Pharmacological stress impairs working memory performance and attenuates dorsolateral prefrontal cortex glutamate modulation (original) (raw)

New Frontiers in Stress Research Modulation of Brain Function

1998

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

Journal of Neuroscience, 2007

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 stressinduced 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.

Stress and memory: behavioral effects and neurobiological mechanisms

Neural plasticity, 2007

Stress is a potent modulator of learning and memory processes. Although there have been a few attempts in the literature to explain the diversity of effects (including facilitating, impairing, and lack of effects) described for the impact of stress on memory function according to single classification criterion, they have proved insufficient to explain the whole complexity of effects. Here, we review the literature in the field of stress and memory interactions according to five selected classifying factors (source of stress, stressor duration, stressor intensity, stressor timing with regard to memory phase, and learning type) in an attempt to develop an integrative model to understand how stress affects memory function. Summarizing on those conditions in which there was enough information, we conclude that high stress levels, whether intrinsic (triggered by the cognitive challenge) or extrinsic (induced by conditions completely unrelated to the cognitive task), tend to facilitate Pavlovian conditioning (in a linear-asymptotic manner), while being deleterious for spatial/explicit information processing (which with regard to intrinsic stress levels follows an inverted U-shape effect). Moreover, after reviewing the literature, we conclude that all selected factors are essential to develop an integrative model that defines the outcome of stress effects in memory processes. In parallel, we provide a brief review of the main neurobiological mechanisms proposed to account for the different effects of stress in memory function. Glucocorticoids were found as a common mediating mechanism for both the facilitating and impairing actions of stress in different memory processes and phases. Among the brain regions implicated, the hippocampus, amygdala, and prefrontal cortex were highlighted as critical for the mediation of stress effects.

Phasic deactivation of the medial temporal lobe enables working memory processing under stress

NeuroImage, 2012

Demanding cognitive tasks are sometimes carried out under stressful conditions. Several studies indicate that whereas severe stress impairs performance, moderate stress can enhance cognitive performance. In this study, we investigated how moderate stress influences the neural systems supporting working memory. We embedded an N-back working memory task in a moderately stressful context, as indicated by our physiological stress measures, and probed phasic and tonic human brain activity using two fMRI-techniques: conventional blood oxygen level dependent fMRI and arterial spin labeling (ASL). The results showed that the stress induction, as compared to the neutral control condition, led to slightly faster reaction times without changes in accuracy. In general, working memory processing was associated with increased activity in a frontoparietal network and reduced activity in the medial temporal lobe (MTL). The stress induction led to enhanced reduction of phasic MTL responses, specifically the hippocampus and amygdala. In addition, ASL showed that stress increased tonic amygdala activity, while tonic hippocampal activity was unaffected. These findings suggest that the influence of stress on MTL deactivation during working memory processing is task-related rather than a general consequence of the stressful state. The temporal suspension of hippocampal processing in favor of more task relevant processes may allow subjects to maintain normal performance levels under moderate stress.

Chronic stress impairs prefrontal cortex-dependent response inhibition and spatial working memory

Behavioral Neuroscience, 2012

Chronic stress leads to neurochemical and structural alterations in the prefrontal cortex (PFC) that correspond to deficits in PFC-mediated behaviors. The present study examined the effects of chronic restraint stress on response inhibition (using a response-withholding task, the fixed-minimum interval schedule of reinforcement, or FMI), and working memory (using a radial arm water maze, RAWM). Adult male Sprague-Dawley rats were first trained on the RAWM and subsequently trained on FMI. After acquisition of FMI, rats were assigned to a restraint stress (6h/d/28d in wire mesh restrainers) or control condition. Immediately after chronic stress, rats were tested on FMI and subsequently on RAWM. FMI results suggest that chronic stress reduces response inhibition capacity and motivation to initiate the task on selective conditions when sucrose reward was not obtained on the preceding trial. RAWM results suggest that chronic stress produces transient deficits in working memory without altering previously consolidated reference memory. Behavioral measures from FMI failed to correlate with metrics from RAWM except for one in which changes in FMI timing imprecision negatively correlated with changes in RAWM working memory errors for the controls, a finding that was not observed following chronic stress. Fisher's r-to-z transformation revealed no significant differences between control and stress groups with correlation coefficients. These findings are the first to show that chronic stress impairs both response inhibition and working memory, two behaviors that have never been directly compared within the same animals after chronic stress, using FMI, an appetitive task, and RAWM, a nonappetitive task.

