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Key Points Depending on the brain region involved, local activation of corticotropin-releasing factor receptor 1 (CRFR1) and CRFR2 by their ligands can induce acute anxiolytic or anxiogenic effects. The region-specific modulation of anxiety-like behaviour by CRFR activation depends on the specific cell type in which it is expressed and the neuronal circuit in which it plays a part. The downstream intracellular pathways triggered by CRFR activation are also brain-region specific and depend on the exact ligand–receptor interaction by which they are induced. Local differences in the regulation of CRFR signalling exist, with processes of desensitization being dependent on local expression of its regulators (including G protein-coupled receptor kinases (GRKs) and β-arrestins) and of the binding ligand. Many effects of CRFR activation that are observed at the cellular and behavioural level depend on the individual's current stress level and history of exposure to stress. These dose-dependent effects may be caused by loss of receptor specificity at higher concentrations of available ligand, whereas previous experience modulates receptor sensitivity by regulating receptor internalization or recruitment. Long-lasting activation of CRFRs, for example, through chronic or repeated exposure to stress, can induce effects that are very distinct from their acute effects and seem to involve remodelling of structural plasticity. Corticotropin-releasing factor (CRF) and urocortins have traditionally been proposed to promote stress and stress recovery, respectively. However, recent findings suggest that this view is overly simplistic. Chen and colleagues review evidence showing that CRF-receptor signalling is region- and cell type-specific and influenced by the individual's experience. Dysregulation of the corticotropin-releasing factor (CRF)–urocortin (UCN) system has been implicated in stress-related psychopathologies such as depression and anxiety. It has been proposed that CRF–CRF receptor type 1 (CRFR1) signalling promotes the stress response and anxiety-like behaviour, whereas UCNs and CRFR2 activation mediate stress recovery and the restoration of homeostasis. Recent findings, however, provide clear evidence that this view is overly simplistic. Instead, a more complex picture has emerged that suggests that there are brain region- and cell type-specific effects of CRFR signalling that are influenced by the individual's prior experience and that shape molecular, cellular and ultimately behavioural responses to stressful challenges.

Acute stress shifts the brain into a state that fosters rapid defense mechanisms. Stress-related neuromodulators are thought to trigger this change by altering properties of large-scale neural populations throughout the brain. We investigated this brain-state shift in humans. During exposure to a fear-related acute stressor, responsiveness and interconnectivity within a network including cortical (frontoinsular, dorsal anterior cingulate, inferotemporal, and temporoparietal) and subcortical (amygdala, thalamus, hypothalamus, and midbrain) regions increased as a function of stress response magnitudes, β-adrenergic receptor blockade, but not cortisol synthesis inhibition, diminished this increase. Thus, our findings reveal that noradrenergic activation during acute stress results in prolonged coupling within a distributed network that integrates information exchange between regions involved in autonomic-neuroendocrine control and vigilant attentional reorienting.

Exposure to stress during critical periods in development can have severe long-term consequences, increasing overall risk on psychopathology. One of the key stress response systems mediating these long-term effects of stress is the hypothalamic-pituitary-adrenal (HPA) axis; a cascade of central and peripheral events resulting in the release of corticosteroids from the adrenal glands. Activation of the HPA-axis affects brain functioning to ensure a proper behavioral response to the stressor, but stress-induced (mal)adaptation of the HPA-axis' functional maturation may provide a mechanistic basis for the altered stress susceptibility later in life. Development of the HPA-axis and the brain regions involved in its regulation starts prenatally and continues after birth, and is protected by several mechanisms preventing corticosteroid over-exposure to the maturing brain. Nevertheless, early life stress (ELS) exposure has been reported to have numerous consequences on HPA-axis function in adulthood, affecting both its basal and stress-induced activity. According to the match/mismatch theory, encountering ELS prepares an organism for similar (\"matching\") adversities during adulthood, while a mismatching environment results in an increased susceptibility to psychopathology, indicating that ELS can exert either beneficial or disadvantageous effects depending on the environmental context. Here, we review studies investigating the mechanistic underpinnings of the ELS-induced alterations in the structural and functional development of the HPA-axis and its key external regulators (amygdala, hippocampus, and prefrontal cortex). The effects of ELS appear highly dependent on the developmental time window affected, the sex of the offspring, and the developmental stage at which effects are assessed. Albeit by distinct mechanisms, ELS induced by prenatal stressors, maternal separation, or the limited nesting model inducing fragmented maternal care, typically results in HPA-axis hyper-reactivity in adulthood, as also found in major depression. This hyper-activity is related to increased corticotrophin-releasing hormone signaling and impaired glucocorticoid receptor-mediated negative feedback. In contrast, initial evidence for HPA-axis hypo-reactivity is observed for early social deprivation, potentially reflecting the abnormal HPA-axis function as observed in post-traumatic stress disorder, and future studies should investigate its neural/neuroendocrine foundation in further detail. Interestingly, experiencing additional (chronic) stress in adulthood seems to normalize these alterations in HPA-axis function, supporting the match/mismatch theory.

