ReviewStress-induced impairments in prefrontal-mediated behaviors and the role of the N-methyl-d-aspartate receptor
Highlights
▶Executive dysfunctions are hallmarks of many stress-related neuropsychiatric disorders. ▶Rodent studies demonstrate stress-induced impairments in prefrontal-mediated cognitive functions. ▶NMDARs are key mediators of cognition and stress responses. ▶Preclinical studies implicate NMDARs in stress-induced prefrontal cognitive deficits. ▶Targeting NMDAR functions may offer novel therapeutics to alleviate stress-related cognitive deficits.
Section snippets
Stress effects on PFC-mediated behaviors
Stress, even when relatively mild and brief, can profoundly alter structure and neuronal morphology in rodent PFC (Arnsten, 2009, Holmes and Wellman, 2009, Shansky and Morrison, 2009). This in and of itself strongly implies that stress would impact behaviors that are dependent upon intact PFC functions. Stress effects on rodent cognitive and executive functions have been directly examined using a range of well-characterized behavioral assays (for more detailed descriptions of these tasks, see
NMDARs in PFC-mediated behaviors
Glutamate, the main excitatory neurotransmitter, binds to multiple metabotropic receptors and three families of ionotropic receptors: AMPA receptors, kainate receptors, and NMDARs. While all three families have been found to play a role in cognitive and stress-related behaviors, NMDARs represent a particularly intriguing mechanism mediating stress-induced changes in prefrontal-mediated behaviors for a number of reasons.
Do NMDARs mediate stress-induced changes in PFC?
Taken together, the literature discussed thus far raises the intriguing possibility that stress acts through NMDARs in the PFC to produce changes in a variety of behaviors that are regulated by this brain region. There remains, however, a paucity of evidence directly testing this hypothesis.
What has been shown is that stress produces changes in the expression of NMDARs that parallel alterations in PFC-mediated behaviors. For example, rats subjected to neonatal maternal separation have decreased
Conclusions and future directions
The current literature sets up a number of critical questions going forward. For example, would systemic treatment with a NMDAR antagonist at the time of stress prevent subsequent alterations in PFC-mediated behaviors, such as cognitive flexibility and fear extinction? If so, would these effects be recapitulated by blockade or gene deletion of NMDARs specifically within the PFC, or are they instead driven by NMDARs localized in other brain regions? What are the specific NMDAR subunits and
References (160)
- et al.
The effect of atypical and classical antipsychotics on sub-chronic PCP-induced cognitive deficits in a reversal-learning paradigm
Behav Brain Res
(2006) - et al.
Behavioral control over shock blocks behavioral and neurochemical effects of later social defeat
Neuroscience
(2010) - et al.
Increased impulsivity and disrupted attention induced by repeated phencyclidine are not attenuated by chronic quetiapine treatment
Pharmacol Biochem Behav
(2009) - et al.
Disruption of performance in the five-choice serial reaction time task induced by administration of N-methyl-d-aspartate receptor antagonists: relevance to cognitive dysfunction in schizophrenia
Biol Psychiatry
(2010) - et al.
Stress, depression, and anhedonia: caveats concerning animal models
Neurosci Biobehav Rev
(2005) - et al.
Catecholamine influences on prefrontal cortical function: relevance to treatment of attention deficit/hyperactivity disorder and related disorders
Pharmacol Biochem Behav
(2011) - et al.
Chronic stress and sex differences on the recall of fear conditioning and extinction
Neurobiol Learn Mem
(2009) - et al.
Controllable versus uncontrollable stressors bi-directionally modulate conditioned but not innate fear
Neuroscience
(2007) - et al.
NMDA receptor blockade and hippocampal neuronal loss impair fear conditioning and position habit reversal in C57Bl/6 mice
Brain Res Bull
(2003) - et al.