The Neurobiology of Executive Function Under Stress and Optimization of Performance

Lecture Notes in Computer Science, 2015

Much basic and clinical research to date has investigated predictors of stress resilience and vulnerability, indicating, for example, that broad impact neurobiological factors, such as neuropeptide Y (NPY) and neuroactive steroids, are mechanistically related to short term stress resilience, as well as longterm patterns of stress-related medical and neuropsychiatric comorbidities. The problem is that we lack good methods for identifying predictors of stress resilience or vulnerability at an individual level, so that human performance and therapeutic interventions can be targeted precisely to underlying points of malfunction for maximum effectiveness. We thus propose modified experimental designs that capitalize on our growing capacities to query and analyze multimodal data across the translational levels of human biology and behavior. We propose that use of these methods in studies of individuals participating in intense military training or returning from deployment could enable better prediction of performance, and development of more effective personalized interventions aimed at optimizing and maintaining stress resilience over time.

Stress signalling pathways that impair prefrontal cortex structure and function

Nature Reviews Neuroscience, 2009

The prefrontal cortex (PFC) intelligently regulates our thoughts, actions and emotions through extensive connections with other brain regions (BOX 1). It creates a "mental sketch pad" (to use a phrase coined by Alan Baddeley) through networks of neurons that can maintain information in the absence of environmental stimulation 1. Neuroscientists such as Patricia Goldman-Rakic referred to this process as working memory: the ability to keep in mind an event that has just occurred, or bring to mind information from long-term storage, and use this representational knowledge to regulate behaviour, thought and emotion 2. The PFC is able to protect these fragile representations from the interference of external or internal distractions, and is key for inhibiting inappropriate actions and promoting task-relevant operations (so-called 'top-down' regulation) 3-6. PFC operations allow the flexible regulation of behaviour to enable us to properly respond to a changing environment for example, the ability to shift attentional set to new dimensions and to alter decision making as reward contingencies shift 7,8. The PFC also monitors errors, giving us the insight that we are incorrect and need to shift strategies 9. All of these abilities depend on proper PFC neuronal network connections, which are highly sensitive to their neurochemical environment. This Review discusses how neuromodulatory changes that occur during stress rapidly disrupt PFC network connections and markedly impair PFC function. It focuses on the spatial working memory functions of the PFC because the circuitry, physiology and modulation of the dorsolateral PFC neurons that mediate working memory are the best characterized of this brain region. The Review first describes how exposure to even mild uncontrollable stress can rapidly impair PFC functions in humans and animals. It then describes the extracel-lular and intracellular mechanisms that contribute to PFC deficits, and how chronic stress exposure leads to structural changes in the PFC. Finally, it highlights how genetic and environmental changes in stress signalling pathways are associated with mental illness, and how an understanding of these pathways might lead to better treatments for neuropsychiatric disorders. Acute stress impairs PFC function Human studies. Some of the first studies on the effects of stress on cognition began after the Second World War, based on observations that pilots who were highly skilled during peacetime often crashed their planes in the stress of battle owing to mental errors 10. Research was initiated to experimentally manipulate stress levels to see how this altered performance and cognitive abilities 11. Many of these early studies showed that stress exposure impaired the performance of tasks that required complex, flexible thinking, but that it could actually improve the performance of simpler and/or well-rehearsed tasks 10,12. We now understand that the types of tasks that were impaired by stress were those that required PFC operations 13 , whereas engrained habits that rely on basal ganglia circuits were spared or enhanced 14. These early studies also pointed to the essential role of the subject's sense of control over the stressor. Subjects who felt in control of the situation (even if this was an Abstract | The prefrontal cortex (PFC)-the most evolved brain region-subserves our highest-order cognitive abilities. However, it is also the brain region that is most sensitive to the detrimental effects of stress exposure. Even quite mild acute uncontrollable stress can cause a rapid and dramatic loss of prefrontal cognitive abilities, and more prolonged stress exposure causes architectural changes in prefrontal dendrites. Recent research has begun to reveal the intracellular signalling pathways that mediate the effects of stress on the PFC. This research has provided clues as to why genetic or environmental insults that disinhibit stress signalling pathways can lead to symptoms of profound prefrontal cortical dysfunction in mental illness.

Prefrontal cortex executive processes affected by stress in health and disease

Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2017

Prefrontal cortical executive functions comprise a number of cognitive capabilities necessary for goal directed behavior and adaptation to a changing environment. Executive dysfunction that leads to maladaptive behavior and is a symptom of psychiatric pathology can be instigated or exacerbated by stress. In this review we survey research addressing the impact of stress on executive function, with specific focus on working memory, attention, response inhibition, and cognitive flexibility. We then consider the neurochemical pathways underlying these cognitive capabilities and, where known, how stress alters them. Finally, we review work exploring potential pharmacological and non-pharmacological approaches that can ameliorate deficits in executive function. Both preclinical and clinical literature indicates that chronic stress negatively affects executive function. Although some of the circuitry and neurochemical processes underlying executive function have been characterized, a great deal is still unknown regarding how stress affects these processes. Additional work focusing on this question is needed in order to make progress on developing interventions that ameliorate executive dysfunction.