Animal models of predator defense distinguish qualitatively different behavioral modes that are activated at increasing levels of predation threat. A defense mode observed at intermediate threat levels is freezing: a cessation of locomotion that is characterized by a parasympathetically dominated autonomic nervous system response that causes heart rate deceleration, or fear bradycardia. Studies in rodents have shown that freezing depends on amygdalar projections to the periaqueductal grey (PAG). In humans, freezing-like behaviors are implicated in development and maintenance of psychopathology, but neural mechanisms underlying freezing or its characteristic autonomic response profile have not been identified. Here, we combined event-related blood oxygenation level-dependent functional MRI (BOLD-fMRI) with autonomic response measures in a picture viewing paradigm to probe activity and interconnectivity within the amygdala–PAG pathway and test for an association with parasympathetic as opposed to sympathetic activation. In response to negatively arousing pictures, we observed parasympathetic (bradycardia) and sympathetic (pupil dilation) autonomic responses, BOLD responses in the amygdala and PAG, and effective connectivity between these regions. Critically, BOLD responses in the PAG to negative pictures correlated on a trial-by-trial basis with bradycardia but not pupil dilation. This correlation with bradycardia remained significant when partialling out pupil dilation. Additionally, activity in regions associated with motor planning and inhibition mirrored the PAG response. Thus, our findings implicate the human PAG in a parasympathetically dominated defense mode that subserves a state of attentive immobility. Mechanistic insight into this qualitatively distinct defense mode may importantly advance translational models of anxiety disorders. ► Aversive stimuli increase activity and connectivity within amygdala–PAG circuitry. ► These stimuli elicit (parasympathetic) bradycardia and (sympathetic) pupil dilation. ► PAG activity uniquely correlates with bradycardia, not pupil dilation. ► This pattern is mirrored in regions involved in motor inhibition.

Corticosteroids are potent modulators of human higher cognitive function. They are released in response to stress, and are thought to be involved in the modulation of cognitive function by inducing distinct rapid nongenomic, and slow genomic changes, affecting neural plasticity throughout the brain. However, their exact effects on the neural correlates of higher-order cognitive function as performed by the prefrontal cortex at the human brain system level remain to be elucidated. Here, we targeted these time-dependent effects of corticosteroids on prefrontal cortex processing in humans using a working memory (WM) paradigm during functional MRI scanning. Implementing a randomized, double-blind, placebo-controlled design, 72 young, healthy men received 10 mg hydrocortisone either 30 min (rapid corticosteroid effects) or 240 min (slow corticosteroid effects), or placebo before a numerical n-back task with differential load (0- to 3-back). Corticosteroids' slow effects appeared to improve working memory performance and increased neuronal activity during WM performance in the dorsolateral prefrontal cortex depending on WM load, whereas no effects of corticosteroids' rapid actions were observed. Thereby, the slow actions of corticosteroids seem to facilitate adequate higher-order cognitive functioning, which may support recovery in the aftermath of stress exposure.

Susceptibility to stress-related psychopathology is associated with reduced expression of the serotonin transporter (5-HTT), particularly in combination with stress exposure. Aberrant physiological and neuronal responses to threat may underlie this increased vulnerability. Here, implementing a cross-species approach, we investigated the association between 5-HTT expression and the neural correlates of fear bradycardia, a defensive response linked to vigilance and action preparation. We tested this during threat anticipation induced by a well-established fear conditioning paradigm applied in both humans and rodents. In humans, we studied the effect of the common 5-HTT-linked polymorphic region (5-HTTLPR) on bradycardia and neural responses to anticipatory threat during functional magnetic resonance imaging scanning in healthy volunteers (n = 104). Compared with homozygous long-allele carriers, the 5-HTTLPR short-allele carriers displayed an exaggerated bradycardic response to threat, overall reduced activation of the medial prefrontal cortex (mPFC), and increased threat-induced connectivity between the amygdala and periaqueductal gray (PAG), which statistically mediated the effect of the 5-HTTLPR genotype on bradycardia. In parallel, 5-HTT knockout (KO) rats also showed exaggerated threat-related bradycardia and behavioral freezing. Immunohistochemistry indicated overall reduced activity of glutamatergic neurons in the mPFC of KO rats and increased activity of central amygdala somatostatin-positive neurons, putatively projecting to the PAG, which—similarly to the human population—mediated the 5-HTT genotype’s effect on freezing. Moreover, the ventrolateral PAG of KO rats displayed elevated overall activity and increased relative activation of CaMKII-expressing projection neurons. Our results provide a mechanistic explanation for previously reported associations between 5-HTT gene variance and a stress-sensitive phenotype.

