Stress-induced impairments in prefrontal-mediated behaviors and the role of the N-methyl-d-aspartate receptor

doi:10.1016/j.neuroscience.2012.02.042

Neuroscience

Volume 211, 1 June 2012, Pages 28-38

https://doi.org/10.1016/j.neuroscience.2012.02.042 Get rights and content

Abstract

The prefrontal cortex (PFC) mediates higher-order cognitive and executive functions that subserve various complex, adaptable behaviors, such as cognitive flexibility, attention, and working memory. Deficits in these functions typify multiple neuropsychiatric disorders that are caused or exacerbated by exposure to psychological stress. Here we review recent evidence examining the effects of stress on executive and cognitive functions in rodents and discuss an emerging body of evidence that implicates the N-methyl-d-aspartate receptor (NMDAR) as a potentially critical molecular mechanism mediating these effects. Future work in this area could open up new avenues for developing pharmacotherapies for ameliorating cognitive dysfunction in neuropsychiatric disease.

This article is part of a Special Issue entitled: Neuroscience Disease Models.

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

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ReviewStress-induced impairments in prefrontal-mediated behaviors and the role of the N-methyl-d-aspartate receptor

Abstract

Highlights

Section snippets

Stress effects on PFC-mediated behaviors

NMDARs in PFC-mediated behaviors

Do NMDARs mediate stress-induced changes in PFC?

Conclusions and future directions

Behav Brain Res

Neuroscience

Pharmacol Biochem Behav

Biol Psychiatry

Neurosci Biobehav Rev

Pharmacol Biochem Behav

Neurobiol Learn Mem

Neuroscience

Brain Res Bull

Physiol Behav

Eur J Pharmacol

Neurosci Biobehav Rev

Biol Psychiatry

Neurobiol Learn Mem

Prog Neuro-Psychopharmacol Biol Psychiatry

Behav Brain Res

Biol Psychiatry

Exp Neurol

Psychoneuroendocrinology

Neuron

Neuroscience

Behav Brain Res

Biol Psychol

Curr Opin Neurobiol

Behav Brain Res

Behav Brain Res

Neurobiol Learn Mem

Behav Brain Res

Physiol Behav

Eur Neuropsychopharmacol

Physiol Behav

Neuroscience

Neuroscience

Neuropharmacology

Neurosci Biobehav Rev

Biol Psychiatry

Neuropsychopharmacology

Front Neuroendocrinol

Trends Cogn Sci

Neuroscience

Neuroscience

Biol Psychiatry

Neurosci Res

Biol Psychiatry

Biol Psychiatry

Neuroscience

Brain Res

Prog Neuropsychopharmacol Biol Psychiatry

Pharmacol Biochem Behav

Review
Stress-induced impairments in prefrontal-mediated behaviors and the role of the N-methyl-d-aspartate receptor