Papers by Benno Roozendaal
Pathophysiology, Jun 1, 1998
Physiology & Behavior, Oct 1, 1991
Attenuated cardiovascular, neuroendocrine, and behavioral responses after a single footshock in c... more Attenuated cardiovascular, neuroendocrine, and behavioral responses after a single footshock in central amygdaloid lesioned male rats. PHYSIOL BEHAV 50(4) 771-775, 1991.-The effect of bilateral electrolytical CEA lesioning on behavioral, cardiovascular and neuroendocrine changes has been studied in male Wistar rats before, during and shortly after a brief aversive stimulus of an unavoidable footshock. Blood samples were withdrawn via a permanent heart catheter. Lesioning of the CEA abolished completely the immobility response normally seen after a footshock. Lesions failed to affect the early tachycardiac response compared to sham-lesioned controls, but the poststress recovery was attenuated, probably due to diminished vagal activation. Furthermore, the magnitude of the responses of all measured hormones (epinephrine, norepinephrine, corticosterone and prolactin) appeared to be attenuated in the lesioned rats. These results suggest that the CEA plays an important and general role in the behavioral, autonomic and hormonal output during a brief unavoidable, unconditioned footshock. This is in contrast with the selective role of the CEA in vagal (parasympathetic) and on inhibitory (immobility) behavioral responses following conditioning. Central amygdaloid nucleus Electrolytic lesion Acute footshock Corticosterone Prolactin Immobility behavior
Annals of the New York Academy of Sciences, Jun 12, 1992
Take-down policy If you believe that this document breaches copyright please contact us providing... more Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Neuroendocrinology Letters, 1988
Efforts have long been directed toward studying stress-induced alterations via stress hormones on... more Efforts have long been directed toward studying stress-induced alterations via stress hormones on brain excitability and synaptic plasticity as inferred from combined behavioral, electrophysiological, and immunohistochemical cellular/molecular observations. Kindling of the brain in the rat serves as one model of synaptic plasticity. Kindling in the dorsal hippocampus and the amygdala induces electrical afterdischarges (AD), motor seizures (MS), and postictally, behavioral depression (ED) accompanied by electrical silence in the limbic system. Behaviorally induced changes in the muscarinic cholinoceptive receptor (mAChR) and protein kinase C gamma isomer (PKC gamma) immunoreactivity in different brain regions served as the other measure of plastic changes. Fragments of the stress hormone opiomelanocortin (OMC) affect kindling-induced electrical and behavioral phenomena in a complex way. The adrenocorticotrophe hormone (ACTH) derivate ACTH 1-16, and melanocyte-stimulating hormone (MSH...
Nature Communications, Oct 18, 2021
It is commonly assumed that episodic memories undergo a time-dependent systems consolidation proc... more It is commonly assumed that episodic memories undergo a time-dependent systems consolidation process, during which hippocampus-dependent memories eventually become reliant on neocortical areas. Here we show that systems consolidation dynamics can be experimentally manipulated and even reversed. We combined a single pharmacological elevation of post-encoding noradrenergic activity through the α 2-adrenoceptor antagonist yohimbine with fMRI scanning both during encoding and recognition testing either 1 or 28 days later. We show that yohimbine administration, in contrast to placebo, leads to a time-dependent increase in hippocampal activity and multivariate encoding-retrieval pattern similarity, an indicator of episodic reinstatement, between 1 and 28 days. This is accompanied by a time-dependent decrease in neocortical activity. Behaviorally, these neural changes are linked to a reduced memory decline over time after yohimbine intake. These findings indicate that noradrenergic activity shortly after encoding may alter and even reverse systems consolidation in humans, thus maintaining vividness of memories over time.
Proceedings of the National Academy of Sciences of the United States of America, Apr 4, 2006
Springer eBooks, 2014
There is extensive evidence that glucocorticoid hormones, normally released from the adrenal cort... more There is extensive evidence that glucocorticoid hormones, normally released from the adrenal cortex during stressful events, enhance the consolidation of long-term memory of emotionally arousing training experiences, yet impair the retrieval of previously acquired information during emotionally arousing test situations. In contrast, glucocorticoids have little effect on the consolidation or retrieval of memory of low-arousing or neutral information. Although it is now well established that glucocorticoid effects on these two memory functions depend on rapid interactions with arousal-induced noradrenergic activity within the basolateral amygdala and several other brain regions, the exact neurobiological mechanism underlying this presumably nongenomically mediated glucocorticoid action remained to be elucidated. In this chapter, we present compelling evidence indicating that the endocannabinoid system, a rapid lipid signaling system in the brain, plays an essential role in regulating glucocorticoid effects on different memory processes via actions through a membrane-associated glucocorticoid receptor.