Maternal care affects male and female offspring working memory and stress reactivity
Physiol Behav
(2007)
Hippocampal NMDA receptors and anxiety: at the interface between cognition and emotion
Eur J Pharmacol
Assessing cognitive function in clinical trials of schizophrenia
Neurosci Biobehav Rev
Antidepressant effects of ketamine in depressed patients
Biol Psychiatry
Block of glucocorticoid synthesis during re-activation inhibits extinction of an established fear memory
Neurobiol Learn Mem
Beneficial effects of desipramine on cognitive function of chronically stressed rats are mediated by [alpha]1-adrenergic receptors in medial prefrontal cortex
Prog Neuro-Psychopharmacol Biol Psychiatry
Effects of orbitofrontal, infralimbic and prelimbic cortical lesions on serial spatial reversal learning in the rat
Behav Brain Res
Nonsteroidal anti-inflammatory treatment prevents delayed effects of early life stress in rats
Biol Psychiatry
Corticosterone facilitates extinction of fear memory in BALB/c mice but strengthens cue related fear in C57BL/6 mice
Exp Neurol
Cognitive and neuroinflammatory consequences of mild repeated stress are exacerbated in aged mice
Psychoneuroendocrinology
Consolidation of fear extinction requires NMDA receptor-dependent bursting in the ventromedial prefrontal cortex
Neuron
Chronic stress-induced hippocampal dendritic retraction requires CA3 NMDA receptors
Neuroscience
The role of prior stressor controllability and the dorsal raphe nucleus in sucrose preference and social exploration
Behav Brain Res
Functions of frontostriatal systems in cognition: comparative neuropsychopharmacological studies in rats, monkeys and humans
Biol Psychol
Role of glutamate in anxiety
NMDA receptor subunits: diversity, development and disease
Curr Opin Neurobiol
Prefrontal cortex, caloric restriction and stress during aging: studies on dopamine and acetylcholine release, BDNF and working memory
Behav Brain Res
Stress, prefrontal cortex and environmental enrichment: studies on dopamine and acetylcholine release and working memory performance in rats
Behav Brain Res
Lesion of infralimbic cortex occludes stress effects on retrieval of extinction but not fear conditioning
Neurobiol Learn Mem
Neural circuits subserving behavioral flexibility and their relevance to schizophrenia
Behav Brain Res
Stress-induced disturbances in Morris water-maze performance: interstrain variability
Physiol Behav
Interactions between ifenprodil and dizocilpine on mouse behaviour in models of anxiety and working memory
Eur Neuropsychopharmacol
Medial prefrontal lesion deficits involving or sparing the prelimbic area in the rat
Physiol Behav
The role of the rat prelimbic/infralimbic cortex in working memory: not involved in the short-term maintenance but in monitoring and processing functions
Neuroscience
Prenatal stress induces long term stress vulnerability, compromising stress response systems in the brain and impairing extinction of conditioned fear after adult stress
Neuroscience
Evaluation of the NR2B-selective NMDA receptor antagonist Ro 63-1908 on rodent behaviour: evidence for an involvement of NR2B NMDA receptors in response inhibition
Neuropharmacology
Stress-induced prefrontal reorganization and executive dysfunction in rodents
Neurosci Biobehav Rev
Extinction memory is impaired in schizophrenia
Biol Psychiatry
Subchronic phencyclidine administration reduces mesoprefrontal dopamine utilization and impairs prefrontal cortical-dependent cognition in the rat
Neuropsychopharmacology
Chronic stress: implications for neuronal morphology, function and neurogenesis
Front Neuroendocrinol
Learning under stress: how does it work?
Trends Cogn Sci
Early stress exposure impairs synaptic potentiation in the rat medial prefrontal cortex underlying contextual fear extinction
Neuroscience
Genetic, pharmacological and lesion analyses reveal a selective role for corticohippocampal GLUN2B in a novel repeated swim stress paradigm
Neuroscience
Dissociation of ketamine effects on rule acquisition and rule implementation: possible relevance to NMDA receptor contributions to executive cognitive functions
Biol Psychiatry
Stress induces the expression of heterotrimeric G protein beta subunits and the phosphorylation of PKB/Akt and ERK1/2 in rat brain
Neurosci Res
Glutamate N-methyl-d-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure
Biol Psychiatry
Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors
Biol Psychiatry
Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: involvement of glucocorticoid secretion and excitatory amino acid receptors
Neuroscience
Role of the medial prefrontal cortex in coping and resilience
Brain Res
d-serine enhances extinction of auditory cued fear conditioning via ERK1/2 phosphorylation in mice
Prog Neuropsychopharmacol Biol Psychiatry
Early postnatal stress alters the extinction of context-dependent conditioned fear in adult rats
Pharmacol Biochem Behav
Cited by (21)
Prefrontal cortex VAMP1 gene network moderates the effect of the early environment on cognitive flexibility in children
2021, Neurobiology of Learning and MemoryResilient and depressive-like rats show distinct cognitive impairments in the touchscreen paired-associates learning (PAL) task
2018, Neurobiology of Learning and MemoryWorking memory performance impaired after exposure to acute social stress: The evidence comes from ERPs
2017, Neuroscience LettersCitation Excerpt :The available data regarding the effect of acute stress on working memory is equivocal. Studies are stemmed from rodents, although there is a lack of effect or facilitating effect that is reported by several studies, and most of the studies have reported deleterious effects of stress on working memory [7]. Similarly, human studies, regarding the influence of acute stress on working memory, have also shown mixed results.
Effect of chronic stress during adolescence in prefrontal cortex structure and function
2017, Behavioural Brain ResearchCitation Excerpt :Other studies had already demonstrated the effects of chronic stress on the morphology of pyramidal neurons, such as structural modifications on dendritic arborization and decrease in the number of dendritic spines [18,20], probably due to an increase in the number of excitatory amino acids (glutamate) induced by greater amounts of glucocorticoids in the bloodstream [50,56,63]. Chronic stress also increased the expression of genes that regulate neuronal metabolism and synaptic changes in glutamate receptors [10,73]. In addition to excitatory neurons, inhibitory neurons are also vulnerable to the effects of chronic stress.
The co-expression of GluN2B subunits of the NMDA receptors and glucocorticoid receptors after chronic restraint stress in low and high anxiety rats
2017, Behavioural Brain ResearchCitation Excerpt :CRF (Corticotropin releasing factor) is an important coordinator of the HPA axis and an essential component in the mediation of the behavioural responses to stress [64]. Stress-induced activation of CRF receptors increases the glutamate transmission in the amygdala and the hippocampus [46,48,65]. An interaction between CRF signalling and NMDA receptors, especially at the specific sites of phosphorylation of the GluN2B subunits, was reported in the regulation anxiety in a model of transgenic mice [66].