity within this circuit revealed a reduction of vHPC and BLA theta power and vHPC-BLA theta coherence through familiarization which was correlated with a return to normal exploratory behavior in control rats. In contrast, a persistent over-activation of the same brain regions was observed in stressed rats that displayed impairments in novel exploration and familiarization processes. Importantly, we show that stress also affected intra-hippocampal synchrony and heightened the coherence between vHPC and BLA. In summary, we demonstrate that modulatory theta activity in the aforementioned circuit, namely in the vHPC and BLA, is correlated with the expression of anxiety in novelty-induced exploration and familiarization in both normal and pathological conditions. [ABSTRACT FROM AUTHOR]

Resting state brain networks (RSNs) are spatially distributed large-scale networks, evidenced by resting state functional magnetic resonance imaging (fMRI) studies. Importantly, RSNs are implicated in several relevant brain functions and present abnormal functional patterns in many neuropsychiatric disorders, for which stress exposure is an established risk factor. Yet, so far, little is known about the effect of stress in the architecture of RSNs, both in resting state conditions or during shift to task performance. Herein we assessed the architecture of the RSNs using functional magnetic resonance imaging (fMRI) in a cohort of participants exposed to prolonged stress (participants that had just finished their long period of preparation for the medical residence selection exam), and respective gender- and age-matched controls (medical students under normal academic activities). Analysis focused on the pattern of activity in resting state conditions and after deactivation. A volumetric estimation of the RSNs was also performed. Data shows that stressed participants displayed greater activation of the default mode (DMN), dorsal attention (DAN), ventral attention (VAN), sensorimotor (SMN), and primary visual (VN) networks than controls. Importantly, stressed participants also evidenced impairments in the deactivation of resting state-networks when compared to controls. These functional changes are paralleled by a constriction of the DMN that is in line with the pattern of brain atrophy observed after stress exposure. These results reveal that stress impacts on activation-deactivation pattern of RSNs, a finding that may underlie stress-induced changes in several dimensions of brain activity. [ABSTRACT FROM AUTHOR]

The bed nucleus of the stria terminalis (BNST) is critically implicated in anxiety behavior and control of the hypothalamus-pituitary-adrenal axis. Having previously shown that chronic stress triggers dendritic/synaptic remodeling in specific nuclei of the BNST, we characterised the pattern of activation of neurons within different regions of the BNST under basal conditions and after an anxiogenic stimulus in control and stressed rats. Under basal conditions, stressed, but not control, animals displayed increased cFOS expression in the dorsomedial nucleus and decreased activation of the principal nucleus. This pattern resembled that observed in controls that had been exposed to the anxiogenic stimulus. Subsequent analysis of various BNST subnuclei revealed differential patterns of gene expression in controls and stressed animals. We found decreased levels of corticotropin-releasing hormone 1 receptor mRNA expression in the dorsomedial and fusiform nuclei, and a global increase in the levels of corticotropin-releasing hormone 2 receptor in the principal nucleus. In addition, we found subnuclei-specific increases in GABAA and NR2B receptors in stressed animals, which suggest changes in the GABAergic and glutamergic innervation of the BNST. Importantly, these findings were associated with increased anxiety-like behavior and impaired control of the hypothalamus-pituitary-adrenal axis in stressed animals. In summary, these data reveal that chronic stress shifts the pattern of response of the BNST to an anxiogenic mode and provide new information on the underlying mechanisms of the stress-induced hypercorticalism and hyperanxious status. [ABSTRACT FROM AUTHOR]

Stress has a strong impact in the brain, impairing decision-making processes as a result of changes in circuits involving the prefrontal and orbitofrontal cortices and the striatum. Given that these same circuits are key for action control and outcome encoding, we hypothesized that adaptive responses to which these are essential functions, could also be targeted by stress. To test this hypothesis we herein assessed the impact of chronic stress in a Pavlovian-to-instrumental transfer (PIT) paradigm, a model of an adaptive response in which a previously conditioned cue biases an instrumental goal-directed action. Data reveals that rats submitted to chronic unpredictable stress did not display deficits in pavlovian conditioning nor on the learning of the instrumental task, but were impaired in PIT; importantly, after a stress-free period the PIT deficits were no longer observed. These results are relevant to understand how stress biases multiple incentive processes that contribute to instrumental performance. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Stress exposure triggers cognitive and behavioral impairments that influence decision-making processes. Decisions under a context of uncertainty require complex reward-prediction processes that are known to be mediated by the mesocorticolimbic dopamine (DA) system in brain areas sensitive to the deleterious effects of chronic stress, in particular the orbitofrontal cortex (OFC). Using a decision-making task, we show that chronic stress biases risk-based decision-making to safer behaviors. This decision-making pattern is associated with an increased activation of the lateral part of the OFC and with morphological changes in pyramidal neurons specifically recruited by this task. Additionally, stress exposure induces a hypodopaminergic status accompanied by increased mRNA levels of the dopamine receptor type 2 (Drd2) in the OFC; importantly, treatment with a D2/D3 agonist quinpirole reverts the shift to safer behaviors induced by stress on risky decision-making. These results suggest that the brain mechanisms related to risk-based decision-making are altered after chronic stress, but can be modulated by manipulation of dopaminergic transmission. [ABSTRACT FROM AUTHOR]