Behavioral and Brain Sciences, 2016
Mather and colleagues postulate that norepinephrine promotes selective processing of emotionally ... more Mather and colleagues postulate that norepinephrine promotes selective processing of emotionally salient information through local "hotspots" where norepinephrine release interacts with glutamatergic activity. However, rodent and human findings show that norepinephrine is ineffective in modulating mnemonic processes in absence of a functional amygdala. We therefore argue that emphasis should shift towards modulatory effects of amygdala-driven changes at the network level.
Psychopharmacology, 2019
Extensive evidence from both animal model and human research indicates that glucocorticoid hormon... more Extensive evidence from both animal model and human research indicates that glucocorticoid hormones are crucially involved in modulating memory performance. Glucocorticoids, which are released during stressful or emotionally arousing experiences, enhance the consolidation of new memories, including extinction memory, but reduce the retrieval of previously stored memories. These memory-modulating properties of glucocorticoids have recently received considerable interest for translational purposes because strong aversive memories lie at the core of several fear-related disorders, including post-traumatic stress disorder and phobias. Moreover, exposure-based psychological treatment of these disorders relies on successful fear extinction. In this review, we argue that glucocorticoid-based interventions facilitate fear extinction by reducing the retrieval of aversive memories and enhancing the consolidation of extinction memories. Several clinical trials have already indicated that glucocorticoids might be indeed helpful in the treatment of fear-related disorders.
Nature Reviews Neuroscience, Nov 24, 2016
Glucocorticoid stress hormones are crucially involved in modulating mnemonic processing of emotio... more Glucocorticoid stress hormones are crucially involved in modulating mnemonic processing of emotionally arousing experiences. They enhance the consolidation of new memories, including those that extinguish older memories, but impair the retrieval of information stored in long-term memory. As strong aversive memories lie at the core of several fear-related disorders, including post-traumatic stress disorder and phobias, the memory-modulating properties of glucocorticoids have recently become of considerable translational interest. Clinical trials have provided the first evidence that glucocorticoid-based pharmacotherapies aimed at attenuating aversive memories might be helpful in the treatment of fear-related disorders. Here, we review important advances in the understanding of how glucocorticoids mediate stress effects on memory processes, and discuss the translational potential of these new conceptual insights.
Neuropsychopharmacology, Dec 30, 2014
Glucocorticoid hormones are known to act synergistically with other stress-activated neuromodulat... more Glucocorticoid hormones are known to act synergistically with other stress-activated neuromodulatory systems, such as norepinephrine and corticotropin-releasing factor (CRF), within the basolateral complex of the amygdala (BLA) to induce optimal strengthening of the consolidation of long-term memory of emotionally arousing experiences. However, as the onset of these glucocorticoid actions appear often too rapid to be explained by genomic regulation, the neurobiological mechanism of how glucocorticoids could modify the memory-enhancing properties of norepinephrine and CRF remained elusive. Here, we show that the endocannabinoid system, a rapidly activated retrograde messenger system, is a primary route mediating the actions of glucocorticoids, via a glucocorticoid receptor on the cell surface, on BLA neural plasticity and memory consolidation. Furthermore, glucocorticoids recruit downstream endocannabinoid activity within the BLA to interact with both the norepinephrine and CRF systems in enhancing memory consolidation. These findings have important implications for understanding the fine-tuned crosstalk between multiple stress hormone systems in the coordination of (mal)adaptive stress and emotional arousal effects on neural plasticity and memory consolidation.
Journal of Neuroendocrinology, Aug 1, 2016
Stress causes a neuroendocrine response cascade, leading to the release of catecholamines and glu... more Stress causes a neuroendocrine response cascade, leading to the release of catecholamines and glucocorticoids (GCs). GCs influence learning and memory by acting on mineralocorticoid (MR) and glucocorticoid (GR) receptors. Typically, GCs enhance the consolidation of memory processing at the same time as impairing the retrieval of memory of emotionally arousing experiences. The present selective review addresses four recent developments in this area. First, the role of the endocannabinoid system in mediating the rapid, nongenomic effects of GCs on memory is illustrated in rodents. Subsequently, studies on the impact of the selective stimulation of MRs on different memory processes in humans are summarised. Next, a series of human experiments on the impact of stress or GC treatment on fear extinction and fear reconsolidation is presented. Finally, the clinical relevance of the effects of exogenous GC administration is highlighted by the description of patients with anxiety disorders who demonstrate an enhancement of extinction-based therapies by GC treatment. The review highlights the substantial progress made in our mechanistic understanding of the memory-modulating properties of GCs, as well as their clinical potential.