Stress exposure is known to precipitate psychological disorders. However, large differences exist in how individuals respond to stressful situations. A major marker for stress sensitivity is hypothalamus–pituitary–adrenal (HPA)-axis function. Here, we studied how interindividual variance in both basal cortisol levels and stress-induced cortisol responses predicts differences in neural vigilance processing during stress exposure. Implementing a randomized, counterbalanced, crossover design, 120 healthy male participants were exposed to a stress-induction and control procedure, followed by an emotional perception task (viewing fearful and happy faces) during fMRI scanning. Stress sensitivity was assessed using physiological (salivary cortisol levels) and psychological measures (trait questionnaires). High stress-induced cortisol responses were associated with increased stress sensitivity as assessed by psychological questionnaires, a stronger stress-induced increase in medial temporal activity and greater differential amygdala responses to fearful as opposed to happy faces under control conditions. In contrast, high basal cortisol levels were related to relative stress resilience as reflected by higher extraversion scores, a lower stress-induced increase in amygdala activity and enhanced differential processing of fearful compared with happy faces under stress. These findings seem to reflect a critical role for HPA-axis signaling in stress coping; higher basal levels indicate stress resilience, whereas higher cortisol responsivity to stress might facilitate recovery in those individuals prone to react sensitively to stress.

The rodent stress hormone corticosterone changes neuronal activity in a slow and persistent manner through transcriptional regulation. In the rat dorsal hippocampus, corticosterone enhances the amplitude of calcium-dependent potassium currents that cause a lingering slow after-hyperpolarization (sAHP) at the end of depolarizing events. In this study we compared the putative region-dependency of the delayed effects of corticosterone (approximately 5 hrs after treatment) on sAHP as well as other active and passive properties of layer 2/3 pyramidal neurons from three prefrontal areas, i.e. the lateral orbitofrontal, prelimbic and infralimbic cortex, with the hippocampus of adult mice. In agreement with previous studies, corticosterone increased sAHP amplitude in the dorsal hippocampus with depolarizing steps of increasing amplitude. However, in the lateral orbitofrontal, prelimbic and infralimbic cortices we did not observe any modifications of sAHP amplitude after corticosterone treatment. Properties of single action potentials or % ratio of the last spike interval with respect to the first spike interval, an indicator of accommodation in an action potential train, were not significantly affected by corticosterone in all brain regions examined. Lastly, corticosterone treatment did not induce any lasting changes in passive membrane properties of hippocampal or cortical neurons. Overall, the data indicate that corticosterone slowly and very persistently increases the sAHP amplitude in hippocampal pyramidal neurons, while this is not the case in the cortical regions examined. This implies that changes in excitability across brain regions reached by corticosterone may vary over a prolonged period of time after stress.

Adolescence is a developmental phase characterized by emotional turmoil and coincides with the emergence of affective disorders. Inherited serotonin transporter (5-HTT) downregulation in humans increases sensitivity to these disorders. To reveal whether and how 5-HTT gene variance affects fear-driven behavior in adolescence, we tested wildtype and serotonin transporter knockout (5-HTT−/−) rats of preadolescent, adolescent, and adult age for cued fear extinction and extinction recall. To analyze neural circuit function, we quantified inhibitory synaptic contacts and, through RT-PCR, the expression of c-Fos, brain-derived neurotrophic factor (BDNF), and NDMA receptor subunits, in the medial prefrontal cortex (mPFC) and amygdala. Remarkably, the impaired recall of conditioned fear that characterizes preadolescent and adult 5-HTT−/− rats was transiently normalized during adolescence. This did not relate to altered inhibitory neurotransmission, since mPFC inhibitory immunoreactivity was reduced in 5-HTT−/− rats across all ages and unaffected in the amygdala. Rather, since mPFC (but not amygdala) c-Fos expression and NMDA receptor subunit 1 expression were reduced in 5-HTT−/− rats during adolescence, and since PFC c-Fos correlated negatively with fear extinction recall, the temporary normalization of fear extinction during adolescence could relate to altered plasticity in the developing mPFC.

Stress-related psychopathology is associated with altered functioning of large-scale brain networks. Animal research into chronic stress, one of the most prominent environmental risk factors for development of psychopathology, has revealed molecular and cellular mechanisms potentially contributing to human mental disease. However, so far, these studies have not addressed the system-level changes in extended brain networks, thought to critically contribute to mental disorders. We here tested the effects of chronic stress exposure (10days immobilization) on the structural integrity and functional connectivity patterns in the brain, using high-resolution structural MRI, diffusion kurtosis imaging, and resting-state functional MRI, while confirming the expected changes in neuronal dendritic morphology using Golgi-staining. Stress effectiveness was confirmed by a significantly lower body weight and increased adrenal weight. In line with previous research, stressed animals displayed neuronal dendritic hypertrophy in the amygdala and hypotrophy in the hippocampal and medial prefrontal cortex. Using independent component analysis of resting-state fMRI data, we identified ten functional connectivity networks in the rodent brain. Chronic stress appeared to increase connectivity within the somatosensory, visual, and default mode networks. Moreover, chronic stress exposure was associated with an increased volume and diffusivity of the lateral ventricles, whereas no other volumetric changes were observed. This study shows that chronic stress exposure in rodents induces alterations in functional network connectivity strength which partly resemble those observed in stress-related psychopathology. Moreover, these functional consequences of stress seem to be more prominent than the effects on gross volumetric change, indicating their significance for future research. •Chronic stress impacts large-scale functional connectivity networks in the rat brain.•Stress increases connectivity in somatosensory, visual, and default mode networks.•Chronic stress does not induce major changes in gray matter volume in the rat brain.•Stress increases the volume and diffusivity of the lateral ventricles.