The Journal of Neuroscience, Mar 26, 2008
Conditions with chronically elevated glucocorticoid levels are usually associated with declarativ... more Conditions with chronically elevated glucocorticoid levels are usually associated with declarative memory deficits. Considerable evidence suggests that long-term glucocorticoid exposure may cause cognitive impairment via cumulative and long-lasting influences on hippocampal function and morphology. However, because elevated glucocorticoid levels at the time of retention testing are also known to have direct impairing effects on memory retrieval, it is possible that such acute hormonal influences on retrieval processes contribute to the memory deficits found with chronic glucocorticoid exposure. To investigate this issue, we examined memory functions and hippocampal volume in 24 patients with rheumatoid arthritis who were treated either chronically (5.3 Ϯ 1.0 years, mean Ϯ SE) with low to moderate doses of prednisone (7.5 Ϯ 0.8 mg, mean Ϯ SE) or without glucocorticoids. In both groups, delayed recall of words learned 24 h earlier was assessed under conditions of either elevated or basal glucocorticoid levels in a double-blind, placebo-controlled crossover design. Although the findings in this patient population did not provide evidence for harmful effects of a history of chronic prednisone treatment on memory performance or hippocampal volume per se, acute prednisone administration 1 h before retention testing to either the steroid or nonsteroid group impaired word recall. Thus, these findings indicate that memory deficits observed under chronically elevated glucocorticoid levels result, at least in part, from acute and reversible glucocorticoid effects on memory retrieval.
Neurology, Jan 24, 2005
In this issue of Neurology , Brunner et al.1 report that a high-dose glucocorticoid treatment reg... more In this issue of Neurology , Brunner et al.1 report that a high-dose glucocorticoid treatment regimen for multiple sclerosis (MS) and acute optic neuritis consisting of 500 mg/d IV methylprednisolone for 5 consecutive days impaired long-term recall of verbally presented words, tested at a delay of 30 minutes. The glucocorticoid treatment did not impair working memory or attentional performance. The findings are important in indicating that a glucocorticoid therapy commonly used in clinical practice to treat neurologic inflammatory disease affects memory. The finding that the mnemonic impairments are completely reversed 5 days after the cessation of therapy indicates that the memory deficits do not reflect any sustained neuronal damage. Rather, the findings appear similar to those of basic and preclinical research examining the physiologic effects of acute stress and stress hormones on memory. Research on learning and memory in experimental animals and healthy human …
Critical Care Medicine, Apr 1, 2011
nimal and human studies have repeatedly shown that glucocorticoids influence memory in situations... more nimal and human studies have repeatedly shown that glucocorticoids influence memory in situations of acute and chronic stress (1-3). Glucocorticoids are known to enhance memory consolidation of emotionally arousing experiences (4, 5) but impair memory retrieval under stressful conditions (6, 7). Persistent traumatic memories of highly stressful experiences are a hallmark of stressrelated disorders such as posttraumatic stress disorder (PTSD), and changes in glucocorticoid signaling have consistently been demonstrated in humans with PTSD (8-10) as well as in animal models of the disorder (11). In critically ill patients, traumatic memories from treatment in an intensive care unit (ICU) can be associated with PTSD stress symptoms and are influenced by the administered dosages of catecholamines and glucocorticoids in the ICU (12-14). Glucocorticoids influence cognitive and emotional processes through the glucocorticoid receptor (GR), and changes in GR sensitivity have been shown in patients with PTSD (10, 15) as well as other Objective: Glucocorticoids play a major role in the consolidation and retrieval of traumatic information. They act through the glucocorticoid receptor, for which, in humans, several polymorphisms have been described. In particular, the BclI single-nucleotide polymorphism is associated with hypersensitivity to glucocorticoids and with susceptibility to development of major depression. Furthermore, in patients with posttraumatic stress disorder carrying the BclI GG genotype, cortisol levels were lower and showed an inverse relationship to posttraumatic stress disorder symptom intensity. Here, we studied the association of the BclI polymorphism with plasma cortisol levels, traumatic memories, posttraumatic stress disorder symptoms, and health-related quality of life outcomes in 126 patients undergoing cardiac surgery and intensive care unit therapy. Design: Prospective observational study. Setting: Cardiovascular intensive care unit in a university hospital. Patients: A total of 126 patients undergoing cardiac surgery and intensive care unit treatment. Interventions: No interventions were performed. Measurements and Main Results: Validated questionnaires were used to quantify end points. Measurements were taken 1 day before and 1 wk and 6 months after cardiac surgery. Homozygous carriers of the BclI G allele (n ؍ 21) had significantly lower preoperative plasma cortisol levels and more long-term traumatic memories from intensive care unit therapy at 6 months after cardiac surgery than heterozygous carriers or noncarriers (1.9 ؎ 1.4 vs. 1.0 ؎ 1.2, p ؍ .01). Anxiety was significantly more common as a long-term traumatic memory in homozygous BclI G allele carriers than in heterozygous carriers or noncarriers (57% vs. 35%, p ؍ .03). Posttraumatic stress disorder symptom scores were significantly higher at discharge from the intensive care unit in homozygous BclI G allele carriers than in heterozygous carriers or noncarriers. Only heterozygous carriers or BclI G allele noncarriers had a significant gain in health-related quality of life physical function at 6 months after cardiac surgery (p < .01). Baseline values were not statistically different between carriers of the different BclI alleles. Conclusion: Homozygous BclI G allele carriers are at risk for traumatic memories, posttraumatic stress disorder symptoms, and lower health-related quality of life after cardiac surgery and intensive care unit therapy. The BclI single-nucleotide polymorphism may help to identify individuals at need for tailored medical care.
Annals of the New York Academy of Sciences, Jul 1, 2006
Like other humans exposed to extreme trauma, patients who have been treated in an intensive care ... more Like other humans exposed to extreme trauma, patients who have been treated in an intensive care unit (ICU) often report traumatic memories. Extremely traumatic memories from the ICU in some of these patients are associated with the development of posttraumatic stress disorder (PTSD), which results in significant impairments in health-related quality of life (HRQL) outcomes of ICU therapy. Severely ill patients in the ICU often show insufficient endogenous glucocorticoid signaling, which has recently been termed critical illness-related corticosteroid insufficiency (CIRCI). We performed several controlled trials in ICU patients with suspected CIRCI from septic shock or cardiac surgery, which indicated that the administration of glucocorticoids (stress doses of hydrocortisone) during ICU treatment results in a significant reduction of PTSD symptoms in long-term survivors as well as improvements in HRQL outcomes. Stress doses of hydrocortisone could help to surmount impaired glucocorticoid signaling from CIRCI during critical illness resulting in a downregulation of the stress response as well as inhibition of traumatic memory retrieval and facilitated extinction of aversive information.
Trials, 2013
Background: Cardiac surgery is one of the most commonly performed surgical procedures worldwide w... more Background: Cardiac surgery is one of the most commonly performed surgical procedures worldwide with > 700,000 surgeries in 2006 in the US alone. Cardiac surgery results in a considerable exposure to physical and emotional stress; stress-related disorders such as depression or post-traumatic stress disorder are the most common adverse outcomes of cardiac surgery, seen in up to 20% of patients. Using information from a genome-wide association study to characterize genetic effects on emotional memory, we recently identified a single nucleotide polymorphism of the glucocorticoid receptor gene (the Bcll single nucleotide polymorphism) as a significant genetic risk factor for traumatic memories from cardiac surgery and symptoms of post-traumaticstress disorder. The Bcll high-risk genotype (Bcll GG) has a prevalence of 16.6% in patients undergoing cardiac surgery and is associated with increased glucocorticoid receptor signaling under stress. Concomitant animal experiments have confirmed an essential role of glucocorticoid receptor activation for traumatic memory formation during stressful experiences. Early cognitive behavioral intervention has been shown to prevent stress-related disorders after heart surgery. Methods/Design: The proposed study protocol is based on the above mentioned earlier findings from animal experiments and preclinical studies in volunteers. Patients (n = 872) will be genotyped for the Bcll single nucleotide polymorphism before surgery, which should result in 120 homozygous high-risk carriers of the Bcll GG allele and 240 randomly selected low-risk heterozygous or non-carriers of the single nucleotide polymorphism. All patients will then undergo randomization to either cognitive behavioral intervention or a control intervention consisting of non-specific general information about the role of stress in heart disease. The primary efficacy endpoint will be post-traumatic stress levels at one year after surgery as determined by a standardized questionnaire that has been specifically validated in patients after critical illness. Discussion: The proposed randomized controlled trial intends to demonstrate that a preoperatively administered minimal cognitive behavioral intervention targeted to homozygous carriers of the Bcll *G high-risk allele reduces traumatic memories and post-traumatic stress disorder symptoms after heart surgery to a level seen in non-carriers of the mutation, and thus improves the neuroemotional outcome of cardiac surgery. Trial registration number: The trial will be registered at http://www.clinicaltrials.gov/ before commencing with the study.
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Papers by Benno Roozendaal